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Sample records for leukaemia virus-related virus

  1. [Prevention of virus-related neurological diseases by vaccines].

    PubMed

    Takahashi, M

    1997-04-01

    Prevention of virus-related neurological diseases are surveyed. Patients of poliomyelitis has recently been drastically reduced by world-wide administrating live vaccines. In view of rare incidence of paralysis after giving live vaccine, adoption of inactivated vaccine has recently been reconsidered. A live varicella vaccine was developed and has been world-wide used for normal and high-risk children. Incidence of zoster in vaccinated acute leukemic children is several times higher in those who with rash after vaccination as compared with those without rash, and as no or few rash appears after vaccination of normal children, it is expected that vaccination of normal children would lead to reduction of zoster after their aging. Measles encephalitis has rapidly been reduced by world-wide use of live vaccines. Mouse-brain derived vaccine against Japanese encephalitis(JE) has been used in Asian countries. Development of tissue-culture derived JE vaccine is under way. PMID:9103901

  2. Xenotropic Murine Leukemia Virus-related Virus (XMRV) Backgrounder

    Cancer.gov

    Researchers have not found evidence that XMRV causes any diseases in humans or in animals. The presence of an infectious agent, such as a virus, in diseased tissue does not mean that the agent causes the disease.

  3. Malnutrition in alcoholic and virus-related cirrhosis.

    PubMed

    Caregaro, L; Alberino, F; Amodio, P; Merkel, C; Bolognesi, M; Angeli, P; Gatta, A

    1996-04-01

    The study aimed to define the prevalence, characteristics, and clinical importance of nutritional disorders in patients with liver cirrhosis. Nutritional status was evaluated in 120 hospitalized patients--77 with alcoholic and 43 with virus-related cirrhosis--by anthropometric, visceral, and immunologic measurements. Energy malnutrition, defined as triceps skinfold thickness (TSF) and/or midarm muscle circumference (MAMC) below the 5th percentile of standard values, was found in 34% of the study population. Patients below the 5th percentile for MAMC and/or TSF showed significantly lower survival rates at e, 6, 12, and 24 mo compared with patients above the 5th percentile. Protein malnutrition (low albumin, transthyretin, transferrin, and retinol-binding-protein concentrations) and immunoincompetence (abnormal response to skin tests) were much more frequent (81% and 59%) than energy malnutrition (34%). Serum proteins correlated with the degree of liver function impairment, but not with immunologic tests. The prevalence, characteristics, and severity of protein-energy malnutrition were comparable in alcoholic and viral cirrhosis. Malnutrition was correlated with the clinical severity of the liver disease. The study shows that protein-energy malnutrition is a common complication of liver cirrhosis. Nutritional disorders appear to be related to the degree of liver injury rather than to its etiology. Compared with other methods, which have important limitations in liver disease, anthropometry is currently the most reliable method for nutritional assessment in clinical practice and may be valuable for predicting survival in cirrhotic patients. PMID:8599326

  4. Immunization against primary, transplanted and spontaneous murine leukaemia using a live Moloney sarcoma virus vaccine.

    PubMed Central

    Mayer, A. M.; Basombrio, M. A.; Pasqualini, C. D.

    1980-01-01

    The purpose of this study was to use an immunization protocol with Moloney sarcoma virus (MSV-M) as active immunogen against exogenous and endogenous leukaemia. The s.c. route was chosen since it offered advantages over the i.m. route: the primary sarcomas were smaller, the regression faster, there were fewer recurrences and there was good persistent immunity. Strong protection was obtained against primary leukaemias induced by Friend leukaemia virus (FLV), Moloney leukaemia virus (MLV), Rauscher leukaemia virus (RLV), Precerutti-Law leukaemia virus (PLLV/T2), and H179A leukaemia virus. It was not possible to protect against leukaemia induced by Gross leukaemia virus (GLV). With transplantable leukaemias the results varied: partial protection was observed against H110 leukaemia (induced with human material) and R14 leukaemia (induced by X-irradiation) whilst no protection was obtained against P277 leukaemia (induced by Moloney leukaemia virus). As for spontaneous leukaemias, immunized BALB/c mice showed an increased incidence over the controls, while in F1 (Swiss x AKR) mice the incidence was similar but the latent period was shorter. Furthermore, in long-term observations the MSV-M-immunized mice showed an increased mortaltiy, which could be related to (1) new phenotypic mixtures between MSV-M and leukaemia viruses; (2) reactivation of MSV-M sarcoma-genesis with age, and (3) genotype susceptibility to MSV-M. PMID:6252923

  5. Links between human LINE-1 retrotransposons and hepatitis virus-related hepatocellular carcinoma

    NASA Astrophysics Data System (ADS)

    Honda, Tomoyuki

    2016-05-01

    Hepatocellular carcinoma (HCC) accounts for approximately 80% of liver cancers, the third most frequent cause of cancer mortality. The most prevalent risk factors for HCC are infections by hepatitis B or hepatitis C virus. Findings suggest that hepatitis virus-related HCC might be a cancer in which LINE-1 retrotransposons, often termed L1, activity plays a potential role. Firstly, hepatitis viruses can suppress host defense factors that also control L1 mobilization. Secondly, many recent studies also have indicated that hypomethylation of L1 affects the prognosis of HCC patients. Thirdly, endogenous L1 retrotransposition was demonstrated to activate oncogenic pathways in HCC. Fourthly, several L1 chimeric transcripts with host or viral genes are found in hepatitis virus-related HCC. Such lines of evidence suggest a linkage between L1 retrotransposons and hepatitis virus-related HCC. Here, I briefly summarize current understandings of the association between hepatitis virus-related HCC and L1. Then, I discuss potential mechanisms of how hepatitis viruses drive the development of HCC via L1 retrotransposons. An increased understanding of the contribution of L1 to hepatitis virus-related HCC may provide unique insights related to the development of novel therapeutics for this disease.

  6. Links between Human LINE-1 Retrotransposons and Hepatitis Virus-Related Hepatocellular Carcinoma

    PubMed Central

    Honda, Tomoyuki

    2016-01-01

    Hepatocellular carcinoma (HCC) accounts for approximately 80% of liver cancers, the third most frequent cause of cancer mortality. The most prevalent risk factors for HCC are infections by hepatitis B or hepatitis C virus. Findings suggest that hepatitis virus-related HCC might be a cancer in which LINE-1 retrotransposon, often termed L1, activity plays a potential role. Firstly, hepatitis viruses can suppress host defense factors that also control L1 mobilization. Secondly, many recent studies also have indicated that hypomethylation of L1 affects the prognosis of HCC patients. Thirdly, endogenous L1 retrotransposition was demonstrated to activate oncogenic pathways in HCC. Fourthly, several L1 chimeric transcripts with host or viral genes are found in hepatitis virus-related HCC. Such lines of evidence suggest a linkage between L1 retrotransposons and hepatitis virus-related HCC. Here, I briefly summarize current understandings of the association between hepatitis virus-related HCC and L1. Then, I discuss potential mechanisms of how hepatitis viruses drive the development of HCC via L1 retrotransposons. An increased understanding of the contribution of L1 to hepatitis virus-related HCC may provide unique insights related to the development of novel therapeutics for this disease. PMID:27242996

  7. Xenotropic Murine Leukemia Virus-Related Virus in Chronic Fatigue Syndrome and Prostate Cancer

    PubMed Central

    2010-01-01

    Xenotropic murine leukemia virus-related virus (XMRV) is a γ retrovirus that has been associated with chronic fatigue syndrome (CFS) and prostate cancer. The search for viral causes of these syndromes was reignited by the finding that RNase L activity was low in hereditary prostate cancer and some CFS patients. The six strains of XMRV that have been sequenced have greater than 99% identity, indicating a new human infection rather than laboratory contamination. DNA, RNA, and proteins from XMRV have been detected in 50% to 67% of CFS patients and in about 3.7% of healthy controls. XMRV infections could be transmitted to permissive cell lines from CFS plasma, suggesting the potential for communicable and blood-borne spread of the virus and potentially CFS. This troubling concept is currently under intense evaluation. The most important steps now are to independently confirm the initial findings; develop reliable assays of biomarkers; and to move on to investigations of XMRV pathophysiology and treatment in CFS, prostate cancer, and potentially other virus-related syndromes, if they exist. PMID:20425007

  8. Feline leukaemia virus and its clinical effects in cats.

    PubMed

    Mackey, L

    1975-01-01

    Feline leukemia virus (FeLV) infection is common among cats where contact is high. The virus can be transmitted readily between cats. It causes a variety of haemopoietic and lymphoid neoplasms; the most common types are alimentary, multicentric and thymic lymphosarcoma and lymphatic leukaemia. The virus is involved in the aetiology of certain other diseases including anaemia, glomerulonephritis and an immunosuppressive syndrome which predisposes cats to intercurrent infections. Many infected cats mount an immune response and do not suffer from any of these. The immune status is shown by serum antibody levels to feline leukaemia virus associated cell membrane antigens. Cats with a titre of 32 or more are most unlikely to suffer any ill effects and may eliminate the virus infection. The outcome of infection in an individual cat depends on the immunological competence of the cat, the dose of virus received and its ability to induce immunosuppression. FeLV infection can be detected by examination of tissues by electron microscopy, and by culture of virus from plasma and other tissues. In the United States, a method is now in use for the detection of leukaemia virus antigen in peripheral blood leukocytes; this is carried out on ordinary blood films. Successful prototype vaccines have been developed against FeLV. This paper describes the natural history of the virus, the diseases in which it is implicated and discusses recently developed diagnostic methods. PMID:163515

  9. Xenotropic Murine Leukemia Virus-Related Virus (XMRV) and the Safety of the Blood Supply.

    PubMed

    Johnson, Andrew D; Cohn, Claudia S

    2016-10-01

    In 2006, a new virus, xenotropic murine leukemia virus-related virus (XMRV), was discovered in a cohort of U.S. men with prostate cancer. Soon after this initial finding, XMRV was also detected in samples from patients with chronic fatigue syndrome (CFS). The blood community, which is highly sensitive to the threat of emerging infectious diseases since the HIV/AIDS crisis, recommended indefinite deferral of all blood donors with a history of CFS. As XMRV research progressed, conflicting results emerged regarding the importance of this virus in the pathophysiology of prostate cancer and/or CFS. Molecular biologists traced the development of XMRV to a recombination event in a laboratory mouse that likely occurred circa 1993. The virus was propagated via cell lines derived from a tumor present in this mouse and spread through contamination of laboratory samples. Well-controlled experiments showed that detection of XMRV was due to contaminated samples and was not a marker of or a causal factor in prostate cancer or CFS. This paper traces the development of XMRV in the prostate and CFS scientific communities and explores the effect it had on the blood community. PMID:27358491

  10. Pathobiology and Treatment of Hepatitis Virus-Related Thrombocytopenia

    PubMed Central

    Stasi, Roberto; Chia, Lian Wea; Kalkur, Pallavi; Lowe, Robert; Shannon, Muriel S.

    2009-01-01

    Thrombocytopenia is a well recognized complication of infections, including those from hepatotropic viruses. Thrombocytopenia may actually be the only manifestation of vital hepatitis, which should therefore be considered in the differential diagnosis of primary immune thrombocytopenia (ITP). The mechanisms of thrombocytopenia associated with viral hepatitis vary widely depending on the specific infectious agent and the severity of liver disease. Most of the studies have described thrombocytopenia in association with chronic hepatitis C virus (HCV) infection, the most common cause of chronic infection worldwide. Studies have shown that treatment of HCV infection often results in substantial improvement or complete recovery of the thrombocytopenia. In patients with thrombocytopenia associated with HCV-related chronic liver disease, the use of eltrombopag, a thrombopoietin receptor agonist, normalizes platelet levels thereby permitting the initiation of antiviral therapy. PMID:21415958

  11. Induction of murine AIDS virus-related sequences after burn injury.

    PubMed

    Cho, Kiho; Adamson, Lee K; Greenhalgh, David G

    2002-05-01

    To better understand the molecular signaling events leading to systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF), changes in gene expression profiles after burn injury were investigated by differential display. C57BLKS/J mice were subjected to 18% total body surface area (TBSA) full-thickness burn and various tissues were harvested at multiple time points after injury. Initial differential display revealed that retroviral transcripts similar to the envelope sequence of murine AIDS (MAIDS) virus were rapidly and transiently up-regulated after injury. Subsequent RT-PCR and DNA sequencing analyses confirmed the transient up-regulation of retroviral sequences similar to those of the MAIDS virus. In addition, the presence and induction of the subgenomic envelope transcripts of these MAIDS virus-related sequences, including a novel double spliced message, were identified after burn injury. These data suggest that the transcriptional efficiency of the integrated retroviral DNA and reactivation of defective MAIDS virus-related sequences may be affected by pathophysiological signals, such as burn injury. The elevated expression of these MAIDS virus-related retroviral sequences may affect the transcriptional activities of the flanking genes at the integration sites and may be a cause of altered local and systemic immune responses to burn-related stress. PMID:11971678

  12. Markers predicting progression of human immunodeficiency virus-related disease.

    PubMed Central

    Tsoukas, C M; Bernard, N F

    1994-01-01

    Human immunodeficiency virus (HIV) interacts with the immune system throughout the course of infection. For most of the disease process, HIV activates the immune system, and the degree of activation can be assessed by measuring serum levels of molecules such as beta 2-microglobulin and neopterin, as well as other serum and cell surface phenotype markers. The levels of some of these markers correlate with clinical progression of HIV disease, and these markers may be useful as surrogate markers for development of clinical AIDS. Because the likelihood and timing of development of clinical AIDS following seroconversion, for any particular individual, are not readily predictable, the use of nonclinical disease markers has become critically important to patient management. Surrogate markers of HIV infection are, by definition, measurable traits that correlate with disease progression. An ideal marker should identify patients at highest risk of disease progression, provide information on how long an individual has been infected, help in staging HIV disease, predict development of opportunistic infections associated with AIDS, monitor the therapeutic efficacy of immunomodulating or antiviral treatments, and the easily quantifiable, reliable, clinically available, and affordable. This review examines the current state of knowledge and the role of surrogate markers in the natural history and treatment of HIV infection. The clinical usefulness of each marker is assessed with respect to the criteria outlined for the ideal surrogate marker for HIV disease progression. PMID:8118788

  13. Hepatitis C virus-related kidney disease: an overview.

    PubMed

    Kamar, N; Izopet, J; Alric, L; Guilbeaud-Frugier, C; Rostaing, L

    2008-03-01

    Hepatitis C virus (HCV)-infection leads to chronic liver disease, but also to extra-hepatic manifestations, including kidney disease. We provide an overview of HCV-related kidney diseases in non-transplanted and in kidney transplant patients, and their therapies. Membranoproliferative glomerulonephritis, associated with Type 2 cryoglobulinemia, is the predominant Type of HCV-related glomerulonephritis. Membranous glomerulonephritis and focal segmental glomerular sclerosis are less commonly described. HCV infection seems to be linked to Type 2 diabetes mellitus, and might alter the progression of diabetic-related nephropathy. Patients infected by HCV should be annually screened for markers of kidney disease and, similarly, patients with membranoproliferative or membranous glomerulonephritis should be screened for HCV infection. After transplantation, cryoglobulinemia is frequent and is associated with HCV markers. HCV-related kidney disease requires specific treatment. In non-kidney-transplant patients, treatment relies on either only anti-HCV therapy in cases of moderate renal disease, or combined anti-viral and immunosuppressive therapies in cases of severe renal disease, i.e., nephrotic syndrome and/or progressive renal failure, and in diseases that are refractory to anti-HCV therapy. In kidney transplant patients, ribavirin monotherapy could be used cautiously, whereas rituximab might be a treatment of choice in the presence of cryoglobulinemia. In liver-transplant patients, in addition to anti-HCV therapy, rituximab might be also used. PMID:18397713

  14. Structural and biochemical characterization of the inhibitor complexes of xenotropic murine leukemia virus-related virus protease

    SciTech Connect

    Li, Mi; Gustchina, Alla; Matúz, Krisztina; Tözsér, Jozsef; Namwong, Sirilak; Goldfarb, Nathan E.; Dunn, Ben M.; Wlodawer, Alexander

    2012-10-23

    Interactions between the protease (PR) encoded by the xenotropic murine leukemia virus-related virus and a number of potential inhibitors have been investigated by biochemical and structural techniques. It was observed that several inhibitors used clinically against HIV PR exhibit nanomolar or even subnanomolar values of K{sub i}, depending on the exact experimental conditions. Both TL-3, a universal inhibitor of retroviral PRs, and some inhibitors originally shown to inhibit plasmepsins were also quite potent, whereas inhibition by pepstatin A was considerably weaker. Crystal structures of the complexes of xenotropic murine leukemia virus-related virus PR with TL-3, amprenavir and pepstatin A were solved at high resolution and compared with the structures of complexes of these inhibitors with other retropepsins. Whereas TL-3 and amprenavir bound in a predictable manner, spanning the substrate-binding site of the enzyme, two molecules of pepstatin A bound simultaneously in an unprecedented manner, leaving the catalytic water molecule in place.

  15. NMR study of xenotropic murine leukemia virus-related virus protease in a complex with amprenavir

    SciTech Connect

    Furukawa, Ayako; Okamura, Hideyasu; Morishita, Ryo; Matsunaga, Satoko; Kobayashi, Naohiro; Ikegami, Takahisa; Kodaki, Tsutomu; Takaori-Kondo, Akifumi; Ryo, Akihide; Nagata, Takashi; Katahira, Masato

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Protease (PR) of XMR virus (XMRV) was successfully synthesized with cell-free system. Black-Right-Pointing-Pointer Interface of XMRV PR with an inhibitor, amprenavir (APV), was identified with NMR. Black-Right-Pointing-Pointer Structural heterogeneity is induced for two PR protomers in the APV:PR = 1:2 complex. Black-Right-Pointing-Pointer Structural heterogeneity is transmitted even to distant regions from the interface. Black-Right-Pointing-Pointer Long-range transmission of structural change may be utilized for drug discovery. -- Abstract: Xenotropic murine leukemia virus-related virus (XMRV) is a virus created through recombination of two murine leukemia proviruses under artificial conditions during the passage of human prostate cancer cells in athymic nude mice. The homodimeric protease (PR) of XMRV plays a critical role in the production of functional viral proteins and is a prerequisite for viral replication. We synthesized XMRV PR using the wheat germ cell-free expression system and carried out structural analysis of XMRV PR in a complex with an inhibitor, amprenavir (APV), by means of NMR. Five different combinatorially {sup 15}N-labeled samples were prepared and backbone resonance assignments were made by applying Otting's method, with which the amino acid types of the [{sup 1}H, {sup 15}N] HSQC resonances were automatically identified using the five samples (Wu et al., 2006) . A titration experiment involving APV revealed that one APV molecule binds to one XMRV PR dimer. For many residues, two distinct resonances were observed, which is thought to be due to the structural heterogeneity between the two protomers in the APV:XMRV PR = 1:2 complex. PR residues at the interface with APV have been identified on the basis of chemical shift perturbation and identification of the intermolecular NOEs by means of filtered NOE experiments. Interestingly, chemical shift heterogeneity between the two protomers of XMRV PR has

  16. The cellular basis of immunosuppression caused by the radiation leukaemia virus

    PubMed Central

    Peled, A.; Haran-Ghera, N.

    1974-01-01

    Infection of adult C57B1/6 mice with the radiation leukaemia virus resulted in suppression of the ability of the animals to respond to an immunizing inoculum of sheep erythrocytes. Results of the transfer experiments indicated that the immunosuppressive effect was expressed at the immunocompetent cell level, and that the virus affected the thymus-derived population of immunocytes. The immunosuppressive effect of the virus on thymus cells, independent of any contribution by cells of bone marrow origin, was verified with thymus-independent immunogens, polyvinylpyrrolidone (PVP) or pneumococcal polysaccharide SIII (PPS). Mice inoculated with the radiation leukaemia virus produced nearly normal amounts of plaque-forming cells producing antibodies against PVP and PPS, thereby confirming that the immunosuppressive effect of the radiation leukaemia virus was on thymus-derived cells. PMID:4369273

  17. Genetic Characterization of Goutanap Virus, a Novel Virus Related to Negeviruses, Cileviruses and Higreviruses

    PubMed Central

    Kallies, René; Kopp, Anne; Zirkel, Florian; Estrada, Alejandro; Gillespie, Thomas R.; Drosten, Christian; Junglen, Sandra

    2014-01-01

    Pools of mosquitoes collected in Côte d’Ivoire and Mexico were tested for cytopathic effects on the mosquito cell line C6/36. Seven pools induced strong cytopathic effects after one to five days post infection and were further investigated by deep sequencing. The genomes of six virus isolates from Côte d’Ivoire showed pairwise nucleotide identities of ~99% among each other and of 56%–60% to Dezidougou virus and Wallerfield virus, two insect-specific viruses belonging to the proposed new taxon Negevirus. The novel virus was tentatively named Goutanap virus. The isolate derived from the Mexican mosquitoes showed 95% pairwise identity to Piura virus and was suggested to be a strain of Piura virus, named C6.7-MX-2008. Phylogenetic inferences based on a concatenated alignment of the methyltransferase, helicase, and RNA-dependent RNA polymerase domains showed that the new taxon Negevirus formed two monophyletic clades, named Nelorpivirus and Sandewavirus after the viruses grouping in these clades. Branch lengths separating these clades were equivalent to those of the related genera Cilevirus, Higrevirus and Blunervirus, as well as to those within the family Virgaviridae. Genetic distances and phylogenetic analyses suggest that Nelorpivirus and Sandewavirus might form taxonomic groups on genus level that may define alone or together with Cilevirus, Higrevirus and Blunervirus a viral family. PMID:25398046

  18. Genetic characterization of goutanap virus, a novel virus related to negeviruses, cileviruses and higreviruses.

    PubMed

    Kallies, René; Kopp, Anne; Zirkel, Florian; Estrada, Alejandro; Gillespie, Thomas R; Drosten, Christian; Junglen, Sandra

    2014-11-01

    Pools of mosquitoes collected in Côte d'Ivoire and Mexico were tested for cytopathic effects on the mosquito cell line C6/36. Seven pools induced strong cytopathic effects after one to five days post infection and were further investigated by deep sequencing. The genomes of six virus isolates from Côte d'Ivoire showed pairwise nucleotide identities of ~99% among each other and of 56%-60% to Dezidougou virus and Wallerfield virus, two insect-specific viruses belonging to the proposed new taxon Negevirus. The novel virus was tentatively named Goutanap virus. The isolate derived from the Mexican mosquitoes showed 95% pairwise identity to Piura virus and was suggested to be a strain of Piura virus, named C6.7-MX-2008. Phylogenetic inferences based on a concatenated alignment of the methyltransferase, helicase, and RNA-dependent RNA polymerase domains showed that the new taxon Negevirus formed two monophyletic clades, named Nelorpivirus and Sandewavirus after the viruses grouping in these clades. Branch lengths separating these clades were equivalent to those of the related genera Cilevirus, Higrevirus and Blunervirus, as well as to those within the family Virgaviridae. Genetic distances and phylogenetic analyses suggest that Nelorpivirus and Sandewavirus might form taxonomic groups on genus level that may define alone or together with Cilevirus, Higrevirus and Blunervirus a viral family. PMID:25398046

  19. Cooperation between bovine leukaemia virus transactivator protein and Ha-ras oncogene product in cellular transformation.

    PubMed Central

    Willems, L; Heremans, H; Chen, G; Portetelle, D; Billiau, A; Burny, A; Kettmann, R

    1990-01-01

    Human T-lymphotropic viruses (HTLV-I and -II) and bovine leukaemia virus (BLV) express transactivator proteins able to increase long terminal repeat (LTR) directed viral expression. These transacting factors are though to be involved in the induction of leukaemia by these viruses. Transfection of BLV transactivator p34tax together with Ha-ras immortalizes and transforms rat embryo fibroblasts, in vitro. The transformed cell induce tumours in nude mice. These data emphasize the causal role exerted by p34tax in in vivo tumorigenesis. Images Fig. 1. Fig. 2. Fig. 3. PMID:2158445

  20. Aberrant Resting-State Functional Connectivity Density in Patients with Hepatitis B Virus-Related Cirrhosis

    PubMed Central

    Lv, Xiao-Fei; Wu, Hua-Wang; Tian, Li; Han, Lu-Jun; Li, Jing; Qiu, Ying-Wei; Jiang, Gui-Hua; Zhang, Xue-Lin; Zhang, Rong; Xie, Chuan-Miao

    2016-01-01

    There is increasing evidence that cirrhosis may affect functional connectivity among various brain regions in patients prior to onset of overt hepatic encephalopathy (HE). However, most investigators have focused mainly on alterations in functional connectivity strengths, and the changes in functional connectivity density (FCD) are largely unknown. Here, we investigated alterations in resting-state FCD in patients with hepatitis B virus-related cirrhosis (HBV-RC) without overt HE. Totally, 31 patients with HBV-RC without overt HE and 30 age- and sex-matched healthy controls underwent resting-state functional MRI examinations. FCD mapping was employed to compute local and global FCD maps. Then, short-range and long-range FCD values were calculated and voxel-based comparisons were performed between the two groups. The HBV-RC group showed significant decreases in FCD, including decreased short-range FCDs in the bilateral middle cingulum gyrus/precuneus, the bilateral cuneus, and the left lingual gyrus/inferior occipital gyrus and decreased long-range FCD in the bilateral cuneus/precuneus. In addition, the decreased long-range FCD in the bilateral cuneus/precuneus in the HBV-RC group was related to performance on the psychometric hepatic encephalopathy score (PHES) test. These findings suggest aberrant functional connectivity density in cirrhotic patients prior to overt HE onset, which may provide better insight into understanding the pathophysiological mechanisms underlying the cirrhotic-related cognitive impairment. PMID:27403426

  1. No Evidence of Murine Leukemia Virus-Related Viruses in Live Attenuated Human Vaccines

    PubMed Central

    Switzer, William M.; Zheng, HaoQiang; Simmons, Graham; Zhou, Yanchen; Tang, Shaohua; Shankar, Anupama; Kapusinszky, Beatrix; Delwart, Eric L.; Heneine, Walid

    2011-01-01

    Background The association of xenotropic murine leukemia virus (MLV)-related virus (XMRV) in prostate cancer and chronic fatigue syndrome reported in previous studies remains controversial as these results have been questioned by recent data. Nonetheless, concerns have been raised regarding contamination of human vaccines as a possible source of introduction of XMRV and MLV into human populations. To address this possibility, we tested eight live attenuated human vaccines using generic PCR for XMRV and MLV sequences. Viral metagenomics using deep sequencing was also done to identify the possibility of other adventitious agents. Results All eight live attenuated vaccines, including Japanese encephalitis virus (JEV) (SA-14-14-2), varicella (Varivax), measles, mumps, and rubella (MMR-II), measles (Attenuvax), rubella (Meruvax-II), rotavirus (Rotateq and Rotarix), and yellow fever virus were negative for XMRV and highly related MLV sequences. However, residual hamster DNA, but not RNA, containing novel endogenous gammaretrovirus sequences was detected in the JEV vaccine using PCR. Metagenomics analysis did not detect any adventitious viral sequences of public health concern. Intracisternal A particle sequences closest to those present in Syrian hamsters and not mice were also detected in the JEV SA-14-14-2 vaccine. Combined, these results are consistent with the production of the JEV vaccine in Syrian hamster cells. Conclusions We found no evidence of XMRV and MLV in eight live attenuated human vaccines further supporting the safety of these vaccines. Our findings suggest that vaccines are an unlikely source of XMRV and MLV exposure in humans and are consistent with the mounting evidence on the absence of these viruses in humans. PMID:22216219

  2. Androgen-independent proliferation of LNCaP prostate cancer cells infected by xenotropic murine leukemia virus-related virus

    SciTech Connect

    Kakoki, Katsura; Kamiyama, Haruka; Izumida, Mai; Yashima, Yuka; Hayashi, Hideki; Yamamoto, Naoki; Matsuyama, Toshifumi; Igawa, Tsukasa; Sakai, Hideki; Kubo, Yoshinao

    2014-04-25

    Highlights: • XMRV infection induces androgen-independent growth in LNCaP cells. • XMRV infection reduces expression of androgen receptor. • XMRV promotes appearance of androgen blocker-resistant prostate cancer cells. - Abstract: Xenotropic murine leukemia virus-related virus (XMRV) is a novel gammaretrovirus that was originally isolated from human prostate cancer. It is now believed that XMRV is not the etiologic agent of prostate cancer. An analysis of murine leukemia virus (MLV) infection in various human cell lines revealed that prostate cancer cell lines are preferentially infected by XMRV, and this suggested that XMRV infection may confer some sort of growth advantage to prostate cancer cell lines. To examine this hypothesis, androgen-dependent LNCaP cells were infected with XMRV and tested for changes in certain cell growth properties. We found that XMRV-infected LNCaP cells can proliferate in the absence of the androgen dihydrotestosterone. Moreover, androgen receptor expression is significantly reduced in XMRV-infected LNCaP cells. Such alterations were not observed in uninfected and amphotropic MLV-infected LNCaP cells. This finding explains why prostate cancer cell lines are preferentially infected with XMRV.

  3. Seroepidemiology of Congo virus (related to the virus of Crimean haemorrhagic fever) in Nigeria

    PubMed Central

    David-West, Tam. S.; Cooke, Angella R.; David-West, Aba Segua

    1974-01-01

    A survey for neutralizing antibodies to Congo virus was carried out in Nigeria. Of a total sample population of 250, comprising 141 males and 109 females, 9 males and 15 females had antibody levels ≥ 1.5 log neutralization index. In the age group 0-10 years 4 of 84 males and 14 of 79 females had antibody levels ≥ 1.5 log neutralization index. There was no evidence of nonspecific antiviral activity in the sera tested. PMID:4219295

  4. New host-virus relations between different Solanum species and viruses.

    PubMed

    Takács, A P; Kazinczi, G; Horváth, J; Pribék, D

    2001-01-01

    We have studied the susceptibility or resistance of Solanum capsicastrum Link. et Schauer, S. comatum Sendt., S. dulcamara L., S. luteum Mill., S. malacoxylon Sendt. and S. nigrum L. to three aphid transmissible viruses [alfalfa mosaic alfamovirus (AMV), potato M. carlavirus (PVM) and potato S carlavirus (PVS)]. Out of the species, S. capsicastrum, S. comatum, S. dulcamara, S. malacoxylon and S. nigrum to AMV, S. capsicastrum and S. malacoxylon to PVM and S. capsicastrum, S. luteum and S. nigrum to PVS showed the highest resistance (immunity). Symptoms could not be seen on inoculated plants and the virus could be detected by them neither by serological nor biological tests. Solanum luteum plants were susceptible to AMV. Solanum comatum, S. dulcamara, S. luteum and S. nigrum showed susceptibility to PVM. Solanum comatum and S. dulcamara were susceptible to PVS. Symptoms (necrotic lesions, mosaic and chlorosis) could be seen after inoculation and the absorbance values (DAS-ELISA) exceeded twice that of the healthy control samples during the serological tests. PMID:12425036

  5. Crystal structures of the reverse transcriptase-associated ribonuclease H domain of xenotropic murine leukemia-virus related virus

    SciTech Connect

    Zhou, Dongwen; Chung, Suhman; Miller, Maria; Le Grice, Stuart F.J.; Wlodawer, Alexander

    2012-06-19

    The ribonuclease H (RNase H) domain of retroviral reverse transcriptase (RT) plays a critical role in the life cycle by degrading the RNA strands of DNA/RNA hybrids. In addition, RNase H activity is required to precisely remove the RNA primers from nascent (-) and (+) strand DNA. We report here three crystal structures of the RNase H domain of xenotropic murine leukemia virus-related virus (XMRV) RT, namely (i) the previously identified construct from which helix C was deleted, (ii) the intact domain, and (iii) the intact domain complexed with an active site {alpha}-hydroxytropolone inhibitor. Enzymatic assays showed that the intact RNase H domain retained catalytic activity, whereas the variant lacking helix C was only marginally active, corroborating the importance of this helix for enzymatic activity. Modeling of the enzyme-substrate complex elucidated the essential role of helix C in binding a DNA/RNA hybrid and its likely mode of recognition. The crystal structure of the RNase H domain complexed with {beta}-thujaplicinol clearly showed that coordination by two divalent cations mediates recognition of the inhibitor.

  6. A Multicenter Blinded Analysis Indicates No Association between Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and either Xenotropic Murine Leukemia Virus-Related Virus or Polytropic Murine Leukemia Virus

    PubMed Central

    Alter, Harvey J.; Mikovits, Judy A.; Switzer, William M.; Ruscetti, Francis W.; Lo, Shyh-Ching; Klimas, Nancy; Komaroff, Anthony L.; Montoya, Jose G.; Bateman, Lucinda; Levine, Susan; Peterson, Daniel; Levin, Bruce; Hanson, Maureen R.; Genfi, Afia; Bhat, Meera; Zheng, HaoQiang; Wang, Richard; Li, Bingjie; Hung, Guo-Chiuan; Lee, Li Ling; Sameroff, Stephen; Heneine, Walid; Coffin, John; Hornig, Mady; Lipkin, W. Ian

    2012-01-01

    ABSTRACT The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection. PMID:22991430

  7. Expression of B7-H4 and hepatitis B virus X in hepatitis B virus-related hepatocellular carcinoma

    PubMed Central

    Hong, Bo; Qian, Yun; Zhang, Hong; Sang, Yi-Wen; Cheng, Lin-Fang; Wang, Qi; Gao, Song; Zheng, Min; Yao, Hang-Ping

    2016-01-01

    AIM: To investigate the expression and clinical significance of B7-H4 and hepatitis B virus X (HBx) protein in hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). METHODS: The expression of B7-H4 in the human HCC cell lines HepG2 and HepG2.2.15 were detected by western blot, flow cytometry, and immunofluorescence. The expression of B7-H4 and HBx in 83 HBV-HCC was detected by immunohistochemistry, and the relationship with clinicopathological features was analyzed. Paraffin sections were generated from 83 HBV-HCC patients (22 females and 61 males) enrolled in this study. The age of these patients ranged from 35 to 77 years, with an average of 52.5 ± 11.3 years. All experiments were approved by the Ethics Committees of the Second Affiliated Hospital, Zhejiang University School of Medicine. RESULTS: B7-H4 was significantly upregulated in HepG2.2.15 cells compared to HepG2 cells. Specifically, the protein expression of B7-H4 in the lysates of HepG2 cells was more than that in HepG2.2.15 cells. In addition, HBx was expressed only in HepG2.2.15 cells. Similar data were obtained by flow cytometry. The positive rates of B7-H4 and HBx in the tissues of 83 HBV-HCC patients were 68.67% (57/83) and 59.04% (49/83), respectively. The expression of HBx was correlated with tumor node metastases (TNM) stage, and the expression of B7-H4 was positively correlated with HBx (rs = 0.388; P < 0.01). The expression level of B7-H4 in HBx-positive HBV-HCC tissues was substantially higher than that in HBx-negative HBV-HCC tissues. The expression level of B7H4 was negatively related to tumor TNM stage. CONCLUSION: Higher expression of HBx and B7-H4 was correlated with tumor progression of HBV-HCC, suggesting that B7-H4 may be involved in facilitating HBV-related hepatocarcinogenesis. PMID:27182163

  8. Differential timing of oxidative DNA damage and telomere shortening in hepatitis C and B virus-related liver carcinogenesis.

    PubMed

    Piciocchi, Marika; Cardin, Romilda; Cillo, Umberto; Vitale, Alessandro; Cappon, Andrea; Mescoli, Claudia; Guido, Maria; Rugge, Massimo; Burra, Patrizia; Floreani, Annarosa; Farinati, Fabio

    2016-02-01

    In viral hepatitis, inflammation is correlated with chronic oxidative stress, one of the biological events leading to DNA damage and hepatocellular carcinoma (HCC) development. Aim of this study was to investigate the complex molecular network linking oxidative damage to telomere length and telomerase activity and regulation in hepatitis C and B virus-related liver carcinogenesis. We investigated 142 patients: 21 with HCC (in both tumor and peritumor tissues) and 121 with chronic viral hepatitis in different stages. We evaluated 8-hydroxydeoxyguanosine (8-OHdG), marker of oxidative DNA damage, OGG1 gene polymorphism, telomere length, telomerase activity, TERT promoter methylation, and mitochondrial TERT localization. In hepatitis C-related damage, 8-OHdG levels increased since the early disease stages, whereas hepatitis B-related liver disease was characterized by a later and sharper 8-OHdG accumulation (P = 0.005). In C virus-infected patients, telomeres were shorter (P = 0.03), whereas telomerase activity was higher in tumors than that in the less advanced stages of disease in both groups (P = 0.0001, P = 0.05), with an earlier increase in hepatitis C. Similarly, TERT promoter methylation was higher in tumor and peritumor tissues in both groups (P = 0.02, P = 0.0001). Finally, TERT was localized in mitochondria in tumor and peritumor samples, with 8-OHdG levels significantly lower in mitochondrial than those in genomic DNA (P = 0.0003). These data describe a pathway in which oxidative DNA damage accumulates in correspondence with telomere shortening, telomerase activation, and TERT promoter methylation with a different time course in hepatitis B and C virus-related liver carcinogenesis. Finally, TERT localizes in mitochondria in HCC, where it lacks a canonical function. PMID:26408804

  9. Isolation of a GB virus-related genome from a chimpanzee.

    PubMed

    Birkenmeyer, L G; Desai, S M; Muerhoff, A S; Leary, T P; Simons, J N; Montes, C C; Mushahwar, I K

    1998-09-01

    Recently, two new flaviviruses, GB virus A (GBV-A) and GB virus B (GBV-B), were identified in the plasma of a tamarin infected with the hepatitis GB agent. A third virus, GB virus C (GBV-C), was subsequently identified in humans. In the current study, representational difference analysis (RDA) was used to search for a new virus in the serum of a chimpanzee that developed acute resolving hepatitis following inoculation with a pool of chimpanzee plasma. The plasma pool originated from serial passages of a human sample containing virus-like particles. Numerous cDNA clones were obtained that exhibited 62-80% identity with GBV-C. With the exception of the extreme 5' and 3' ends, the complete viral genome was sequenced, revealing a single large open reading frame encoding a 2833 amino acid polyprotein that contains two envelope proteins, two proteases, a helicase, and an RNA-dependent RNA polymerase. Phylogenetic analysis of the new virus indicates that it is closely related to GBV-C, yet still sufficiently divergent as to be placed in a separate group, tentatively labeled GB virus Ctroglodytes (GBV-Ctro). Numerous human samples were screened by reverse transcriptase-polymerase chain reaction (RT-PCR), but GBV-Ctro sequence was not detected. However, a second chimpanzee inoculated with the same plasma pool was shown to develop a GBV-Ctro infection. Although isolated from an Old World primate with hepatitis, the primary host of GBV-Ctro and any association with disease remains to be determined. PMID:9700632

  10. Hepatitis C virus related lymphoproliferative disorder in a renal transplant recipient.

    PubMed

    Aravindan, A N; Moger, Venkatesh; Sakhuja, Vinay; Kohli, Harbir S; Varma, Neelam; Jha, Vivekanand

    2006-01-01

    Posttransplant lymphoproliferative disorders (PTLD) are commonly caused by Ebstein-Barr Virus infection. The role of hepatitis C virus (HCV) in the genesis of lymphomas has been recognized recently. We report a HCV infected renal transplant recipient who developed PTLD 11 months after transplantation. Reduction of immunosuppression led to disappearance of viremia and clearance of PTLD. This is the first such report in the world literature. PMID:16868710

  11. Association of the interleukin-28B gene polymorphism with development of hepatitis virus-related hepatocellular carcinoma and liver cirrhosis: a meta-analysis.

    PubMed

    Suo, G J; Zhao, Z X

    2013-01-01

    We examined the association of the interleukin-28B (IL-28B) gene rs12979860 T/C polymorphism with development of hepatitis virus-related hepatocellular carcinoma (HCC) and liver cirrhosis (LC). Two investigators independently searched the PubMed, Elsevier, EMBASE, Web of Science, Wiley Online Library, and Chinese National Knowledge Infrastructure data bases. Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) for rs12979860 and HCC/LC were calculated in a fixed-effect model (the Mantel-Haenszel method) and a random-effect model (the DerSimonian and Laird method) when appropriate. This meta-analysis included 7 eligible studies, with 1152 HCC and/or LC cases and 1326 controls. Overall, the rs12979860 T/C polymorphism was significantly associated with risk of hepatitis virus-related HCC and LC development (TT vs CC+CT, pooled OR = 1.597, 95%CI = 1.254-2.036). When they were grouped by type of hepatitis virus, similar results were found for hepatitis C virus-related groups (TT vs CC+CT, pooled OR = 1.732, 95%CI = 1.343-2.235, P value < 0.0001). In the overall analysis, the IL-28B rs12979860 T/C polymorphism was identified as a genetic risk factor for hepatitis virus-related HCC and LC development. A significant increase in the frequency of the T/T genotype was detected from chronic hepatitis to HCC and LC. PMID:24085431

  12. Characterization of a novel murine leukemia virus-related subgroup within mammals.

    PubMed Central

    Tristem, M; Kabat, P; Lieberman, L; Linde, S; Karpas, A; Hill, F

    1996-01-01

    The murine leukemia virus (MuLV)-related retroviruses are one of seven genera which together constitute the family Retroviridae. They are widespread as both endogenous and exogenous agents within vertebrates and have been associated with a variety of malignancies and other disorders. We isolated and characterized 12 endogenous representatives of this genus from a number of mammalian hosts. Subsequent sequence analysis revealed that the isolated viruses cluster into two clearly distinct groups. All of the exogenous MuLV-related retroviruses which have been isolated to date, as well as several endogenous examples, fall into the first group, whereas the second group is represented solely by endogenous representatives, including human endogenous retrovirus type E (HERV.E). The two groups are widespread within mammals, with both often present within one animal species. Despite this, there is no evidence to date that recombination between members of the different groups has occurred. Genetic distances and several other properties of the HERV.E genome suggest that if exogenous members of this subgroup exist, they are likely to have biological properties different from those of the other exogenous viruses of this genus. Several of these viruses are known to have been integrated within their hosts' genomes for a long period of time, and a most recent divergence date for the MuLV and HERV.E subgroups can thus be proposed. This date, approximately 30 million years ago, is the most recent date possible, and it is probable that the actual period of time since their divergence is significantly longer. PMID:8892961

  13. Plant genomes enclose footprints of past infections by giant virus relatives

    PubMed Central

    Maumus, Florian; Epert, Aline; Nogué, Fabien; Blanc, Guillaume

    2014-01-01

    Nucleocytoplasmic large DNA viruses (NCLDVs) are eukaryotic viruses with large genomes (100 kb–2.5 Mb), which include giant Mimivirus, Megavirus and Pandoravirus. NCLDVs are known to infect animals, protists and phytoplankton but were never described as pathogens of land plants. Here, we show that the bryophyte Physcomitrella patens and the lycophyte Selaginella moellendorffii have open reading frames (ORFs) with high phylogenetic affinities to NCLDV homologues. The P. patens genes are clustered in DNA stretches (up to 13 kb) containing up to 16 NCLDV-like ORFs. Molecular evolution analysis suggests that the NCLDV-like regions were acquired by horizontal gene transfer from distinct but closely related viruses that possibly define a new family of NCLDVs. Transcriptomics and DNA methylation data indicate that the NCLDV-like regions are transcriptionally inactive and are highly cytosine methylated through a mechanism not relying on small RNAs. Altogether, our data show that members of NCLDV have infected land plants. PMID:24969138

  14. MicroRNA expression in hepatitis C virus-related malignancies: A brief review

    PubMed Central

    Gragnani, Laura; Piluso, Alessia; Fognani, Elisa; Zignego, Anna Linda

    2015-01-01

    Not only is chronic hepatitis C virus (HCV) infection a major public health problem, but also it can cause hepatocellular carcinoma and, more rarely, non-Hodgkin’s lymphoma. These characteristics mean that HCV is the only virus infecting humans that is able to cause two different cancers. The fine pathogenetic and molecular mechanisms by which HCV induces these two malignancies are not completely clear. In the last decade, it has been shown that microRNAs (miRNAs), a class of 21-23-nucleotide molecules modulating post-transcriptional gene expression, make an important contribution to the pathogenesis of several cancers and are also considered highly promising biomarkers. Here, we briefly describe the current knowledge about microRNAs’ involvement in HCV-related molecular oncogenesis. We decided to focus our attention on studies fully conducted on ex vivo samples with this specific etiology, and on cultured cell lines partially or completely expressing the HCV genome. Some of the results reported in this review are controversial, possibly because of methodological issues, differences in sampling size and features, and ethnicity of patients. What is certain is that miRNAs play a remarkable role in regulating gene expression during oncogenetic processes and in viral infection. A clear understanding of their effects is fundamental to elucidating the mechanisms underlying virus-induced malignancies. PMID:26229398

  15. BoLA antigens are associated with increased frequency of persistent lymphocytosis in bovine leukaemia virus infected cattle and with increased incidence of antibodies to bovine leukaemia virus.

    PubMed

    Stear, M J; Dimmock, C K; Newman, M J; Nicholas, F W

    1988-01-01

    The association between bovine major histocompatibility system (BoLA) type and persistent lymphocytosis in cattle with antibodies to bovine leukaemia virus was examined by comparing antigen frequencies in cattle with persistent lymphocytosis to controls matched for age, sex, breed and presence of antibodies to BLV. The cattle came from nine dairy herds in south-east Queensland, Australia; six herds were Australian Illawarra Shorthorn (AIS), two herds were Jersey and one herd was Friesian. Antigen W6 and Eu28R were more common in cattle with persistent lymphocytosis than in controls. Antigen W8 was less common in AIS cattle with persistent lymphocytosis. A study of 24 offspring from one sire, heterozygous for W10 and Eu28R, showed that offspring inheriting Eu28R from the sire were significantly more likely to have antibodies to BLV than offspring inheriting the opposing W10 haplotype. PMID:2843067

  16. Primary attachment of murine leukaemia virus vector mediated by particle-associated heparan sulfate proteoglycan

    PubMed Central

    Kureishy, Nina; Faruque, Daisy; Porter, Colin D.

    2006-01-01

    Target cell entry of murine leukaemia virus vectors proceeds via primary attachment, independent of the viral envelope protein and subsequent envelope–receptor interaction. Although much attention has been paid to modifying the latter for target cell specificity, the initial binding interaction has been overlooked, despite its opposing involvement both in providing the virus available for receptor binding and in depleting free virus. As a first step towards modifying primary attachment, both to provide specificity and to enhance vector availability, we sought to determine the nature of this interaction. Following an initial screen of GAGs (glycosaminoglycans) for their ability to inhibit virus binding and transduction, we have shown that production of virus from cells in which GAG sulfation is inhibited, or treatment of virus with heparinase III, reduces both particle attachment and infection. Detection in purified virus preparations of a neo-epitope generated by heparinase III confirmed the presence of virus-associated HSPG [HS (heparan sulfate) proteoglycan], acquired from the producer cell. We propose that host-acquired cell-surface HSPG (potentially including syndecan-2) provides a means of virus attachment to target cells that precedes specific receptor interaction and membrane fusion. Inhibition of HS biosynthesis may provide a sufficiently reduced background of primary binding such that novel mechanisms of attachment, ideally with appropriate target cell specificity, can be introduced. PMID:16895523

  17. MG-Digger: An Automated Pipeline to Search for Giant Virus-Related Sequences in Metagenomes.

    PubMed

    Verneau, Jonathan; Levasseur, Anthony; Raoult, Didier; La Scola, Bernard; Colson, Philippe

    2016-01-01

    The number of metagenomic studies conducted each year is growing dramatically. Storage and analysis of such big data is difficult and time-consuming. Interestingly, analysis shows that environmental and human metagenomes include a significant amount of non-annotated sequences, representing a 'dark matter.' We established a bioinformatics pipeline that automatically detects metagenome reads matching query sequences from a given set and applied this tool to the detection of sequences matching large and giant DNA viral members of the proposed order Megavirales or virophages. A total of 1,045 environmental and human metagenomes (≈ 1 Terabase) were collected, processed, and stored on our bioinformatics server. In addition, nucleotide and protein sequences from 93 Megavirales representatives, including 19 giant viruses of amoeba, and 5 virophages, were collected. The pipeline was generated by scripts written in Python language and entitled MG-Digger. Metagenomes previously found to contain megavirus-like sequences were tested as controls. MG-Digger was able to annotate 100s of metagenome sequences as best matching those of giant viruses. These sequences were most often found to be similar to phycodnavirus or mimivirus sequences, but included reads related to recently available pandoraviruses, Pithovirus sibericum, and faustoviruses. Compared to other tools, MG-Digger combined stand-alone use on Linux or Windows operating systems through a user-friendly interface, implementation of ready-to-use customized metagenome databases and query sequence databases, adjustable parameters for BLAST searches, and creation of output files containing selected reads with best match identification. Compared to Metavir 2, a reference tool in viral metagenome analysis, MG-Digger detected 8% more true positive Megavirales-related reads in a control metagenome. The present work shows that massive, automated and recurrent analyses of metagenomes are effective in improving knowledge about the

  18. MG-Digger: An Automated Pipeline to Search for Giant Virus-Related Sequences in Metagenomes

    PubMed Central

    Verneau, Jonathan; Levasseur, Anthony; Raoult, Didier; La Scola, Bernard; Colson, Philippe

    2016-01-01

    The number of metagenomic studies conducted each year is growing dramatically. Storage and analysis of such big data is difficult and time-consuming. Interestingly, analysis shows that environmental and human metagenomes include a significant amount of non-annotated sequences, representing a ‘dark matter.’ We established a bioinformatics pipeline that automatically detects metagenome reads matching query sequences from a given set and applied this tool to the detection of sequences matching large and giant DNA viral members of the proposed order Megavirales or virophages. A total of 1,045 environmental and human metagenomes (≈ 1 Terabase) were collected, processed, and stored on our bioinformatics server. In addition, nucleotide and protein sequences from 93 Megavirales representatives, including 19 giant viruses of amoeba, and 5 virophages, were collected. The pipeline was generated by scripts written in Python language and entitled MG-Digger. Metagenomes previously found to contain megavirus-like sequences were tested as controls. MG-Digger was able to annotate 100s of metagenome sequences as best matching those of giant viruses. These sequences were most often found to be similar to phycodnavirus or mimivirus sequences, but included reads related to recently available pandoraviruses, Pithovirus sibericum, and faustoviruses. Compared to other tools, MG-Digger combined stand-alone use on Linux or Windows operating systems through a user-friendly interface, implementation of ready-to-use customized metagenome databases and query sequence databases, adjustable parameters for BLAST searches, and creation of output files containing selected reads with best match identification. Compared to Metavir 2, a reference tool in viral metagenome analysis, MG-Digger detected 8% more true positive Megavirales-related reads in a control metagenome. The present work shows that massive, automated and recurrent analyses of metagenomes are effective in improving knowledge about

  19. X region mutations of hepatitis B virus related to clinical severity

    PubMed Central

    Kim, Hong; Lee, Seoung-Ae; Kim, Bum-Joon

    2016-01-01

    Chronic hepatitis B virus (HBV) infection remains a major health problem, with more than 240 million people chronically infected worldwide and potentially 650000 deaths per year due to advanced liver diseases including liver cirrhosis and hepatocellular carcinoma (HCC). HBV-X protein (HBx) contributes to the biology and pathogenesis of HBV via stimulating virus replication or altering host gene expression related to HCC. The HBV X region contains only 465 bp encoding the 16.5 kDa HBx protein, which also contains several critical cis-elements such as enhancer II, the core promoter and the microRNA-binding region. Thus, mutations in this region may affect not only the HBx open reading frame but also the overlapped cis-elements. Recently, several types of HBx mutations significantly associated with clinical severity have been described, although the functional mechanism in most of these cases remains unsolved. This review article will mainly focus on the HBx mutations proven to be significantly related to clinical severity via epidemiological studies. PMID:27350725

  20. Expression of mink cell focus-forming murine leukemia virus-related transcripts in AKR mice

    SciTech Connect

    Khan, A.S.; Laigret, F.; Rodi, C.P.

    1987-03-01

    The authors used a synthetic 16-base-pair mink cell focus-forming (MCF) env-specific oligomer as radiolabeled probe to study MCF murine leukemia virus (MuLV)-related transcripts in brain, kidney, liver, spleen, and thymus tissues of AKR mice ranging from 5 weeks to 6 months (mo) of age. Tissue-specific expression of poly(A)/sup +/ RNAs was seen. In addition, all the tissues tested contained 3.0-kb messages. The transcription of these MCF-related mRNAs was independent of the presence of ecotropic and xenotropic MuLVs. In general, expression of the MCF env-related transcripts appeared to peak at 2 mo of age; these messages were barely detectable in brain, kidney, liver, and spleen tissues after 2 mo and in thymus tissue after 4 mo of age. All of the subgenomic MCF env-related mRNAs appeared to contain the 190-base-pair cellular DNA insert, characteristic of the long terminal repeats associated with endogenous MCF env-related proviruses. No genomic-size (8.4-kb) transcripts corresponding to endogenous MCF-related proviruses were detected. An 8.4-kb MCF env-related mRNA was first seen at 3 mo of age, exclusively in thymus tissue. This species most likely represents the first appearance of a recombinant MCF-related MuLV genome. The transcripts which were detected in thymus tissue might be involved in the generation of leukemogenic MCF viruses.

  1. Genomics-enabled sensor platform for rapid detection of viruses related to disease outbreak.

    SciTech Connect

    Brozik, Susan Marie; Manginell, Ronald Paul; Moorman, Matthew Wallace; Xiao, Xiaoyin; Edwards, Thayne L.; Anderson, John Moses; Pfeifer, Kent Bryant; Branch, Darren W.; Wheeler, David Roger; Polsky, Ronen; Lopez, DeAnna M.; Ebel, Gregory D.; Prasad, Abhishek N.; Brozik, James A.; Rudolph, Angela R.; Wong, Lillian P.

    2013-09-01

    Bioweapons and emerging infectious diseases pose growing threats to our national security. Both natural disease outbreak and outbreaks due to a bioterrorist attack are a challenge to detect, taking days after the outbreak to identify since most outbreaks are only recognized through reportable diseases by health departments and reports of unusual diseases by clinicians. In recent decades, arthropod-borne viruses (arboviruses) have emerged as some of the most significant threats to human health. They emerge, often unexpectedly, from cryptic transmission foci causing localized outbreaks that can rapidly spread to multiple continents due to increased human travel and trade. Currently, diagnosis of acute infections requires amplification of viral nucleic acids, which can be costly, highly specific, technically challenging and time consuming. No diagnostic devices suitable for use at the bedside or in an outbreak setting currently exist. The original goals of this project were to 1) develop two highly sensitive and specific diagnostic assays for detecting RNA from a wide range of arboviruses; one based on an electrochemical approach and the other a fluorescent based assay and 2) develop prototype microfluidic diagnostic platforms for preclinical and field testing that utilize the assays developed in goal 1. We generated and characterized suitable primers for West Nile Virus RNA detection. Both optical and electrochemical transduction technologies were developed for DNA-RNA hybridization detection and were implemented in microfluidic diagnostic sensing platforms that were developed in this project.

  2. X region mutations of hepatitis B virus related to clinical severity.

    PubMed

    Kim, Hong; Lee, Seoung-Ae; Kim, Bum-Joon

    2016-06-28

    Chronic hepatitis B virus (HBV) infection remains a major health problem, with more than 240 million people chronically infected worldwide and potentially 650000 deaths per year due to advanced liver diseases including liver cirrhosis and hepatocellular carcinoma (HCC). HBV-X protein (HBx) contributes to the biology and pathogenesis of HBV via stimulating virus replication or altering host gene expression related to HCC. The HBV X region contains only 465 bp encoding the 16.5 kDa HBx protein, which also contains several critical cis-elements such as enhancer II, the core promoter and the microRNA-binding region. Thus, mutations in this region may affect not only the HBx open reading frame but also the overlapped cis-elements. Recently, several types of HBx mutations significantly associated with clinical severity have been described, although the functional mechanism in most of these cases remains unsolved. This review article will mainly focus on the HBx mutations proven to be significantly related to clinical severity via epidemiological studies. PMID:27350725

  3. Holoprosencephaly and Pure Red Cell Aplasia in a Feline Leukaemia Virus-Positive Kitten.

    PubMed

    Southard, T L; Rodriguez-Ramos Fernandez, J; Priest, H; Stokol, T

    2016-01-01

    A 9-month-old, female, domestic longhair cat with severe anaemia tested positive for feline leukaemia virus (FeLV) and was humanely destroyed and submitted for necropsy examination. Gross findings included a non-divided rostral telencephalon, consistent with semilobar holoprosencephaly. Histological examination of the bone marrow revealed an almost complete absence of erythroid precursor cells, consistent with pure red cell aplasia, and mild to moderate myelofibrosis. This case demonstrates a very unusual central nervous system defect, as well as an atypical presentation of pure red cell aplasia, in a FeLV-positive kitten. PMID:26897097

  4. Epstein-Barr Virus-Related Hemophagocytic Lymphohistiocytosis: Hematologic Emergency in the Critical Care Setting

    PubMed Central

    Hashemi-Sadraei, Neda; Vejpongsa, Pimprapa; Baljevic, Muhamed; Chen, Lei; Idowu, Modupe

    2015-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a rare and potential life-threatening clinical syndrome that results from uncontrolled activation of the immune system. Secondary HLH, more commonly observed in adult patients, is seen in the context of underlying triggering conditions. Epstein-Barr virus (EBV) has been recognized as the leading infectious cause and is associated with a poor outcome. As clinical and laboratory features of HLH could overlap with septic shock syndrome in most patients, the diagnosis of HLH, especially in adults, is the most challenging aspect of the disease that results in delayed recognition and treatment of rapidly progressive multiorgan system failure. We report a case of Hemophagocytic lymphohistiocytosis in a patient who presented with signs of septic shock syndrome and we review the literature on the topic. PMID:25755898

  5. Nucleoporin 88 expression in hepatitis B and C virus-related liver diseases

    PubMed Central

    Knoess, Martina; Kurz, Anna Kordelia; Goreva, Olga; Bektas, Nuran; Breuhahn, Kai; Odenthal, Magarethe; Schirmacher, Peter; Dienes, Hans Peter; Bock, C Thomas; Zentgraf, Hanswalter; zur Hausen, Axel

    2006-01-01

    AIM: To investigate the expression of nucleoporin 88 (Nup88) in hepatitis B virus (HBV) and C virus (HCV)-related liver diseases. METHODS: We generated a new monoclonal Nup88 antibody to investigate the Nup88 protein expression by immunohistochemistry (IHC) in 294 paraffin-embedded liver specimens comprising all stages of hepatocellular carcinogenesis. In addition, in cell culture experiments HBV-positive (HepG2.2.15 and HB611) and HBV-negative (HepG2) hepatoma cell lines were tested for the Nup88 expression by Western-immunoblotting to test data obtained by IHC. RESULTS: Specific Nup88 expression was found in chronic HCV hepatitis and unspecific chronic hepatitis, whereas no or very weak Nup88 expression was detected in normal liver. The Nup88 expression was markedly reduced or missing in mild chronic HBV infection and inversely correlated with HBcAg expression. Irrespective of the HBV- or HCV-status, increasing Nup88 expression was observed in cirrhosis and dysplastic nodules, and Nup88 was highly expressed in hepatocellular carcinomas. The intensity of Nup88 expression significantly increased during carcinogenesis (P < 0.0001) and correlated with dedifferentiation (P < 0.0001). Interestingly, Nup88 protein expression was significantly downregulated in HBV-positive HepG2.2.15 (P < 0.002) and HB611 (P < 0.001) cell lines as compared to HBV-negative HepG2 cells. CONCLUSION: Based on our immunohistochemical data, HBV and HCV are unlikely to influence the expression of Nup88 in cirrhotic and neoplastic liver tissue, but point to an interaction of HBV with the nuclear pore in chronic hepatitis. The expression of Nup88 in nonneoplastic liver tissue might reflect enhanced metabolic activity of the liver tissue. Our data strongly indicate a dichotomous role for Nup88 in non-neoplastic and neoplastic conditions of the liver. PMID:17007055

  6. Nutrition status and small intestinal bacterial overgrowth in patients with virus-related cirrhosis.

    PubMed

    Yao, Jia; Chang, Le; Yuan, Lili; Duan, Zhongping

    2016-01-01

    Malnutrition and small intestinal bacterial overgrowth (SIBO) is frequently present in patients with liver cirrhosis (LC). However, the direct relationship between SIBO and nutrition status in the LC patients has not been elucidated. The aim of this study was to investigate whether there was an association between nutrition status, evaluated by the subjective global assessment (SGA) and SIBO in patients with Hepatitis B virus (HBV) or hepatitis C virus (HCV) related cirrhosis. A total of 120 patients with HBV or HCV-related cirrhosis and 30 healthy controls were included. Nutritional status was determined according to SGA and anthropometry. All patients and healthy controls underwent a glucose hydrogen breath test for SIBO. The prevalence of malnutrition for the patients with HBV or HCV related cirrhosis ranged 19.4%-60% in China. The highest prevalence of malnutrition was detected by SGA, the lowest by triceps skinfold thickness. The frequency of SIBO was significantly higher in the malnourished (SGA-B/C) than in the well-nourished (SGA-A) patients with HBV or HCV related cirrhosis [41/72 (56.9%) vs 12/48 (25.0%) (p=0.001)]. Univariate analysis showed that SIBO, ascites, and Child-Turcotte-Pugh (CTP) class were associated with malnutrition. Multivariate analysis demonstrated that SIBO [odds ratio (OR) 8.10; p=0.002] and ascites (OR 4.56; p=0.022) were independently associated with the occurrence of malnutrition (SGA-B/C) in the same subjects. SIBO is independently related to the occurrence of malnutrition (SGA-B/C) in patients with HBV or HCV cirrhosis. We deduce that SIBO may play an important role in nutrition status in patients with HBV or HCV cirrhosis. PMID:27222411

  7. Quality of different in-clinic test systems for feline immunodeficiency virus and feline leukaemia virus infection.

    PubMed

    Hartmann, Katrin; Griessmayr, Pascale; Schulz, Bianka; Greene, Craig E; Vidyashankar, Anand N; Jarrett, Os; Egberink, Herman F

    2007-12-01

    Many new diagnostic in-house tests for identification of feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) infection have been licensed for use in veterinary practice, and the question of the relative merits of these kits has prompted comparative studies. This study was designed to define the strengths and weaknesses of seven FIV and eight FeLV tests that are commercially available. In this study, 536 serum samples from randomly selected cats were tested. Those samples reacting FIV-positive in at least one of the tests were confirmed by Western blot, and those reacting FeLV-positive were confirmed by virus isolation. In addition, a random selection of samples testing negative in all test systems was re-tested by Western blot (100 samples) and by virus isolation (81 samples). Specificity, sensitivity, positive and negative predictive values of each test and the quality of the results were compared. PMID:17604205

  8. Species distribution in human immunodeficiency virus-related mycobacterial infections: implications for selection of initial treatment.

    PubMed

    Montessori, V; Phillips, P; Montaner, J; Haley, L; Craib, K; Bessuille, E; Black, W

    1996-06-01

    Management of mycobacterial infection is species specific; however, treatment is prompted by positive smears or cultures, often several weeks before species identification. The objective of this study was to determine the species distribution of mycobacterial isolates from various body sites in patients infected with human immunodeficiency virus (HIV). All mycobacterial isolates recovered at St. Paul's Hospital (Vancouver, British Columbia, Canada) from April 1989 to March 1993 were reviewed. Among 357 HIV-positive patients with mycobacterial infections, 64% (96) of the sputum isolates were Mycobacterium avium complex (MAC), 18% were Mycobacterium tuberculosis, and 17% were Mycobacterium kansasii. Lymph node involvement (25 patients) was due to either MAC (72%) or M. tuberculosis (24%). Two hundred ninety-eight episodes of mycobacteremia were due to MAC (98%), M. tuberculosis (1%), and M. kansasii (1%). Similarly, cultures of 84 bone marrow biopsy specimens (99%), 19 intestinal biopsy specimens (100%), and 30 stool specimens (97%) yielded predominantly MAC. These results have implications for initial therapy, particularly in areas where rapid methods for species identification are not readily available. Because of considerable geographic variation, development of guidelines for selection of initial therapy depends on regional determination of species distribution in HIV-related mycobacterial infections. PMID:8783698

  9. Vitamin A deficiency in patients with hepatitis C virus-related chronic liver disease.

    PubMed

    Peres, W A F; Chaves, G V; Gonçalves, J C S; Ramalho, A; Coelho, H S M

    2011-12-01

    Hepatitis C virus (HCV) infection is associated with oxidative stress and vitamin A possesses antioxidant activity. The objective of the present study was to investigate vitamin A nutritional status in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC), according to biochemical, functional and dietetic indicators correlating these findings with liver function, liver damage and death. Vitamin A nutritional status was analysed by serum retinol levels, dietetic indicators and functional indicators. A total of 140 patients with HCV-related liver disease were enrolled. Vitamin A deficiency was detected in 54·3 % of all patients, and there was a progressive drop in serum retinol levels from chronic hepatitis C patients towards cirrhosis and HCC patients. Increased total bilirubin, liver transaminases and prothrombin time, presence of hepatic encephalopathy and ascites were related to reduced serum retinol levels, and values ≤ 0·78 μmol/l of serum retinol were associated with liver-related death. A high prevalence of inadequate intake of vitamin A was observed in all stages of chronic liver disease. The functional indicator was not an adequate parameter for evaluating the vitamin A nutritional status. Therefore, serum retinol concentration is related to severity of the disease, liver complications and mortality. The effectiveness of nutritional counselling and measures of intervention in this group in improving vitamin A nutritional status should be examined further in a controlled study. PMID:21736776

  10. Nucleos(t)ide analogs in the prevention of hepatitis B virus related hepatocellular carcinoma

    PubMed Central

    Baran, Bulent

    2015-01-01

    Hepatocellular carcinoma (HCC) is among the most common cancer types and causes of cancer related mortality worldwide. Almost 50% of all HCC cases globally are attributable to chronic hepatitis B virus (HBV) infection. The incidence rates of HCC in untreated Asian subjects with HBV infection was estimated to be 0.2% in inactive carriers, 0.6% for those with chronic hepatitis without cirrhosis, and 3.7% for those with compensated cirrhosis. In Western populations, HCC incidences are reported to be 0.02% in inactive carriers, 0.3% in subjects with chronic hepatitis without cirrhosis, and 2.2% in subjects with compensated cirrhosis. Despite effective antiviral treatment options which are able to transform chronic hepatitis into an inactive carrier state, the risk of HCC cannot be fully ruled out to exclude those patients from surveillance. Newer nucleos(t)ide analogues (NAs) as entecavir and tenofovir are very potent in terms of sustained virological suppression which leads to improved liver histology. However, they do not have any influence on the cccDNA or integrated DNA of HBV in the liver. Nonetheless, viral replication is the only modifiable component among the established risk factors for HBV-related HCC with the current treatment options. In this review, it was aimed to summarize cumulative evidence behind the concept of prevention of HBV related HCC by NAs, and to discuss remaining obstacles to eliminate the risk of HCC. PMID:26167247

  11. Long-term sequelae of West Nile virus-related illness: a systematic review.

    PubMed

    Patel, Hetal; Sander, Beate; Nelder, Mark P

    2015-08-01

    We systematically reviewed the clinical outlook of West Nile virus (WNV)-related illness in North America and western Europe. As of March, 2015, more than 45 000 cases of WNV-related illness have been reported in North America. Unlike acute morbidity and mortality, the long-term physical, cognitive, and functional sequelae associated with WNV-related illness are not well characterised. An understanding of WNV-related sequelae and their prognostic factors can support physicians with early diagnosis and tertiary prevention efforts. We searched Ovid Medline, Embase, Scopus, and Environment Complete for studies published between 1999 and 2015. We included 67 studies in our Review. Although muscle weakness, memory loss, and difficulties with activities of daily living were among the most common physical, cognitive, and functional sequelae, respectively, some population groups were reported to be at greater risk of severe neurological disease or death (ie, older men with underlying illnesses such as cardiovascular disease or cancer). A high level of heterogeneity was reported among studies included in this Review, suggesting a need for consistent methods for collecting data and reporting findings. Further, more than half of the studies reporting sequelae relied exclusively on subjective assessment and only two studies used matched control groups. Therefore, opportunities exist for more robust primary studies in future research. PMID:26163373

  12. Precore/core region mutations of hepatitis B virus related to clinical severity

    PubMed Central

    Kim, Hong; Lee, Seoung-Ae; Do, Seung Yeon; Kim, Bum-Joon

    2016-01-01

    Despite the availability of an effective vaccine, hepatitis B virus (HBV) infection remains a major health problem, with more than 350 million chronically infected people worldwide and over 1 million annual deaths due to cirrhosis and liver cancer. HBV mutations are primarily generated due both to a lack of proofreading capacity by HBV polymerase and to host immune pressure, which is a very important factor for predicting disease progression and therapeutic outcomes. Several types of HBV precore/core (preC/C) mutations have been described to date. The host immune response against T cells drives mutation in the preC/C region. Specifically, preC/C mutations in the MHC class II restricted region are more common than in other regions and are significantly related to hepatocellular carcinoma. Certain mutations, including preC G1896A, are also significantly related to HBeAg-negative chronic infection. This review article mainly focuses on the HBV preC/C mutations that are related to disease severity and on the HBeAg serostatus of chronically infected patients. PMID:27158197

  13. The role of eltrombopag in the management of hepatitis C virus-related thrombocytopenia

    PubMed Central

    Danish, Fazal-i-Akbar; Yasmin, Saeeda

    2013-01-01

    Eltrombopag is a 2nd generation thrombopoietin-receptor agonist. It binds with the thrombopoietin-receptors found on the surfaces of the megakaryocytes & increases platelet production. Many recent studies have suggested a potential role for this novel agent in the treatment of thrombocytopenia associated with hepatitis-C infection. Studies have shown that adjunct treatment with Eltrombopag can help avoid dose reductions/withdrawals of pegylated interferon secondary to thrombocytopenia. It may also have a role in priming up platelet levels to help initiate antiviral therapy. Similarly, chronic liver disease patients with thrombocytopenia who need to undergo an invasive procedure may be potential candidates for short two-week courses of eltrombopag in the periprocedural period to help reduce the risk of bleeding. Besides the price (deemed very expensive and probably not cost-effective), there are some legitimate concerns about the safety profile of this novel agent (most importantly, portal vein thrombosis, bone marrow fibrosis and hepatotoxicity). In this article, the potential role of eltrombopag in the context of hepatitis C virus (HCV)-related thrombocytopenia is reviewed. To write this article, a MEDLINE search was conducted (1990 to November 2012) using the search terms “eltrombopag,” “HCV,” and “thrombocytopenia.” PMID:24696622

  14. Characterization of a novel wood mouse virus related to murid herpesvirus 4.

    PubMed

    Hughes, David J; Kipar, Anja; Milligan, Steven G; Cunningham, Charles; Sanders, Mandy; Quail, Michael A; Rajandream, Marie-Adele; Efstathiou, Stacey; Bowden, Rory J; Chastel, Claude; Bennett, Malcolm; Sample, Jeffery T; Barrell, Bart; Davison, Andrew J; Stewart, James P

    2010-04-01

    Two novel gammaherpesviruses were isolated, one from a field vole (Microtus agrestis) and the other from wood mice (Apodemus sylvaticus). The genome of the latter, designated wood mouse herpesvirus (WMHV), was completely sequenced. WMHV had the same genome structure and predicted gene content as murid herpesvirus 4 (MuHV4; murine gammaherpesvirus 68). Overall nucleotide sequence identity between WMHV and MuHV4 was 85 % and most of the 10 kb region at the left end of the unique region was particularly highly conserved, especially the viral tRNA-like sequences and the coding regions of genes M1 and M4. The partial sequence (71 913 bp) of another gammaherpesvirus, Brest herpesvirus (BRHV), which was isolated ostensibly from a white-toothed shrew (Crocidura russula), was also determined. The BRHV sequence was 99.2 % identical to the corresponding portion of the WMHV genome. Thus, WMHV and BRHV appeared to be strains of a new virus species. Biological characterization of WMHV indicated that it grew with similar kinetics to MuHV4 in cell culture. The pathogenesis of WMHV in wood mice was also extremely similar to that of MuHV4, except for the absence of inducible bronchus-associated lymphoid tissue at day 14 post-infection and a higher load of latently infected cells at 21 days post-infection. PMID:19940063

  15. Characterization of a novel wood mouse virus related to murid herpesvirus 4

    PubMed Central

    Hughes, David J.; Kipar, Anja; Milligan, Steven G.; Cunningham, Charles; Sanders, Mandy; Quail, Michael A.; Rajandream, Marie-Adele; Efstathiou, Stacey; Bowden, Rory J.; Chastel, Claude; Bennett, Malcolm; Sample, Jeffery T.; Barrell, Bart; Davison, Andrew J.; Stewart, James P.

    2010-01-01

    Two novel gammaherpesviruses were isolated, one from a field vole (Microtus agrestis) and the other from wood mice (Apodemus sylvaticus). The genome of the latter, designated wood mouse herpesvirus (WMHV), was completely sequenced. WMHV had the same genome structure and predicted gene content as murid herpesvirus 4 (MuHV4; murine gammaherpesvirus 68). Overall nucleotide sequence identity between WMHV and MuHV4 was 85 % and most of the 10 kb region at the left end of the unique region was particularly highly conserved, especially the viral tRNA-like sequences and the coding regions of genes M1 and M4. The partial sequence (71 913 bp) of another gammaherpesvirus, Brest herpesvirus (BRHV), which was isolated ostensibly from a white-toothed shrew (Crocidura russula), was also determined. The BRHV sequence was 99.2 % identical to the corresponding portion of the WMHV genome. Thus, WMHV and BRHV appeared to be strains of a new virus species. Biological characterization of WMHV indicated that it grew with similar kinetics to MuHV4 in cell culture. The pathogenesis of WMHV in wood mice was also extremely similar to that of MuHV4, except for the absence of inducible bronchus-associated lymphoid tissue at day 14 post-infection and a higher load of latently infected cells at 21 days post-infection. PMID:19940063

  16. Human Immunodeficiency Virus-related Microbial Translocation and Progression of Hepatitis C

    PubMed Central

    Balagopal, Ashwin; Philp, Frances H.; Astemborski, Jacquie; Block, Timothy M.; Mehta, Anand; Long, Ronald; Kirk, Gregory D.; Mehta, Shruti H.; Cox, Andrea L.; Thomas, David L.; Ray, Stuart C.

    2009-01-01

    Background & Aims HIV-1 infection has been associated with enhanced microbial translocation, and microbial translocation is a mechanism through which alcohol and some enteric conditions cause liver disease. We hypothesized that HIV promotes liver disease by enhancing microbial translocation. Methods We studied human cohorts in which hepatitis C virus (HCV) and HIV outcomes were carefully characterized. Results HIV-related CD4+ lymphocyte depletion was strongly associated with microbial translocation as indicated by elevated levels of circulating lipopolysaccharide (LPS), LPS binding protein, soluble CD14, fucose-binding lectin (AAL) reactive to IgG specific for the alpha galactose epitope, and suppressed levels of endotoxin-core antibodies (EndoCAb IgM) in HIV-infected subjects compared with the same persons before they had HIV infection and compared with HIV-uninfected subjects. The same measures of microbial translocation were strongly associated with HCV-related liver disease progression (cirrhosis), e.g. LPS, odds ratio 19.0 (p = 0.002), AAL, odds ratio 27.8 (p<0.0001); in addition, levels of LPS were elevated prior to recognition of cirrhosis. Conclusions Microbial translocation may be a fundamental mechanism through which HIV accelerates progression of chronic liver disease. PMID:18457674

  17. Barriers to human immunodeficiency virus related risk reduction among male street prostitutes.

    PubMed

    Simon, P M; Morse, E V; Balson, P M; Osofsky, H J; Gaumer, H R

    1993-01-01

    Two hundred eleven male street prostitutes between the ages of 18 and 51 years were interviewed and tested for antibodies to the human immunodeficiency virus (HIV). Economic, social, and emotional barriers to the reduction of HIV-related risk behavior were examined within the context of several concepts present in the Health Belief Model (HBM). Three lifestyle factors were found to function as barriers to engaging in risk reduction behavior. Subjects who were more economically dependent on prostitution, perceived less control over the hustling encounter, and reported increased pleasure from sexual activity with their customers were more likely to engage in risk-taking behavior. Prostitutes' perception of the severity of HIV infection was not significantly associated with their risk behavior. Unexpected findings indicated that increases in perceived susceptibility to HIV and perceived benefit of condom use for HIV prevention were significantly related to increased risk-taking behavior. Practical applications of findings in the design and implementation of future HIV-related preventive health education programs are discussed. PMID:8491637

  18. Altered microRNA expression profile in hepatitis B virus-related hepatocellular carcinoma.

    PubMed

    Park, Keon Uk; Seo, Young-Su; Lee, Yun-Han; Park, Jungwook; Hwang, Ilseon; Kang, Koo Jeong; Nam, Jehyun; Kim, Sang-Woo; Kim, Jin Young

    2015-12-01

    Hepatocellular carcinoma (HCC) is one of the most lethal cancers, accounting for about 600,000 cancer deaths worldwide. Despite aggressive chemotherapy, the 5-year survival rate is less than 30% in the United States. This underscores the need for a better understanding of the molecular and cellular disease features. Many studies have demonstrated that aberrant regulation of microRNA (miRNA) expression plays a critical role in the development of various types of cancers including HCC. Here we analyzed the miRNA expression profile of HCC cases associated with chronic hepatitis B virus infection, one of the major etiologies of HCC. Our study identified 267 miRNAs that were differentially regulated in HCC specimens compared to adjacent normal tissues. We next analyzed putative target genes and the relevant signaling pathways that are regulated by these miRNAs. Our findings support the notion that dysfunction of miRNAs is linked to HCC pathogenesis and may lead to the identification of novel targets for diagnosing and treating HCC. PMID:26190160

  19. NON-INVASIVE PREDICTORS OF PORTAL HYPERTENSION IN PATIENTS WITH HEPATITIS C VIRUS RELATED HEPATOCELLULAR CARCINOMA.

    PubMed

    Mohran, Zakaria; Sakr, Mohamed; Barakat, Eman; Elbaz, Ahmed; Al-Hamid, Mohamed Abd; Abou-Elmaaty, Mohamed

    2015-12-01

    The reference standard for portal venous pressure measurement which is clinically important for estimating the. feasibility of resection of hepatocellular carcinoma is the hepatic venous pressure gradient, which is, invasive and expqnsive. The present study evaluated the noninvasive parameters for assessment of portal hypertension in Child A patients with hepatocellular carcinoma on top of hepatitis C virus. A total of 112 patients were subjected to clinical assessment, biochemical assay, ultrasonographic Doppler study, triphasic spiral abdominal computed tomography, upper gastrointestinal endoscopy and hepatic venous pressure gradient measurement. According to hepatic venous pressure gradient measurement, they were classified into groups: GI: 58 patients with hepatic venous pressure gradient <10 mmHg and GII: 54 patients with hepatic venous pressure gradient > or = 10 mmHg. Significant variables in univariate analysis were included in a multivariate analysis to establish a model for prediction of clinically significant portal hypertension. Results showed that portal vein diameter > or = 1.3 cm, mono or biphasic pattern of flow in hepatic veins and Giannini index < or = 909 were independent risk factors for the clinically significant portal hypertension as indicated by HVPG > or = 10 mmHg. A model with highest likelihood ratio and good fitness was created. This prediction model was displayed by the receiver operating characteristic curve and under the curve area was 0.969 (0.938-1). PMID:26939231

  20. The Epidemic of Zika Virus-Related Microcephaly in Brazil: Detection, Control, Etiology, and Future Scenarios.

    PubMed

    Teixeira, Maria G; Costa, Maria da Conceição N; de Oliveira, Wanderson K; Nunes, Marilia Lavocat; Rodrigues, Laura C

    2016-04-01

    We describe the epidemic of microcephaly in Brazil, its detection and attempts to control it, the suspected causal link with Zika virus infection during pregnancy, and possible scenarios for the future. In October 2015, in Pernambuco, Brazil, an increase in the number of newborns with microcephaly was reported. Mothers of the affected newborns reported rashes during pregnancy and no exposure to other potentially teratogenic agents. Women delivering in October would have been in the first trimester of pregnancy during the peak of a Zika epidemic in March. By the end of 2015, 4180 cases of suspected microcephaly had been reported. Zika spread to other American countries and, in February 2016, the World Health Organization declared the Zika epidemic a public health emergency of international concern. This unprecedented situation underscores the urgent need to establish the evidence of congenital infection risk by gestational week and accrue knowledge. There is an urgent call for a Zika vaccine, better diagnostic tests, effective treatment, and improved mosquito-control methods. PMID:26959259

  1. Long non-coding RNA expression profiles of hepatitis C virus-related dysplasia and hepatocellular carcinoma

    PubMed Central

    Li, Ming; Wu, Liangcai; Yang, Xiaobo; Wan, Xueshuai; Wang, Anqiang; Zhang, Michael Q.; Sang, Xinting; Zhao, Haitao

    2015-01-01

    Recently, long non-coding RNAs (lncRNAs) were found to be implicated in cancer progression. However, the contributions of lncRNAs to Hepatitis C virus-related hepatocellular carcinoma (HCC) remain largely unknown. Here, we characterized lncRNA expression in 73 tissue samples from several different developmental stages of HCV-related hepatocarcinogenesis by repurposing microarray data sets. We found that the expression of 7 lncRNAs in preneoplastic lesions and HCC was significantly different. Among these significantly differently expressed lncRNAs, the lncRNA LINC01419 transcripts were expressed at higher levels in early stage HCC compared to dysplasia and as compared with early stage HCC, lncRNA AK021443 level increase in advanced stage HCC while lncRNA AF070632 level decrease in advanced stage HCC. Using quantitative real-time reverse-transcription PCR, we validated that LINC01419 was significantly overexpressed in HBV-related and HCV-related HCC when compared with matched non-tumor liver tissues. Moreover, functional predictions suggested that LINC01419 and AK021443 regulate cell cycle genes, whereas AF070632 is associated with cofactor binding, oxidation-reduction and carboxylic acid catabolic process. These findings provide the first large-scale survey of lncRNAs associated with the development of hepatocarcinogenesis and may offer new diagnostic biomarkers and therapeutic targets for HCV-related HCC. PMID:26540467

  2. Surgical results in patients with hepatitis virus-related hepatocellular carcinoma in Taiwan.

    PubMed

    Chen, Miin-Fu; Jeng, Long-Bin; Lee, Wei-Chen

    2002-06-01

    To investigate the surgical results of hepatectomy for hepatocellular carcinoma in relation to hepatitis virus status in Taiwan, 252 patients (196 men and 56 women; March 1992 to August 1998) were reviewed. The patients were divided into four groups: 30 patients (11.9%) seronegative for both hepatitis B surface antigen (HBsAg) and antihepatitis C antibody (HCVAb) (N-HCC group); 133 patients (52.8%) seropositive for HBsAg and seronegative for HCVAb (B-HCC group); 66 patients (26.2%) seronegative for HBsAg and seropositive for HCVAb (C-HCC group); and 23 patients (9.1%) seropositive for both HBsAg and HCVAb (BC-HCC group). Patients in group C-HCC were older (p = 0.001) and had a higher incidence of diabetes mellitus (p = 0.004). Also, they had a higher indocyanine green retention rate at 15 minutes (p = 0.021), longer international normalization ratio for the prothrombin time (p = 0.049), and smaller tumor (p = 0.006). Postoperative complications and hospital mortality were significantly higher in patients in the C-HCC and BC-HCC groups (p = 0.046, 0.021). All patients were followed 12 to 76 months after hepatectomy (mean 23.5 +/- 16.3 months). The 1-, 3-, and 5-year overall cumulative survival rates of the 252 patients in this series were 80%, 54.3%, and 34.2%, respectively. The cumulative intrahepatic recurrence rates were 46.5%, 64.9%, and 72.9% at 1, 3, and 5 years, respectively. The mean disease-free survival time was longest in group C-HCC and shortest in group BC-HCC (p = 0.020). The overall survival time and cumulative survival rates in the four groups were not significantly different (p = 0.146). PMID:12053231

  3. Serological evidence for a hepatitis e virus-related agent in goats in the United States.

    PubMed

    Sanford, B J; Emerson, S U; Purcell, R H; Engle, R E; Dryman, B A; Cecere, T E; Buechner-Maxwell, V; Sponenberg, D P; Meng, X J

    2013-12-01

    Hepatitis E virus (HEV) causes an important public health disease in many developing countries and is also endemic in some industrialized countries. In addition to humans, strains of HEV have been genetically identified from pig, chicken, rat, mongoose, deer, rabbit and fish. While the genotypes 1 and 2 HEV are restricted to humans, the genotypes 3 and 4 HEV are zoonotic and infect humans and other animal species. As a part of our ongoing efforts to search for potential animal reservoirs for HEV, we tested goats from Virginia for evidence of HEV infection and showed that 16% (13/80) of goat sera from Virginia herds were positive for IgG anti-HEV. Importantly, we demonstrated that neutralizing antibodies to HEV were present in selected IgG anti-HEV positive goat sera. Subsequently, in an attempt to genetically identify the HEV-related agent from goats, we conducted a prospective study in a closed goat herd with known anti-HEV seropositivity and monitored a total of 11 kids from the time of birth until 14 weeks of age for evidence of HEV infection. Seroconversion to IgG anti-HEV was detected in seven of the 11 kids, although repeated attempts to detect HEV RNA by a broad-spectrum nested RT-PCR from the faecal and serum samples of the goats that had seroconverted were unsuccessful. In addition, we also attempted to experimentally infect laboratory goats with three well-characterized mammalian strains of HEV but with no success. The results indicate that a HEV-related agent is circulating and maintained in the goat population in Virginia and that the goat HEV is likely genetically very divergent from the known HEV strains. PMID:22909079

  4. Vitamin D pathway gene polymorphisms as predictors of hepatitis C virus-related mixed cryoglobulinemia.

    PubMed

    Cusato, Jessica; Boglione, Lucio; De Nicolò, Amedeo; Cardellino, Chiara Simona; Carcieri, Chiara; Cariti, Giuseppe; Di Perri, Giovanni; D'Avolio, Antonio

    2016-06-01

    Mixed cryoglobulinemia (MC) is the most frequent extrahepatic hepatitis C virus (HCV) complication. Vitamin D is a modulator of several biological processes, including immune and skeletal systems and MC presence and systemic vasculitis were associated independently with low levels of vitamin D. Considering the impact of vitamin D, we aimed to evaluate the role of some single nucleotide polymorphisms (SNPs) of vitamin D pathway genes in the prediction of MC in HCV patients treated with pegylated interferon and ribavirin. We investigated SNPs in IL-28B, CYP27B1, CYP27A1, CYP24A1, VDBP, and VDR genes through real-time PCR. VDR gene SNPs were related to baseline viral load: VDR BsmI AA (P=0.018), TaqI CC (P=0.009), and ApaI AA (P=0.004) showed a lower baseline HCV count. Among vitamin D pathway gene polymorphisms, VDR FokI T>C was a factor associated with the presence of MC in the study population (P=0.011): related to C allele carriers (TT vs. TC/CC), we obtained a P-value of 0.003. In the logistic regression analysis to assess which demographic, clinical, or genetic factors could predict the presence of cryoglobulin, the TT/CC IL-28B rs8099917/rs12979860 haplotype [P<0.001; odds ratio (OR) 3.516 (1.951-6.336)], baseline viral load [P<0.001; OR 1.000 (0.999-1.001)], and VDR FokI TC/CC genotypes [0.044; OR 0.463 (0.218-0.981)] remained in the final regression model. These data could help physicians identify patients with a higher probability of developing MC extrahepatic complications. PMID:27139837

  5. Bats worldwide carry hepatitis E virus-related viruses that form a putative novel genus within the family Hepeviridae.

    PubMed

    Drexler, Jan Felix; Seelen, Annika; Corman, Victor Max; Fumie Tateno, Adriana; Cottontail, Veronika; Melim Zerbinati, Rodrigo; Gloza-Rausch, Florian; Klose, Stefan M; Adu-Sarkodie, Yaw; Oppong, Samuel K; Kalko, Elisabeth K V; Osterman, Andreas; Rasche, Andrea; Adam, Alexander; Müller, Marcel A; Ulrich, Rainer G; Leroy, Eric M; Lukashev, Alexander N; Drosten, Christian

    2012-09-01

    Hepatitis E virus (HEV) is one of the most common causes of acute hepatitis in tropical and temperate climates. Tropical genotypes 1 and 2 are associated with food-borne and waterborne transmission. Zoonotic reservoirs (mainly pigs, wild boar, and deer) are considered for genotypes 3 and 4, which exist in temperate climates. In view of the association of several zoonotic viruses with bats, we analyzed 3,869 bat specimens from 85 different species and from five continents for hepevirus RNA. HEVs were detected in African, Central American, and European bats, forming a novel phylogenetic clade in the family Hepeviridae. Bat hepeviruses were highly diversified and comparable to human HEV in sequence variation. No evidence for the transmission of bat hepeviruses to humans was found in over 90,000 human blood donations and individual patient sera. Full-genome analysis of one representative virus confirmed formal classification within the family Hepeviridae. Sequence- and distance-based taxonomic evaluations suggested that bat hepeviruses constitute a distinct genus within the family Hepeviridae and that at least three other genera comprising human, rodent, and avian hepeviruses can be designated. This may imply that hepeviruses invaded mammalian hosts nonrecently and underwent speciation according to their host restrictions. Human HEV-related viruses in farmed and peridomestic animals might represent secondary acquisitions of human viruses, rather than animal precursors causally involved in the evolution of human HEV. PMID:22696648

  6. Epstein-Barr virus: general factors, virus-related diseases and measurement of viral load after transplant

    PubMed Central

    Gequelin, Luciana Cristina Fagundes; Riediger, Irina N.; Nakatani, Sueli M.; Biondo, Alexander W.; Bonfim, Carmem M.

    2011-01-01

    The Epstein-Barr virus is responsible for infectious mononucleosis syndrome and is also closely associated to several types of cancer. The main complication involving Epstein-Barr virus infection, both in recipients of hematopoietic stem cells and solid organs, is post-transplant lymphoproliferative disease. The importance of this disease has increased interest in the development of laboratory tools to improve post-transplant monitoring and to detect the disease before clinical evolution. Viral load analysis for Epstein-Barr virus through real-time polymerase chain reaction is, at present, the best tool to measure viral load. However, there is not a consensus on which sample type is the best for the test and what is its predictive value for therapeutic interventions. PMID:23049344

  7. Anomalous Gray Matter Structural Networks in Patients with Hepatitis B Virus-Related Cirrhosis without Overt Hepatic Encephalopathy

    PubMed Central

    Qiu, Ying-Wei; Cai, Pei-Qiang; Li, Jing; Jiang, Gui-Hua; Deng, Yan-Jia; Zhang, Xue-Lin; Wu, Pei-Hong; Xie, Chuan-Miao; Wen, Ge

    2015-01-01

    Background and Purpose Increasing evidence suggests that cirrhosis may affect the connectivity among different brain regions in patients before overt hepatic encephalopathy (OHE) occurs. However, there has been no study investigating the structural reorganization of these altered connections at the network level. The primary focus of this study was to investigate the abnormal topological organization of the structural network in patients with hepatitis B virus-related cirrhosis (HBV-RC) without OHE using structural MRI. Methods Using graph theoretical analysis, we compared the global and regional topological properties of gray matter structural networks between 28 patients with HBV-RC without OHE and 30 age-, sex- and education-matched healthy controls. The structural correlation networks were constructed for the two groups based on measures of gray matter volume. Results The brain network of the HBV-RC group exhibited a significant decrease in the clustering coefficient and reduced small-worldness at the global level across a range of network densities. Regionally, brain areas with altered nodal degree/betweenness centrality were observed predominantly in association cortices (frontal and temporal regions) (p < 0.05, uncorrected), including a significantly decreased nodal degree in the inferior temporal gyrus (p < 0.001, uncorrected). Furthermore, the HBV-RC group exhibited a loss of association hubs and the emergence of an increased number of non-association hubs compared with the healthy controls. Conclusion The results of this large-scale gray matter structural network study suggest reduced topological organization efficiency in patients with HBV-RC without OHE. Our findings provide new insight concerning the mechanisms of neurobiological reorganization in the HBV-RC brain from a network perspective. PMID:25786256

  8. Hepatitis B Virus Reactivation After Three-Dimensional Conformal Radiotherapy in Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma

    SciTech Connect

    Kim, Ji Hoon; Park, Joong-Won Kim, Tae Hyun; Koh, Dong Wook; Lee, Woo Jin; Kim, Chang-Min

    2007-11-01

    Purpose: To investigate whether three-dimensional conformal radiotherapy (3D-CRT) influences hepatitis B virus (HBV) reactivation and chronic hepatitis B (CHB) exacerbation in patients with HBV-related hepatocellular carcinoma (HCC). Methods and Materials: Of the 48 HCC patients with HBV who underwent 3D-CRT to the liver, 16 underwent lamivudine therapy before and during 3D-CRT (Group 1) and 32 did not receive antiviral therapy before 3D-CRT (Group 2). To analyze spontaneous HBV reactivation, we included a control group of 43 HCC patients who did not receive any specific treatment for HCC or CHB. Results: The cumulative rate of radiation-induced liver disease for Groups 1 and 2 was 12.5% (2 of 16) and 21.8% (7 of 32), respectively (p > 0.05). The cumulative rate of HBV reactivation was significantly greater in Group 2 (21.8%, 7 of 32) than in Group 1 (0%, 0/16) or the control group (2.3%, 1 of 43; p < 0.05 each). The cumulative rate of CHB exacerbation, however, did not differ significantly between Groups 2 (12.5%, 4 of 32) and 1 (0%, 0 of 16) or the control group (2.3%, 1 of 43; p > 0.05 each). The CHB exacerbations in the 4 Group 2 patients had radiation-induced liver disease features but were differentiated by serum HBV DNA changes. Two of these patients required antiviral therapy and effectively recovered with lamivudine therapy. Conclusions: In patients with HBV-related HCC undergoing 3D-CRT, HBV reactivation and consequent CHB exacerbation should be considered in the differential diagnosis of radiation-induced liver disease, and antiviral therapy might be considered for the prevention of liver function deterioration after RT.

  9. Meta-analysis of associations of interleukin-28B polymorphisms rs8099917 and rs12979860 with development of hepatitis virus-related hepatocellular carcinoma

    PubMed Central

    Zhang, Yu; Zhu, Shao-Liang; Chen, Jie; Li, Le-Qun

    2016-01-01

    Background This meta-analysis aimed to assess available evidence on possible associations of interleukin-28B polymorphisms rs8099917 and rs12979860 with development of hepatitis virus-related hepatocellular carcinoma (HCC). Methods PubMed, EMBASE, Google Scholar, and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Meta-analyses were performed to examine the association of interleukin-28B rs8099917 G/T and rs12979860 T/C polymorphisms with development of hepatitis virus-related HCC. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results A total of ten studies involving 2,529 cases and 2,412 controls were included. The G-allele and GT genotype of rs8099917 were significantly associated with increased risk of hepatitis B virus (HBV)-related HCC (allelic model, OR 1.49, 95% CI 1.13–1.96, P=0.005; heterozygous model, OR 1.39, 95% CI 1.04–1.88, P=0.03). Conversely, the TT genotype was found to be significantly associated with lower risk of HBV-related HCC (dominant model, OR 0.68, 95% CI 0.51–0.91, P=0.01). Similar results were observed in the subgroup of Chinese patients and controls. In the pooled data set, the T-allele and TT genotype of rs12979860 showed a significant association with increased HCC risk (allelic model, OR 1.36, 95% CI 1.05–1.78, P=0.02; recessive model, OR 1.75, 95% CI 1.28–2.39, P=0.005; homozygous model, OR 1.99, 95% CI 1.41–2.80, P<0.001). Subgroup analysis based on ethnicity and etiology showed rs12979860 polymorphism to be significantly associated with HCC risk in Caucasians, especially hepatitis C virus-related HCC, according to all five genetic models. In contrast, only the TT genotype of rs12979860 was found to be significantly associated with increased risk of HBV-related HCC, especially in Asians. Conclusion The G-allele of rs8099917 may confer elevated risk of HBV-related HCC, while the wild-type TT genotype may protect against the disease

  10. Laparoscopic liver resection for hepatitis B and C virus-related hepatocellular carcinoma in patients with Child B or C cirrhosis

    PubMed Central

    Brytska, Nataliya; Shehta, Ahmed; Yoon, Yoo-Seok; Cho, Jai Young; Choi, YoungRok

    2015-01-01

    Background The aim of this study was to evaluate the clinical and oncological outcomes after laparoscopic liver resection (LLR) in patients with hepatitis B and C virus-related hepatocellular carcinoma (HCC) with Child B or C cirrhosis. Methods Between January 2004 and December 2013, LLR was performed in 232 patients with HCC. Of these, 141 patients also had pathologically proven cirrhosis. Sixteen patients with hepatitis B and C virus-related HCC with Child B or C cirrhosis were included in the study. Thirteen (81.3%) patients had Child B disease and three (18.8%) patients had Child C disease. Results The median operation time was 215 min, the median estimated blood loss was 350 mL, and the median hospital stay was eight days. Three patients (18.8%) experienced complications after surgery. There was no postoperative mortality or reoperation. The mean follow-up period was 51.6 months. HCC recurred in eight (50%) patients: seven intrahepatic recurrences and one extrahepatic recurrence. The treatments for recurrence were laparoscopic reoperation in one (6.3%) patient, trans-catheter arterial chemo-embolization (TACE) in one (6.3%) patient, radiofrequency ablation (RFA) in one (6.3%) patient, and combined TACE and RFA in four (25%) patients. The five-year postoperative overall survival (OS) and disease-free survival (DFS) were 84.4% and 41.7%, respectively. Conclusions This study demonstrates that LLR can be safely used in patients with hepatitis B and C virus-related HCC and Child B or C cirrhosis, with acceptable survival outcomes. PMID:26734621

  11. Targeted gene transfer to lymphocytes using murine leukaemia virus vectors pseudotyped with spleen necrosis virus envelope proteins.

    PubMed

    Engelstädter, M; Buchholz, C J; Bobkova, M; Steidl, S; Merget-Millitzer, H; Willemsen, R A; Stitz, J; Cichutek, K

    2001-08-01

    In contrast to murine leukaemia virus (MLV)-derived vector systems, vector particles derived from the avian spleen necrosis virus (SNV) have been successfully targeted to subsets of human cells by envelope modification with antibody fragments (scFv). However, an in vivo application of the SNV vector system in gene transfer protocols is hampered by its lack of resistance against human complement. To overcome this limitation we established pseudotyping of MLV vector particles produced in human packaging cell lines with the SNV envelope (Env) protein. Three variants of SNV Env proteins differing in the length of their cytoplasmic domains were all efficiently incorporated into MLV core particles. These pseudotype particles infected the SNV permissive cell line D17 at titers of up to 10(5) IU/ml. A stable packaging cell line (MS4) of human origin released MLV(SNV) pseudotype vectors that were resistant against human complement inactivation. To redirect their tropism to human T cells, MS4 cells were transfected with the expression gene encoding the scFv 7A5 in fusion with the transmembrane domain (TM) of the SNV Env protein, previously shown to retarget SNV vector particles to human lymphocytes. MLV(SNV-7A5)-vector particles released from these cells were selectively infectious for human T cell lines. The data provide a proof of principle for targeting MLV-derived vectors to subpopulations of human cells through pseudotyping with SNV targeting envelopes. PMID:11509952

  12. Herd-level determinants of bovine leukaemia virus prevalence in dairy farms.

    PubMed

    Erskine, Ronald J; Bartlett, Paul C; Byrem, Todd M; Render, Chelsea L; Febvay, Catherine; Houseman, Jessica T

    2012-11-01

    The prevalence of bovine leukaemia virus (BLV) was determined in 113 Michigan dairy herds by ELISA testing for anti-BLV antibodies in milk. Additionally, an interview regarding management practices with cooperating herd managers identified farm-level variables thought to be associated with prevalence of BLV. Twenty-three risk factors (P ≤ 0·1) were identified on one-way ANOVA or simple linear regression. Multivariate analysis identified several management practices whose predictive value for increased prevalence of BLV may relate to transmission among herd mates, e.g. reuse of hypodermic needles, lack of fly control, gouge dehorning and increased use of injections in dry cows. Additionally, exclusive breeding of heifers with artificial insemination was associated with decreased BLV prevalence, as compared with at least some use of natural service by a bull. Although intervention studies are needed before causal relationships can be concluded, and unaccounted variables related to transmission exist among dairy herds, these findings suggest management practices that may help dairy producers reduce the transmission of BLV within their herds. PMID:22963749

  13. Production and related variables in bovine leukaemia virus-infected cows.

    PubMed

    Jacobs, R M; Heeney, J L; Godkin, M A; Leslie, K E; Taylor, J A; Davies, C; Valli, V E

    1991-01-01

    A newly developed milk dot blot test was used to detect anti-bovine leukaemia virus (BLV) antibody in milk samples from 2079 lactating adult cows from among 61 herds. The milk dot blot test was highly repeatable; the concordance rate, compared with the agar gel immunodiffusion test performed on serum, was 83.5%. All herds contained BLV-positive cows; the prevalence rate was 36%. BLV-positive cows tended to come from larger herds and were older and more often later in lactation. Fourteen production and related variables (herd size, age, days open, days in milk, milk somatic cell count, milk, fat, and protein produced in the current lactation, projected production of milk, fat, and protein, and breed class average deviations for milk, fat, and protein) were compared between BLV-positive and BLV-negative cows. Although somatic cell count, milk produced, and projected production of milk and protein were related significantly to BLV status using simple tests of association, once the variables herd size, age and days in milk were controlled, these differences were removed. Further analyses using logistic (outcome: individual cow BLV status) and least-squares regression (outcome: herd proportion of BLV-positive cows) failed to show an association between any of the measured production or related variables and BLV-positivity. We concluded that the effect of BLV on production and related variables in dairy cows was below the sensitivity of our analytical techniques or was non-existent. PMID:1666473

  14. A survey of feline leukaemia virus infection of domestic cats from selected areas in Harare, Zimbabwe.

    PubMed

    Muchaamba, Francis; Mutiringindi, Takudzwa H; Tivapasi, Musavenga T; Dhliwayo, Solomon; Matope, Gift

    2014-01-01

    A cross-sectional study was conducted to detect the feline leukaemia virus (FeLV) p27 antigen and to determine risk factors and the haematological changes associated with infection in domestic cats in Zimbabwe. Sera were collected for detection of the p27 antigen, urea, creatinine, alanine aminotransferase and gamma-glutamyl transferase levels, whilst whole blood was collected for haematology. FeLV p27 antigen was detected using a rapid enzyme-linked immunosorbent assay (ELISA) test kit. Data on risk factors were analysed using a logistic regression model. Of the 100 cats tested, 41% (95% CI: 31.19% - 50.81%) (41/100) were positive for the FeLV p27 antigen. Sex and health status of cats were not significantly (p > 0.05) associated with infection. Intact cats (OR = 9.73), those living in multicat housing (OR = 5.23) and cats that had access to outdoor life (OR = 35.5) were found to have higher odds of infection compared with neutered cats, those living in single-cat housing, and without access to outdoor life, respectively. Biochemistry and haematology revealed no specific changes. The results showed that FeLV infection was high in sampled cats, providing evidence of active infection. Thus, it would be prudent to introduce specific control measures for FeLV infection in Zimbabwe. PMID:25686080

  15. A neutron study of the feline leukaemia virus fusion peptide: Implications for biological fusion?

    NASA Astrophysics Data System (ADS)

    Davies, Sarah M. A.; Darkes, Malcolm J. M.; Bradshaw, Jeremy P.

    Neutron diffraction studies were performed on stacked phospholipid bilayers to determine the effects of the feline leukaemia virus (FeLV) fusion peptide on membrane structure. Bilayers were composed of dioleoylphosphatidylcholine with 50% (mol) dioleoylphosphatidylglycerol. Neutron scattering profiles with peptide present showed an increase in scattering density in the lipid-tails region, whilst scattering by the lipid headgroup region was decreased. This is interpreted as a lowering of the packing density of the lipid headgroups and an increase in the packing density of the lipid tails. Modelling studies and experimental evidence have suggested that fusion peptides catalyse fusion by increasing the negative curvature of the target membrane's outer monolayer. Our results presented here add support to this hypothesis for the fusion mechanism. The 2H 2O scattering profile was also slightly perturbed in the lipid headgroup region with 1% (mol)FeLV fusion peptide present. The FeLV peptide had no significant effect on the organisation of bilayers containing only dioleoylphosphatidylcholine.

  16. Nucleotide sequence of a chickpea chlorotic stunt virus relative that infects pea and faba bean in China.

    PubMed

    Zhou, Cui-Ji; Xiang, Hai-Ying; Zhuo, Tao; Li, Da-Wei; Yu, Jia-Lin; Han, Cheng-Gui

    2012-07-01

    We determined the genome sequence of a new polerovirus that infects field pea and faba bean in China. Its entire nucleotide sequence (6021 nt) was most closely related (83.3% identity) to that of an Ethiopian isolate of chickpea chlorotic stunt virus (CpCSV-Eth). With the exception of the coat protein (encoded by ORF3), amino acid sequence identities of all gene products of this virus to those of CpCSV-Eth and other poleroviruses were <90%. This suggests that it is a new member of the genus Polerovirus, and the name pea mild chlorosis virus is proposed. PMID:22476900

  17. Expression of interleukin 6 receptors and interleukin 6 mRNA by bovine leukaemia virus-induced tumour cells.

    PubMed

    Droogmans, L; Cludts, I; Cleuter, Y; Kerkhofs, P; Adam, E; Willems, L; Kettmann, R; Burny, A

    1994-11-01

    Bovine leukaemia virus (BLV) is the aetiologic agent of bovine leucosis. The virus induces malignancies of the B-cell lineage (leukaemia/lymphoma). The role played by interleukin 6 (IL-6) in the BLV-induced leukemogenesis process was evaluated. Six cell lines derived from BLV-induced tumours were tested for the expression of IL-6 receptors. Two cell lines (LB155 and YR2) display 250-300 receptor per cell (kd = 1.7 10(-10) M and 1.4 10(-10) M, respectively) whereas the other four (LB159, LB167, YR1 and M51) do not display detectable amounts of receptors. Very low (if any) expression of IL-6 receptors has been found in the case of the B lymphocytes of animals in persistent lymphocytosis (PL). Despite the presence of IL-6 receptors on the surface of LB155 and YR2 cells, no influence of exogenous IL-6 on their growth has been observed. Northern analyses indicated the presence of IL-6 transcripts only in the case of mRNA isolated from LB155 cells. Since this cell line also expresses receptors for the cytokine, an autocrine loop may exist in these cells. Experiments in which bovine and bovine epithelial cell lines were transfected with a plasmid containing the bovine IL-6 promoter controlling the expression of the reporter cat gene failed to indicate any influence of the viral transactivator p34tax on the activity of this promoter. We conclude that IL-6 receptors and IL-6 mRNA can be found in some BLV-induced tumours, but this does not correlate with viral expression in BLV-induced leukaemia/lymphoma. PMID:7893972

  18. Trends in Human Immunodeficiency Virus-Related Risk Behaviors among High School Students--United States, 1991-2005

    ERIC Educational Resources Information Center

    Brener, Nancy; Kann, Laura; Lowry, Richard; Wechsler, Howell; Romero, Lisa

    2006-01-01

    This paper examined changes in human immunodeficiency virus (HIV)-related risk behaviors among high school students in the United States during 1991-2005. Data from 8 national Youth Risk Behavior Surveys conducted during that period were analyzed. During 1991-2005, the percentage of US high school students engaging in HIV-related sexual risk…

  19. Regression of esophageal varices during entecavir treatment in patients with hepatitis-B-virus-related liver cirrhosis

    PubMed Central

    Jwa, Hye Young; Cho, Yoo-Kyung; Choi, Eun Kwang; Kim, Heung Up; Song, Hyun Joo; Na, Soo-Young; Boo, Sun-Jin; Jeong, Seung Uk; Kim, Bong Soo; Lee, Byoung-Wook; Song, Byung-Cheol

    2016-01-01

    Recent studies suggest that liver cirrhosis is reversible after administering oral nucleos(t)ide analogue therapy to patients with hepatitis B virus (HBV) infection. However, few studies have addressed whether esophageal varices can regress after such therapy. We report a case of complete regression of esophageal varices during entecavir therapy in patients with HBV-related liver cirrhosis, suggesting that complications of liver cirrhosis such as esophageal varices can regress after the long-term suppression of HBV replication. PMID:27044771

  20.  Autochthonous infection with hepatitis E virus related to subtype 3a, France: a case report.

    PubMed

    Saint-Jacques, Pauline; Tissot-Dupont, Hervé; Colson, Philippe

    2016-01-01

    Hepatitis E virus (HEV) recently emerged in Europe as a cause of autochthonous acute hepatitis and a porcine zoonosis. European autochthonous cases almost exclusively involved viruses of genotype 3, subtype 3a being only recently reported in France, from farm pigs. We report an autochthonous human infection with a HEV related to subtype 3a in Southeastern France. A 55-year-old human immunodeficiency virus-infected man presented liver cytolysis in June 2014. HEV RNA was detected in serum and three months later, anti-HEV IgM and IgG were positive whereas HEV RNA was no more detectable in serum. No biological or clinical complication did occur. HEV phylogeny based on two capsid gene fragments showed clustering of sequences obtained from the case-patient with HEV-3a, mean nucleotide identity being 91.7 and 91.3% with their 10 best GenBank matches that were obtained in Japan, South Korea, USA, Canada, Germany and Hungria from humans, pigs and a mongoose. Identity between HEV sequence obtained here and HEV-3a sequences obtained at our laboratory from farm pigs sampled in 2012 in Southeastern France was only 90.2-91.4%. Apart from these pig sequences, best hits from France were of subtypes 3i, 3f, or undefined. The patient consumed barely cooked wild-boar meat; no other risk factor for HEV infection was documented. In Europe, HEV-3a has been described in humans in England and Portugal, in wild boars in Germany, and in pigs in Germany, the Netherlands, and, recently, France. These findings suggest to gain a better knowledge of HEV-3a circulation in France. PMID:27049499

  1. [Diagnosis, treatment, and follow-up of hepatitis C-virus related liver disease. Hungarian national consensus guideline].

    PubMed

    Hunyady, Béla; Gervain, Judit; Horváth, Gábor; Makara, Mihály; Pár, Alajos; Szalay, Ferenc; Telegdy, László; Tornai, István

    2014-03-01

    Approximately 70 000 people are infected with hepatitis C virus in Hungary, more than half of whom are not aware of their infection. Early recognition and effective treatment of related liver injury may prevent consequent advanced liver diseases (liver cirrhosis and liver cancer) and its complications. In addition, it may increase work productivity and life expectancy of infected individual, and can prevent further viral transmission. Early recognition can substantially reduce the long term financial burden of related morbidity from socioeconomic point of view. Pegylated interferon + ribavirin dual therapy, which is available in Hungary since 2003, can kill the virus in 40-45% of previously not treated (naïve), and in 5-21% of previous treatment-failure patients. Addition of two direct acting first generation protease inhibitor drugs (boceprevir and telaprevir) to the dual therapy increased the chance of sustained clearance of virus to 63-75% and 59-66%, respectively. These two protease inhibitor drugs are available and financed for a segment of Hungarian patients since May 2013. Indication of therapy includes exclusion of contraindications to the drugs and demonstration of viral replication with consequent liver injury, i.e., inflammation and/or fibrosis in the liver. For initiation of treatment as well as for on-treatment decisions accurate and timely molecular biology tests are mandatory. Staging of liver damage (fibrosis) non-invasive methods (transient elastography and biochemical methods) are acceptable to avoid concerns of patients related to liver biopsy. Professional decision for treatment is balanced against budget limitations in Hungary, and priority is given to those with urgent need using a national Priority Index system reflecting stage of liver disease as well as additional factors (activity and progression of liver disease, predictive factors and other special circumstances). All naïve patients are given a first chance with dual therapy. Those

  2. Reduced Prevalence of Epstein-Barr Virus-Related Lymphocryptovirus Infection in Sera from a New World Primate

    PubMed Central

    Fogg, Mark H.; Carville, Angela; Cameron, Jennifer; Quink, Carol; Wang, Fred

    2005-01-01

    The recent discovery of an Epstein-Barr virus (EBV)-related lymphocryptovirus (LCV) naturally infecting common marmosets demonstrated that gamma-1 herpesviruses are not limited to human and Old World nonhuman primate hosts. We developed serologic assays to detect serum antibodies against lytic- and latent-infection marmoset LCV antigens in order to perform the first seroepidemiologic study of LCV infection in New World primates. In three different domestic colonies and in animals recently captured from the wild, we found that the seroprevalence of marmoset LCV infection was not as ubiquitous as with EBV or Old World LCV. These biologic differences in LCV infection of New World versus human and Old World primate hosts correlate with the evolution of the LCV viral gene repertoire. PMID:16014968

  3. Successful hepatitis B vaccination in patients who underwent transplantation for hepatitis B virus-related cirrhosis: preliminary results.

    PubMed

    Bienzle, Ulrich; Günther, Matthias; Neuhaus, Ruth; Neuhaus, Peter

    2002-06-01

    Long-term hepatitis B immunoglobulin (HBIg) prophylaxis prevents endogenous hepatitis B virus (HBV) reinfection in the majority of liver transplant recipients. Active hepatitis B vaccination after orthotopic liver transplantation (OLT) in these patients has produced conflicting results to date. On this study, patients who remained hepatitis B surface antigen (HBsAg) negative with passive immunization after OLT for HBV cirrhosis were actively immunized using recombinant HBV antigen (Engerix), together with a novel adjuvant system (monophosphoryl lipid A and a natural saponine molecule). This led to a sustained antibody response to HBsAg (>500 IU/L) in 5 of 10 patients. This antibody response prevented reinfection and allowed termination of prophylactic HBIg substitution for more than 12 months in these patients. PMID:12037789

  4. The impact of surveillance and rapid reduction in immunosuppression to control BK virus-related graft injury in kidney transplantation.

    PubMed

    Elfadawy, Nissreen; Flechner, Stuart M; Liu, Xiaobo; Schold, Jesse; Tian, Devin; Srinivas, Titte R; Poggio, Emilio; Fatica, Richard; Avery, Robin; Mossad, Sherif B

    2013-08-01

    We prospectively screened 609 consecutive kidney (538) and kidney-pancreas (71) transplant recipients for BK viremia over a 4-year interval using polymerase chain reaction viral load detection and protocol kidney biopsies. We found that BK viremia is common at our center: total cases 26.7%, cases during first year 21.3% (mean 4 months), and recipients with ≥ 10 000 copies/ml 12.3%. We found few predictive clinical or demographic risk factors for any BK viremia or viral loads ≥ 10,000 copies/ml, other than prior treatment of biopsy confirmed acute rejection and/or higher immunosuppressive blood levels of tacrolimus (P = 0.001) or mycophenolate mofetil (P = 0.007). Viral loads at diagnosis (<10 000 copies/ml) demonstrated little impact on graft function or survival. However, rising copy numbers demand early reductions in immunosuppressive drug doses of at least 30-50%. Viral loads >185 000 copies/ml at diagnosis were predictive of BK virus-associated nephropathy (BKVAN; OR: 113.25, 95% CI: 17.22-744.6, P < 0.001). Surveillance for BK viremia and rapid reduction of immunosuppression limited the incidence of BKVAN to 1.3%. The addition of leflunomide or ciprofloxacin to immunosuppressive dose reduction did not result in greater rates of viral clearance. These data support the role of early surveillance for BK viremia to limit the impact on transplant outcome, although the most effective schedule for screening awaits further investigation. PMID:23763289

  5. Intravenous immune globulin use in patients with human immunodeficiency virus-related thrombocytopenia who require dental extraction.

    PubMed Central

    Rarick, M. U.; Burian, P.; de Guzman, N.; Espina, B.; Montgomery, T.; Jamin, D.; Levine, A. M.

    1991-01-01

    Five patients with human immunodeficiency virus (HIV)-related immune thrombocytopenia who were undergoing dental extraction were treated with intravenous immune globulin (IVIG). All patients received IVIG, 1 gram per kg, the day before the dental extraction and again the day of the dental extraction. Four patients had a previous history of minor clinical bleeding. The median baseline platelet count before extraction was 20 X 10(9) per liter (range 13 to 44). The median peak platelet count was 100 X 10(9) per liter (range 56 to 528) following infusion. This peak response was achieved by day 2 in 3 patients and by days 5 and 7 in 1 patient each. No patients had complications or toxicity from the infusions or perioperative bleeding. No patients required blood product transfusions for the surgical procedure. In conclusion, IVIG infusion should be considered in patients with HIV-related immune thrombocytopenia requiring surgical procedures when a prompt rise in platelet count is desired. PMID:1812630

  6. Th1/Th2 cytokines and their genotypes as predictors of hepatitis B virus related hepatocellular carcinoma

    PubMed Central

    Saxena, Roli; Kaur, Jyotdeep

    2015-01-01

    Hepatocellular carcinoma (HCC), the predominant type of primary liver cancer, is one of the most serious life-threatening malignancies, worldwide. In majority of the cases, HCC develops after prolonged and persistent chronic liver disease. hepatitis B virus (HBV) or HCV infection is prominent etiological factors, attributing to this condition. It has been well documented that HBV, being the inducer of chronic inflammation, is the main causative agent in causing HCC, particularly in Asian countries. The HBV infection leads to a wide range of clinical symptoms from carrier state to malignancy. Cytokines being immune-modulatory molecules, are the key mediators in the defense mechanism against viral infection. In this regard, this review will detail the substantial role of key Th1: interleukin 1 (IL-1), IL-2, IL-12, tumor necrosis factor-α, interferon-γ; Th2: IL-4, IL-10 and non Th1/Th2: IL-6, transforming growth factor-β1 cytokines genotypes in analyzing the variability in the clinical manifestations in an HBV-afflicted individual, which might finally, culminates into HCC. Since cytokine production is regulated genetically, the cytokine promoter region single-nucleotide polymorphisms induced changes, greatly affects the cytokine production, thus resulting into differential outcome of immune balance. PMID:26085916

  7. Combination therapy with pegylated interferon plus ribavirin in the treatment of hepatitis C virus-related thrombocytopenia

    PubMed Central

    Karakan, Tarkan; Cindoruk, Mehmet; Degertekin, Bulent; Dogan, Ibrahim; Sancak, Alper; Dumlu, Sukru; Gorgul, Ahmet; Unal, Selahattin

    2005-01-01

    Background: Isolated thrombocytopenia is a common manifestation of hepatitis C virus (HCV) infection. There is no established treatment modality for this condition. The efficacy of standard interferon (IFN) monotherapy has been reported in some studies. The major disadvantage of this treatment is the high rate of recurrence due to viral breakthrough during the first 12 weeks of treatment. Pegylated IFNs are now the standard regimen for chronic hepatic disease due to HCV infection. However, due to a lack of evidence, pegylated IFNs are not widely used for HCV-related isolated thrombocytopenia. Objective: The aim of this report was to present the case of a male patientwith severe symptomatic thrombocytopenia due to HCV infection. Methods: Thrombocytopenia was treated with pegylated IFN plus ribavirin. Results: Although standard IFN monotherapy failed to achieve virologic and hematologic improvement, therapy with pegylated IFN alfa-2a plus ribavirin was associated with both virologic and hematologic improvement without any significant adverse effects. Conclusions: Pegylated IFN plus ribavirin was effective in this patient for thetreatment of HCV-related thrombocytopenia. However, further research is needed to define the response rate in different patient populations. PMID:24764593

  8. Role of antiviral therapy in the natural history of hepatitis B virus-related chronic liver disease

    PubMed Central

    Russo, Francesco Paolo; Rodríguez-Castro, Kryssia; Scribano, Laura; Gottardo, Giorgia; Vanin, Veronica; Farinati, Fabio

    2015-01-01

    Hepatitis B virus (HBV) infection is a dynamic state of interactions among HBV, hepatocytes, and the host immune system. Natural history studies of chronic hepatitis B (CHB) infection have shown an association between active viral replication and adverse clinical outcomes such as cirrhosis and hepatocellular carcinoma. The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, hepatocellular carcinoma (HCC) and death. This goal can be achieved if HBV replication is suppressed in a sustained manner. The accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and of HCC, particularly in non-cirrhotic patients. However, CHB infection cannot be completely eradicated, due to the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the integration of the HBV genome into the host genome may favour oncogenesis, development of HCC and may also contribute to HBV reactivation. PMID:26052398

  9. Predictors of Refractory Ascites Development in Patients with Hepatitis B Virus-Related Cirrhosis Hospitalized to Control Ascitic Decompensation

    PubMed Central

    Seo, Ju Hee; Kim, Seung Up; Park, Jun Yong; Kim, Do Young; Han, Kwang-Hyub; Chon, Chae Yoon

    2013-01-01

    Purpose Refractory ascites (RA) is closely related to a high morbidity and mortality. In this study, we investigated predictors of RA development in patients with hepatitis B virus (HBV)-related cirrhosis who were hospitalized to control ascitic decompensation, and determined predictors for survival in patients who experienced RA. Materials and Methods We analyzed 199 consecutive patients with HBV-related cirrhosis who were hospitalized to control ascitic decompensation between January 1996 and December 2008. Results Multivariate analyses showed that only serum potassium at admission predicted RA development independently [p=0.013; hazard ratio (HR), 2.800; 95% confidence interval (CI), 1.166-6.722]. During the follow-up period, 16 (8.0%) patients experienced RA within 4.2 (range, 1.0-39.2) months after admission for controlling ascitic decompensation, and they survived a median of 8.7 (range, 3.9-51.3) months. Child-Pugh class and RA type were identified as independent prognostic factors affecting the survival in patients with RA (p=0.045; HR, 8.079; 95% CI, 1.231-67.984 and p=0.013; HR, 14.510; 95% CI, 1.771-118.874, respectively). Conclusion Serum potassium was an independent predictor of RA development in patients with HBV-related cirrhosis who were hospitalized to control ascitic decompensation. After RA development, Child-Pugh class and RA type were independent predictors for survival. PMID:23225811

  10. The Relation between Obesity and Survival after Surgical Resection of Hepatitis C Virus-Related Hepatocellular Carcinoma

    PubMed Central

    Nishikawa, Hiroki; Arimoto, Akira; Wakasa, Tomoko; Kita, Ryuichi; Kimura, Toru; Osaki, Yukio

    2013-01-01

    Background and Aims. We aimed to investigate the relationship between obesity and survival in hepatitis C virus-(HCV-) related hepatocellular carcinoma (HCC) patients who underwent curative surgical resection (SR). Methods. A total of 233 patients with HCV-related HCC who underwent curative SR were included. They included 60 patients (25.8%) with a body mass index (BMI) of > 25 kg/m2 (obesity group) and 173 patients with a BMI of < 25 kg/m2 (control group). Overall survival (OS) and recurrence-free survival (RFS) rates were compared. Results. The median follow-up periods were 3.6 years in the obesity group and 3.1 years in the control group. The 1-, 3-, and 5-year cumulative OS rates were 98.3%, 81.0%, and 63.9% in the obesity group and 90.0%, 70.5%, and 50.3% in the control group (P = 0.818). The corresponding RFS rates were 70.1%, 27.0%, and 12.0% in the obesity group and 70.1%, 39.0%, and 21.7% in the control group (P = 0.124). There were no significant differences between the obesity group and the control group in terms of blood loss during surgery (P = 0.899) and surgery-related serious adverse events (P = 0.813). Conclusions. Obesity itself did not affect survival in patients with HCV-related HCC after curative SR. PMID:23710167

  11. The Relationship Between Serum Interleukin-6 and the Recurrence of Hepatitis B Virus Related Hepatocellular Carcinoma after Curative Resection

    PubMed Central

    Sheng, Tao; Wang, Bin; Wang, Shu-yun; Deng, Biao; Qu, Lei; Qi, Xiao-sheng; Wang, Xiao-liang; Deng, Gui-long; Sun, Xing

    2015-01-01

    Abstract The aim of this study is to assess whether preoperative serum interleukin-6 (IL-6) can predict recurrence of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). The association between preoperative IL-6 levels and HCC recurrence following curative hepatectomy in 146 patients with chronic HBV infection was determined. Patients were divided into groups based on the presence or absence of HCC recurrence. Serum IL-6 levels were compared between groups, and the association between serum IL-6 level and greatest tumor dimension was also analyzed. Receiver operating characteristics (ROC) curve was used to define the optimal cutoff value for predicting recurrence-free survival (RFS) and overall survival (OS) rates. The OS and RFS rates were calculated using the Kaplan-Meier method. Out of 146 patients, 80 (54.8%) patients were documented as having HCC recurrence during the follow-up period. After adjusting for potential confounders, serum IL-6 levels were significantly associated with HCC recurrence, and a saturation effect existed with serum IL-6 levels up to 3.7 pg/mL. In addition, patients with preoperative serum IL-6 levels over 3.1 pg/mL had lower RFS and OS rates (P < 0.01). There was no significant correlation between preoperative serum IL-6 levels and maximal tumor dimension (r = 0.0003, P = 0.84). Elevated serum levels of IL-6 were significantly associated with an increased risk of HBV-associated HCC recurrence suggesting that preoperative IL-6 serum level is potential biomarker for early prediction of HBV-associated HCC recurrence.

  12. Soluble CD23 as a sensitive marker for Epstein-Barr virus-related disorders after liver transplantation.

    PubMed

    Kato, H; Inamoto, T; Nakamura, H; Furuke, K; Uemoto, S; Tanaka, K; Ozawa, K; Hori, T; Yodoi, J

    1993-11-01

    Plasma levels of the soluble fragments of Fc epsilon RII/CD23 (sCD23/IgE-binding factor) were measured to assess the level of activation of B lymphocytes associated with Epstein-Barr virus infection in 28 patients who received living-related liver transplantation and were treated with FK506 and steroids. In 6 patients with symptoms of EBV infection (EBV-related disorders), the plasma concentration of sCD23 increased to more than 9.8 ng/ml at the onset of symptoms. In a patient with B cell lymphoma, the plasma levels of sCD23 increased significantly when peripheral lymphadenopathy was noticed, and remained more than 10 ng/ml during the terminal period. In 4 of 6 patients, the increase of plasma levels of sCD23 preceded the increase of anti-EBV capsid antigen IgM. In the other 2 of 6 patients, there was no significant increase of the antibody, despite the integration of EBV DNA in the mononuclear cells in their ascites. The plasma levels of sCD23 of the patients without symptoms of EBV infection did not exceed 7.5 ng/ml. In contrast, the proportion of CD20+/CD23+ B lymphocytes in peripheral blood mononuclear cells was not significantly different in the patients with EBV-related disorders and those with latent asymptomatic EBV infection. Therefore, the plasma level of sCD23 is a sensitive and useful marker of EBV-related polyclonal and/or monoclonal B cell proliferation in transplanted patients with immunosuppression. PMID:8249109

  13. Circulating microRNA-101 as a potential biomarker for hepatitis B virus-related hepatocellular carcinoma

    PubMed Central

    FU, YU; WEI, XUFU; TANG, CHENGYONG; LI, JIANPING; LIU, RUI; SHEN, AI; WU, ZHONGJUN

    2013-01-01

    Circulating microRNAs (miRNAs) are emerging as promising biomarkers for cancer; however, the significance of circulating miRNAs in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains largely unknown. Based on our prior observations that miRNA-101 (miR-101) is downregulated by HBV and induces epigenetic modification, we sought to test whether circulating miR-101 may serve as a potential biomarker for HCC. The expression of miR-101 in HCCs and serum was evaluated by real-time polymerase chain reaction. Tissue and serum miR-101 levels were assessed in samples from patients with HBV-related HCC and healthy controls. A potential correlation was also evaluated between miR-101 expression and the clinicopathological features and prognosis of HCC patients. miR-101 was downregulated in HBV-related HCC tissues compared with adjacent noncancerous tissues. Furthermore, the miR-101 levels in these tissues from HCC patients were significantly lower than those in tissues from control subjects. Notably, serum miR-101 levels were found to have an inverse correlation with tissue miR-101 expression levels. The expression of serum miR-101 in patients with HBV-related HCC was significantly higher than that in the healthy controls, and this increase correlated with hepatitis B surface antigen positivity, HBV DNA levels and tumor size. These results indicate that different factors govern the levels of miR-101 in the tissue and serum of HCC patients. Given the marked and consistent increase in serum miR-101 levels in HCC patients, circulating miR-101 may serve as a promising biochemical marker for monitoring the progression of tumor development in HBV-related HCC. PMID:24260081

  14. Annual economic burden of hepatitis B virus-related diseases among hospitalized patients in twelve cities in China.

    PubMed

    Zhang, S; Ma, Q; Liang, S; Xiao, H; Zhuang, G; Zou, Y; Tan, H; Liu, J; Zhang, Y; Zhang, L; Feng, X; Xue, L; Hu, D; Cui, F; Liang, X

    2016-03-01

    A nationwide survey of hepatitis B virus (HBV)-associated economic burden has not previously been performed in China. The purpose of this study was to examine the direct, indirect, and intangible costs of HBV-related diseases within the span of one year. A random sample was taken from specialty and general hospitals across 12 cities in six provinces of China. Intangible costs were estimated based on willingness to pay or open-ended answers provided by patients. The results showed that 27 hospitals were enrolled, with a sample population of 4726 patients (77.7% response rate). The average annual costs were $4454.0 (direct), $924.3 (indirect), and $6611.10 (intangible), corresponding to 37.3%, 7.7%, and 55.1% of the total costs, respectively. The direct medical fees were substantially greater than the non-medical fees. Annual indirect costs were divided into outpatient ($112.9) and inpatient ($811.40) loss of income. The intangible costs of chronic HBV were notably higher than either the direct or indirect costs, consistent with the social stigma in China. The comparison amongst individual cities for the average ratio of direct to indirect costs revealed that the sizes of ratios were negatively correlated with the socioeconomic status of the regions. This study suggested that as a whole in China, the HBV-related diseases caused a heavy financial burden which was positively associated with disease severity. Although the intangible costs coincided with a high prevalence of discrimination against CHB patients in Chinese society, our study may serve as future reference for detailed exploration. PMID:26663525

  15. Autologous Peripheral Blood Stem Cell Transplantation Improves Portal Hemodynamics in Patients with Hepatitis B Virus-related Decompensated Cirrhosis

    PubMed Central

    Deng, Qinzhi; Cai, Ting; Zhang, Shun; Hu, Airong; Zhang, Xingfen; Wang, Yinyin; Huang, Jianrong

    2015-01-01

    Background: Chronic hepatitis B virus (HBV) infection may eventually lead to decompensated liver cirrhosis, which is a terminal illness. Objectives: The aim of this study was to investigate the therapeutic efficacy of autologous peripheral blood stem cell (APBSC) transplantation to improve portal vein hemodynamics in patients with HBV-related decompensated cirrhosis. Patients and Methods: This prospective study included 68 hospitalized patients who were diagnosed with HBV-related decompensated cirrhosis. These patients were divided into two groups: the transplantation group included 33 patients, while the control group included 35. Both groups received conventional medical treatment simultaneously, and APBSC transplantation was performed on the patients in the transplantation group. We evaluated the effects of APBSC transplantation on postoperative liver function using the following indices: total bilirubin, serum prothrombin and albumin, spleen size, and portal vein hemodynamics. Postoperatively, all of the patients were followed up at 24, 36, and 48 weeks. Results: The transplantation group had no serious reactions. Compared with the control group, albumin and prothrombin activity in the transplantation group was significantly improved at 24, 36, and 48 weeks after the procedure, and spleen length and portal vein diameter were substantially reduced at 48 weeks. The velocity of peak portal vein blood flow and mean maximum portal vein blood flow were greatly increased in the APBSC transplantation group at 36 and 48 weeks, respectively; however, there was also decreased portal vein diameter, which reduced portal vein pressure in patients with HBV-related decompensated cirrhosis. Conclusions: APBSC transplantation greatly benefits HBV-linked decompensated cirrhosis patients and should be recommended in clinical practice. PMID:26977164

  16. Tie2-Expressing Monocytes Are Associated with Identification and Prognoses of Hepatitis B Virus Related Hepatocellular Carcinoma after Resection

    PubMed Central

    Song, Kang; Sun, Qi-Man; Zhou, Jian

    2015-01-01

    Background Tie2-expressing monocytes (TEMs) are found in various tumors, involved in forming tumor blood vessels and expressing several important proangiogenic factors. The goals of this study were to evaluate the value of TEMs in diagnosing and predicting the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods Flow cytometry was performed to identify and count TEMs in peripheral blood monocytes from HCC patients (n = 84) receiving hepatectomy, HBV cirrhotic patients (n = 21), benign tumors patients (n = 15) and healthy volunteers (n = 23). Angiopoietin-2 (Ang-2) levels in the plasma were determined by enzyme linked immunosorbent assay. The distribution of TEMs in tumor tissue was observed by immunofluorescence staining. Then we determined the vascular area as a percentage of tumor area (vascular area/tumor area) by immunohistochemical staining. Finally the prognostic significance of TEMs and other clinicopathologic factors was evaluated. Results Percentage of TEMs in peripheral blood monocytes significantly increased in HCC patients compared with HBV cirrhotic patients and healthy donors (both P< 0.001). However there was no significance in benign liver tumor (P = 0.482). In addition, the percentage of circulating TEMs was positively correlated with plasma Ang-2 concentration (P<0.001, r2 = 0.294) and vascular area/tumor area (P<0.001, r2 = 0.126). Furthermore the percentage of intratumoral TEMs was significantly higher than that of paratumoral TEMs (P<0.001). Increased circulating TEMs was associated with poor overall survival (P = 0.043) and a shorter time to recurrence (P = 0.041). Multivariate Cox analysis also revealed that the percentage of TEMs in peripheral blood was an independent factor for HCC patients’ prognosis. Conclusions TEMs may promote angiogenesis in HCC regarding the angiopoietin/Tie2 signal pathway. Percentage of TEMs in peripheral blood monocytes may be applied as a biomarker for identifying HBV-related HCC

  17. Functional analysis of miR-181a and Fas involved in hepatitis B virus-related hepatocellular carcinoma pathogenesis

    SciTech Connect

    Zou, Chengcheng; Chen, Juan; Chen, Ke; Wang, Sen; Cao, Yiyi; Zhang, Jinnan; Sheng, Yanrui; Huang, Ailong; Tang, Hua

    2015-02-15

    The hepatitis B virus (HBV) is responsible for most of hepatocellular carcinoma (HCC). However, whether HBV plays an important role during hepatocarcinogenesis through effecting miRNAs remains unknown. Here, we reported that HBV up-regulated microRNA-181a (miR-181a) by enhancing its promoter activity. Simultaneously, we found that miR-181a inhibited apoptosis in vitro and promoted tumor cell growth in vivo. TNF receptor superfamily member 6 (Fas) was further identified as a target of miR-181a. We also found that Fas could reverse the apoptosis-inhibition effect induced by miR-181a. Moreover, HBV could inhibit cell apoptosis by down-regulating Fas expression, which could be reversed by miR-181a inhibitor. Our data demonstrated that HBV suppressed apoptosis of hepatoma cells by up-regulating miR-181a expression and down-regulating Fas expression, which may provide a new understanding of the mechanism in HBV-related HCC pathogenesis. - Highlights: • HBV could up-regulate miR-181a expression by interacting with nt−800 to +240 in its promoter region in HCC cell lines. • HBV could down-regulate Fas expression and suppress apoptosis of hepatoma cells, which could be reversed by miR-181a inhibitor. • Up-regulation of miR-181a promoted proliferation of hepatoma cells and repressed apoptosis, which could be reversed by Fas. • Our study provides a new understanding of the mechanism in HBV-related HCC pathogenesis.

  18. Postoperative hepatitis B virus reactivation in hepatitis B virus-related hepatocellular carcinoma patients with hepatitis B virus DNA levels <500 copies/mL

    PubMed Central

    Xie, Zhi-Bo; Wang, Xiao-Bo; Fu, De-Liang; Zhong, Jian-Hong; Yang, Xia-Wei; Li, Le-Qun

    2016-01-01

    Background Patients with hepatocellular carcinoma have the risk of postoperative hepatitis B virus (HBV) reactivation (PHR). Antiviral therapy was given to patients with detectable HBV DNA levels but not to patients with undetectable HBV DNA levels. Methods In this retrospective study, 258 patients were enrolled (HBV DNA levels <500 copies/mL group, n=159, and HBV DNA levels >500 copies/mL group, n=99). Results A total of 50 patients (19.4%) had PHR. The following significant factors related to PHR were found: without antiviral therapy (hazard ratio [HR] =0.17, 95% confidence interval [CI] 0.031–0.911), hepatitis B e antigen positivity (HR =5.20, 95% CI 1.931–14.007), hepatitis B core antigen S1 positivity (HR =2.54, 95% CI 1.116–5.762), preoperative HBV DNA levels ≥500 copies/mL (HR =1.28, 95% CI 1.085–2.884), hepatic inflow occlusion (HR =3.60, 95% CI 1.402–9.277), moderate liver cirrhosis or more (HR =2.26, 95% CI 1.001–5.121), and blood transfusion (HR =2.89, 95% CI 0.836–10.041). Recurrence-free survival time was significantly shorter in patients with PHR (23.06±2.46 months) than in patients without PHR (29.30±1.27 months). Conclusion Antiviral therapy could efficiently decrease the incidence of PHR. Patients with HBV DNA levels <500 copies/mL still have the risk of PHR. PHR remained as a prognostic risk factor for hepatocellular carcinoma recurrence and recurrence-free survival. PMID:27524913

  19. A Novel H1N2 Influenza Virus Related to the Classical and Human Influenza Viruses from Pigs in Southern China

    PubMed Central

    Song, Yafen; Wu, Xiaowei; Wang, Nianchen; Ouyang, Guowen; Qu, Nannan; Cui, Jin; Qi, Yan; Liao, Ming; Jiao, Peirong

    2016-01-01

    Southern China has long been considered to be an epicenter of pandemic influenza viruses. The special environment, breeding mode, and lifestyle in southern China provides more chances for wild aquatic birds, domestic poultry, pigs, and humans to be in contact. This creates the opportunity for interspecies transmission and generation of new influenza viruses. In this study, we reported a novel reassortant H1N2 influenza virus from pigs in southern China. According to the phylogenetic trees and homology of the nucleotide sequence, the virus was confirmed to be a novel triple-reassortant H1N2 virus containing genes from classical swine (PB2, PB1, HA, NP, and NS genes), triple-reassortant swine (PA and M genes), and recent human (NA gene) lineages. It indicated that the novel reassortment virus among human and swine influenza viruses occurred in pigs in southern China. The isolation of the novel reassortant H1N2 influenza viruses provides further evidence that pigs are “mixing vessels,” and swine influenza virus surveillance in southern China will provide important information about genetic evaluation and antigenic variation of swine influenza virus to formulate the prevention and control measures for the viruses. PMID:27458456

  20. A Novel H1N2 Influenza Virus Related to the Classical and Human Influenza Viruses from Pigs in Southern China.

    PubMed

    Song, Yafen; Wu, Xiaowei; Wang, Nianchen; Ouyang, Guowen; Qu, Nannan; Cui, Jin; Qi, Yan; Liao, Ming; Jiao, Peirong

    2016-01-01

    Southern China has long been considered to be an epicenter of pandemic influenza viruses. The special environment, breeding mode, and lifestyle in southern China provides more chances for wild aquatic birds, domestic poultry, pigs, and humans to be in contact. This creates the opportunity for interspecies transmission and generation of new influenza viruses. In this study, we reported a novel reassortant H1N2 influenza virus from pigs in southern China. According to the phylogenetic trees and homology of the nucleotide sequence, the virus was confirmed to be a novel triple-reassortant H1N2 virus containing genes from classical swine (PB2, PB1, HA, NP, and NS genes), triple-reassortant swine (PA and M genes), and recent human (NA gene) lineages. It indicated that the novel reassortment virus among human and swine influenza viruses occurred in pigs in southern China. The isolation of the novel reassortant H1N2 influenza viruses provides further evidence that pigs are "mixing vessels," and swine influenza virus surveillance in southern China will provide important information about genetic evaluation and antigenic variation of swine influenza virus to formulate the prevention and control measures for the viruses. PMID:27458456

  1. Genetic Diversity of the KIR/HLA System and Susceptibility to Hepatitis C Virus-Related Diseases

    PubMed Central

    De Re, Valli; Caggiari, Laura; De Zorzi, Mariangela; Repetto, Ombretta; Zignego, Anna Linda; Izzo, Francesco; Tornesello, Maria Lina; Buonaguro, Franco Maria; Mangia, Alessandra; Sansonno, Domenico; Racanelli, Vito; De Vita, Salvatore; Pioltelli, Pietro; Vaccher, Emanuela; Beretta, Massimiliano; Mazzaro, Cesare; Libra, Massimo; Gini, Andrea; Zucchetto, Antonella; Cannizzaro, Renato; De Paoli, Paolo

    2015-01-01

    Background The variability in the association of host innate immune response to Hepatitis C virus (HCV) infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma (HCC) or lymphoproliferative disease progression. Methods and Findings We analyzed data from 396 HCV-positive patients with CHC (n = 125), HCC (118), and lymphoproliferative diseases (153), and 501 HCV-negative patients. All were HIV and HBV negative. KIR-SSO was used to determine the KIR typing. KIR2DL5 and KIR2DS4 variants were performed using PCR and GeneScan analysis. HLA/class-I genotyping was performed using PCR-sequence-based typing. The interaction between the KIR gene and ligand HLA molecules was investigated. Differences in frequencies were estimated using Fisher’s exact test, and Cochran-Armitage trend test. The non-random association of KIR alleles was estimated using the linkage disequilibrium test. We found an association of KIR2DS2/KIR2DL2 genes, with the HCV-related lymphoproliferative disorders. Furthermore, individuals with a HLA-Bw6 KIR3DL1+ combination of genes showed higher risk of developing lymphoma than cryoglobulinemia. KIR2DS3 gene was found to be the principal gene associated with chronic HCV infection, while a reduction of HLA-Bw4 + KIR3DS1+ was associated with an increased risk of developing HCC. Conclusions Our data highlight a role of the innate-system in developing HCV-related disorders and specifically KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression, and mainly towards lymphoproliferative disorders. Moreover the determination of KIR3D/HLA combination of genes direct the HCV progression towards a lymphoma rather than an hepatic disease. In this contest IFN-α therapy, a standard therapy for HCV-infection and lymphoproliferative

  2. Elevated core-fucosylated IgG is a new marker for hepatitis B virus-related hepatocellular carcinoma

    PubMed Central

    Yi, Chang-Hong; Weng, Hong-Lei; Zhou, Fei-Guo; Fang, Meng; Ji, Jun; Cheng, Cheng; Wang, Hao; Liebe, Roman; Dooley, Steven; Gao, Chun-Fang

    2015-01-01

    Immunoglubulin G (IgG) and its abnormal glycosylations are associated with carcinogenesis. The present study investigates the relationship between cancer-derived IgG and clinicopathological characteristics in hepatocellular carcinoma (HCC) and assesses the value of serum N-glycosylated IgG in diagnosing and monitoring hepatitis B virus (HBV)-related HCC. Tissue microarray analysis of 90 HCC tissues showed that HCC patients with IgG immunopositivity had higher levels of core-fucosylated α fetoprotein (AFP-L3), larger tumors, and a higher incidence of portal vein tumor thrombus. HCC-derived IgG stimulated the growth of liver cancer cells in vitro. HCC patients presented a significantly increased fraction of Lens culinaris agglutinin binding IgG (core-fucosylated IgG, IgG-L3) among total serum IgG. The clinical diagnostic performance of serum IgG-L3% was evaluated in 3 case-control studies (1 training set and 2 validation cohorts), including 293 patients with HCC, 131 with liver cirrhosis, 132 HBV carriers, and 151 healthy controls. IgG-L3% had better general diagnostic performance than AFP in the training set and validation cohort 1 (accuracy: 81.33–85.11% versus 63.33–78.61%). In validation cohort 2, where we aimed to assess the efficiency of IgG-L3% in patients with AFP-negative HCC, the diagnostic accuracy of IgG-L3% was 72.54–73.60%. Finally, a longitudinal evaluation based on 31 HCC patients demonstrated that IgG-L3% decreased in 24 patients after curative surgery. The remaining 7 patients showed elevated IgG-L3% and post-operative recurrence. HCC patients with higher IgG-L3% had poor survival during a 3-year follow up. We conclude that HCC-derived IgG is correlated with progressive behavior of HCC. Therefore, elevated core-fucosylated IgG is a new diagnostic and prognostic marker in HBV-related HCC. PMID:26587313

  3. Serum from patients with hepatitis E virus-related acute liver failure induces human liver cell apoptosis

    PubMed Central

    WU, FAN; WANG, MINXIN; TIAN, DEYING

    2014-01-01

    The pathogenesis of acute liver failure has not been fully elucidated. The present study investigated the effects of the serum from patients with hepatitis E virus (HEV)-related acute liver failure on human liver cell survival and apoptosis, and evaluated the protective effects of anti-lipopolysaccharide(LPS) antibody recognizing core polysaccharide against acute liver failure serum-induced apoptosis. Serum was collected from patients with HEV-related acute liver failure. The levels of endotoxin (LPS) in the serum were measured using a quantitative tachypleus amebocyte lysate endotoxin detection kit with a chromogenic endpoint. Serum with a mean concentration of LPS was incubated with L02 human liver cells and the rate of apoptosis was detected by flow cytometry. The apoptotic rate was also evaluated in liver cells incubated with antibody and the HEV-related acute liver failure serum. The results indicated that the concentration of LPS in the serum of patients with HEV-related acute liver failure was 0.26±0.02 EU/ml, which was significantly higher than that of the control group (P<0.05). The rate of apoptosis in the human liver cells induced by acute liver failure serum was 5.83±0.42%, which was significantly increased compared with that in the cells treated with the serum of healthy individuals (P<0.05). The apoptotic rate of the cells incubated with antibody and the acute liver failure serum was 5.53±0.51%, which was lower than that of the cells incubated with acute liver failure serum alone (P>0.05). These results indicate that the serum of patients with HEV-related acute liver failure induces the apoptosis of human liver cells. LPS may be directly involved in the apoptosis of human liver cells. Moreover, the presence of the antibody did not significantly reduce the level of apoptosis of liver cells exposed to HEV-related acute liver failure serum. PMID:24348810

  4. Prognostic factors in patients with hepatitis B virus-related hepatocellular carcinoma undergoing nucleoside analog antiviral therapy

    PubMed Central

    NISHIKAWA, HIROKI; NISHIJIMA, NORIHIRO; ARIMOTO, AKIRA; INUZUKA, TADASHI; KITA, RYUICHI; KIMURA, TORU; OSAKI, YUKIO

    2013-01-01

    In the present era of entecavir (ETV) use for chronic hepatitis B (CHB), the prognostic factors in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unclear. The aims of the present study were to investigate the prognostic factors in patients with HBV-related HCC treated with ETV who underwent curative therapy. A total of 74 HBV-related HCC patients treated with ETV who underwent curative therapy were analyzed. Predictive factors associated with overall survival (OS) and recurrence-free survival (RFS) were examined using univariate and multivariate analysis. Our study population included 49 males and 25 females with a median age of 62 years. The median observation period was 3.4 years (range, 0.2–11.5 years). The 1-, 3- and 5-year cumulative OS rates were 100, 89.8 and 89.8%, respectively. The corresponding RFS rates were 82.8, 52.1 and 25.6%, respectively. In this study, 73 patients (98.6%) achieved an HBV DNA level of <400 copies/ml during the follow-up period. No viral breakthrough hepatitis, as defined by 1 log increase from nadir, was observed during ETV therapy. According to multivariate analysis, only hepatitis B e antigen (HBeAg) positivity was significantly associated with OS [hazard ratio (HR), 0.058; 95% confidence interval (CI), 0.005–0.645; P=0.020)], whereas HCC stage (HR, 0.359; 95% CI, 0.150–0.859; P=0.021), HBeAg positivity (HR, 0.202; 95% CI, 0.088–0.463; P<0.001) and γ-glutamyl transpeptidase ≥50 IU/l (HR, 0.340; 95% CI, 0.152–0.760; P=0.009) were significant predictive factors linked to RFS. In conclusion, HBeAg positivity was significantly associated with OS and RFS in HBV-related HCC patients treated with ETV who underwent curative therapy. In such patients, close observation is required, even after curative therapy for HCC. PMID:24179497

  5. Serum anti-Ku86 is a potential biomarker for early detection of hepatitis C virus-related hepatocellular carcinoma

    SciTech Connect

    Nomura, Fumio; Sogawa, Kazuyuki; Noda, Kenta; Seimiya, Masanori; Matsushita, Kazuyuki; Miura, Toshihide; Tomonaga, Takeshi; Yoshitomi, Hideyuki; Imazeki, Fumio; Takizawa, Hirotaka; Mogushi, Kaoru; Miyazaki, Masaru; Yokosuka, Osamu

    2012-05-18

    Highlights: Black-Right-Pointing-Pointer Overexpression of Ku86 in human liver cancer was shown by immunohistochemistry. Black-Right-Pointing-Pointer Serum anti-Ku86 was significantly elevated in early hepatocellular carcinoma. Black-Right-Pointing-Pointer Anti-Ku86 may be more sensitive than the conventional markers for early detection. Black-Right-Pointing-Pointer Serum anti-Ku86 significantly decreased after surgical resection of liver tumors. Black-Right-Pointing-Pointer Elevation of serum anti-Ku86 in other non-liver solid tumors was minimal. -- Abstract: Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is one of the most common cancers worldwide and the third most common cause of cancer-related death. Imaging studies including ultrasound and computed tomography are recommended for early detection of HCC, but they are operator dependent, costly and involve radiation. Therefore, there is a need for simple and sensitive serum markers for the early detection of hepatocellular carcinoma (HCC). In our recent proteomic studies, a number of proteins overexpressed in HCC tissues were identified. We thought if the serum autoantibodies to these overexpressed proteins were detectable in HCC patients. Of these proteins, we focused on Ku86, a nuclear protein involved in multiple biological processes and aimed to assess the diagnostic value of serum anti-Ku86 in the early detection of HCC. Serum samples were obtained prior to treatment from 58 consecutive patients with early or relatively early hepatitis C virus (HCV)-related HCC and 137 patients with HCV-related liver cirrhosis without evidence of HCC. Enzyme immunoassays were used to measure serum levels of autoantibodies. Serum levels of anti-Ku86 antibodies were significantly elevated in HCC patients compared to those in liver cirrhosis patients (0.41 {+-} 0.28 vs. 0.18 {+-} 0.08 Abs at 450 nm, P < 0001). Setting the cut-off level to give 90% specificity, anti-Ku86 was positive in 60.7% of

  6. Diagnostic Evaluation of Des-Gamma-Carboxy Prothrombin versus α-Fetoprotein for Hepatitis B Virus-Related Hepatocellular Carcinoma in China: A Large-Scale, Multicentre Study.

    PubMed

    Ji, Jun; Wang, Hao; Li, Yan; Zheng, Lei; Yin, Yuepeng; Zou, Zhenzhen; Zhou, Feiguo; Zhou, Weiping; Shen, Feng; Gao, Chunfang

    2016-01-01

    An efficient serum marker for hepatocellular carcinoma (HCC) is currently lacking and requires intensive exploration. We aimed to evaluate the performance of des-gamma-carboxy prothrombin (DCP) for identifying hepatitis B virus-related HCC in a large, multicentre study in China. A total of 1034 subjects in three cohorts (A, B, and C) including HCC and various non-HCC controls were enrolled from 4 academic medical centers in China from January 2011 to February 2014. Blind parallel detections were conducted for DCP and AFP. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic efficacies. In cohort A, which comprised 521 subjects, including patients with HCC, liver metastasis, liver cirrhosis (LC), and liver hemangiomas as well as healthy controls (HCs), the accuracy of DCP for distinguishing HCC from various controls was 6.2-9.7% higher than that of AFP. In cohort B, which comprised 447 subjects, including patients with HCC, LC, and chronic hepatitis B as well as HC, the accuracy of DCP was further elevated (12.3-20.67% higher than that of AFP). The superiority of DCP to AFP was more profound in the surveillance of early HCC [AUC 0.837 (95% CI: 0.771-0.903) vs. 0.650 (0.555-0.745)] and AFP-negative HCC [AUC: 0.856 (0.798-0.914)] and in discriminating HCC from LC (accuracy: 92.9% vs.64.71%). Higher DCP levels were associated with worse clinical behaviors and shorter disease-free survival. DCP not only is complementary to AFP in identifying AFP-negative HCC and in excluding AFP-positive non-HCC (liver cirrhosis), but also demonstrates improved performance in HCC surveillance, early diagnosis, treatment response and recurrence monitoring in the HBV-related population. PMID:27070780

  7. Diagnostic Evaluation of Des-Gamma-Carboxy Prothrombin versus α-Fetoprotein for Hepatitis B Virus-Related Hepatocellular Carcinoma in China: A Large-Scale, Multicentre Study

    PubMed Central

    Zheng, Lei; Yin, Yuepeng; Zou, Zhenzhen; Zhou, Feiguo; Zhou, Weiping; Shen, Feng; Gao, Chunfang

    2016-01-01

    An efficient serum marker for hepatocellular carcinoma (HCC) is currently lacking and requires intensive exploration. We aimed to evaluate the performance of des-gamma-carboxy prothrombin (DCP) for identifying hepatitis B virus-related HCC in a large, multicentre study in China. A total of 1034 subjects in three cohorts (A, B, and C) including HCC and various non-HCC controls were enrolled from 4 academic medical centers in China from January 2011 to February 2014. Blind parallel detections were conducted for DCP and AFP. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic efficacies. In cohort A, which comprised 521 subjects, including patients with HCC, liver metastasis, liver cirrhosis (LC), and liver hemangiomas as well as healthy controls (HCs), the accuracy of DCP for distinguishing HCC from various controls was 6.2–9.7% higher than that of AFP. In cohort B, which comprised 447 subjects, including patients with HCC, LC, and chronic hepatitis B as well as HC, the accuracy of DCP was further elevated (12.3–20.67% higher than that of AFP). The superiority of DCP to AFP was more profound in the surveillance of early HCC [AUC 0.837 (95% CI: 0.771–0.903) vs. 0.650 (0.555–0.745)] and AFP-negative HCC [AUC: 0.856 (0.798–0.914)] and in discriminating HCC from LC (accuracy: 92.9% vs.64.71%). Higher DCP levels were associated with worse clinical behaviors and shorter disease-free survival. DCP not only is complementary to AFP in identifying AFP-negative HCC and in excluding AFP-positive non-HCC (liver cirrhosis), but also demonstrates improved performance in HCC surveillance, early diagnosis, treatment response and recurrence monitoring in the HBV-related population. PMID:27070780

  8. Black Beetle Virus: Propagation in Drosophila Line 1 Cells and an Infection-Resistant Subline Carrying Endogenous Black Beetle Virus-Related Particles

    PubMed Central

    Friesen, Paul; Scotti, Paul; Longworth, John; Rueckert, Roland

    1980-01-01

    Black beetle virus (BBV), one of a recently discovered class of viruses with a bipartite genome, multiplied readily in Schneider's line 1 of Drosophila cells. Virus yields, on the order of 100 mg per liter of culture, were unusually high and represented some 20% of the total cell protein within 3 days after infection. A derivative subline of these Drosophila cells was found to be resistant to infection by BBV. These resistant cells were also found to carry small amounts of BBV-related particles, possibly a maturation-defective form of BBV. PMID:16789201

  9. Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for Diagnosis and Treatment of Human Respiratory Syncytial Virus, Parainfluenza Virus, Metapneumovirus, Rhinovirus, and Coronavirus

    PubMed Central

    Hirsch, Hans H.; Martino, Rodrigo; Ward, Katherine N.; Boeckh, Michael; Einsele, Hermann; Ljungman, Per

    2013-01-01

    Community-acquired respiratory virus (CARV) infections have been recognized as a significant cause of morbidity and mortality in patients with leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). Progression to lower respiratory tract infection with clinical and radiological signs of pneumonia and respiratory failure appears to depend on the intrinsic virulence of the specific CARV as well as factors specific to the patient, the underlying disease, and its treatment. To better define the current state of knowledge of CARVs in leukemia and HSCT patients, and to improve CARV diagnosis and management, a working group of the Fourth European Conference on Infections in Leukaemia (ECIL-4) 2011 reviewed the literature on CARVs, graded the available quality of evidence, and made recommendations according to the Infectious Diseases Society of America grading system. Owing to differences in screening, clinical presentation, and therapy for influenza and adenovirus, ECIL-4 recommendations are summarized for CARVs other than influenza and adenovirus. PMID:23024295

  10. Serologic and PCR testing of persons with chronic fatigue syndrome in the United States shows no association with xenotropic or polytropic murine leukemia virus-related viruses

    PubMed Central

    2011-01-01

    In 2009, a newly discovered human retrovirus, xenotropic murine leukemia virus (MuLV)-related virus (XMRV), was reported by Lombardi et al. in 67% of persons from the US with chronic fatigue syndrome (CFS) by PCR detection of gag sequences. Although six subsequent studies have been negative for XMRV, CFS was defined more broadly using only the CDC or Oxford criteria and samples from the US were limited in geographic diversity, both potentially reducing the chances of identifying XMRV positive CFS cases. A seventh study recently found polytropic MuLV sequences, but not XMRV, in a high proportion of persons with CFS. Here we tested blood specimens from 45 CFS cases and 42 persons without CFS from over 20 states in the United States for both XMRV and MuLV. The CFS patients all had a minimum of 6 months of post-exertional malaise and a high degree of disability, the same key symptoms described in the Lombardi et al. study. Using highly sensitive and generic DNA and RNA PCR tests, and a new Western blot assay employing purified whole XMRV as antigen, we found no evidence of XMRV or MuLV in all 45 CFS cases and in the 42 persons without CFS. Our findings, together with previous negative reports, do not suggest an association of XMRV or MuLV in the majority of CFS cases. PMID:21342521

  11. tax and rex Sequences of bovine leukaemia virus from globally diverse isolates: rex amino acid sequence more variable than tax.

    PubMed

    McGirr, K M; Buehring, G C

    2005-02-01

    Bovine leukaemia virus (BLV) is an important agricultural problem with high costs to the dairy industry. Here, we examine the variation of the tax and rex genes of BLV. The tax and rex genes share 420 bases and have overlapping reading frames. The tax gene encodes a protein that functions as a transactivator of the BLV promoter, is required for viral replication, acts on cellular promoters, and is responsible for oncogenesis. The rex facilitates the export of viral mRNAs from the nucleus and regulates transcription. We have sequenced five new isolates of the tax/rex gene. We examined the five new and three previously published tax/rex DNA and predicted amino acid sequences of BLV isolates from cattle in representative regions worldwide. The highest variation among nucleic acid sequences for tax and rex was 7% and 5%, respectively; among predicted amino acid sequences for Tax and Rex, 9% and 11%, respectively. Significantly more nucleotide changes resulted in predicted amino acid changes in the rex gene than in the tax gene (P < or = 0.0006). This variability is higher than previously reported for any region of the viral genome. This research may also have implications for the development of Tax-based vaccines. PMID:15702995

  12. PAI-1 4G-4G and MTHFR 677TT in non-hepatitis C virus/hepatitis B virus-related liver cirrhosis

    PubMed Central

    Pasta, Linda; Pasta, Francesca

    2015-01-01

    AIM: To evaluate the different roles of thrombophilia in patients with and without viral etiology. The thrombophilic genetic factors (THRGFs), PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q and prothrombin 20210A, were studied as risk factors in 1079 patients with liver cirrhosis (LC), enrolled from January 2000 to January 2014. METHODS: All Caucasian LC patients consecutively observed in a fourteen-year period were included; the presence of portal vein thrombosis (PVT) and Budd Chiari syndrome (BCS) was registered. The differences between the proportions of each THRGF with regard to the presence or absence of viral etiology and the frequencies of the THRGF genotypes with those predicted in a population by the Hardy-Weinberg equilibrium were registered. RESULTS: Four hundred and seventeen/one thousand and seventy-six patients (38.6%) showed thrombophilia: 217 PAI-1 4G-4G, 176 MTHFR C677TT, 71 V Leiden factor and 41 prothrombin G20210 A, 84 with more than 1 THRGF; 350 presented with no viral liver cirrhosis (NVLC) and 729 with, called viral liver cirrhosis (VLC), of whom 56 patients were hepatitis C virus + hepatitis B virus. PAI-1 4G-4G, MTHFR C677TT, the presence of at least one TRHGF and the presence of > 1 THRGF, were statistically more frequent in patients with NVLC vs patients with VLC: All χ2 > 3.85 and P < 0.05. Patients with PVT and/or BCS with at least one TRHGF were 189/352 (53.7%). The Hardy-Weinberg of PAI-1 and MTHFR 677 genotypes deviated from that expected from a population in equilibrium in patients with NVLC (respectively χ2 = 39.3; P < 0.000 and χ2 = 27.94; P < 0.05), whereas the equilibrium was respected in VLC. CONCLUSION: MTHFR 677TT was nearly twofold and PAI-1 4G-4G more than threefold more frequently found in NVLC vs patients with VLC; the Hardy-Weinberg equilibrium of these two polymorphisms confirms this data in NVLC. We suggest that PAI-1 4G-4G and MTHFR 677TT could be considered as factors of fibrosis and thrombosis mechanisms, increasing

  13. Comparison of Clinical Manifestations and Outcomes between Hepatitis B Virus- and Hepatitis C Virus-Related Hepatocellular Carcinoma: Analysis of a Nationwide Cohort

    PubMed Central

    Sinn, Dong Hyun; Gwak, Geum-Youn; Cho, Juhee; Paik, Seung Woon; Yoo, Byung Chul

    2014-01-01

    Background We analyzed whether difference exist in the clinical manifestations and outcomes of hepatocellular carcinoma (HCC) according to the two major etiologies of HCC from a nationwide, population-based, random HCC registry. Methods Of the 31,521 new HCC cases registered at the Korea Central Cancer Registry between 2003 and 2005, 4,630 (14.7%) were randomly abstracted, and followed up until December 2011. Of those, 2,785 hepatitis B virus (HBV)-related and 447 hepatitis C virus (HCV)-related HCC patients were compared. Results The mean annual incidence rates of HBV- and HCV-related HCC incidence per 100,000 persons were 20.8 and 4.9, respectively. The annual incidence rate of HBV-related HCC peaked at 50–59 age group (46.5 per 100,000 persons), while the annual incidence rate of HCV-related HCC increased gradually to the ≥70 year age group (13.2 per 100,000 persons). Large tumors (≥5 cm) and portal vein invasion at initial diagnosis were more frequent in HBV-related HCC, while multiple tumors were more frequent in HCV-related HCC. In outcome analysis, HBV-related HCC showed poorer survival than HCV-related HCC [median survival: 1.34 vs. 2.17 years, adjusted hazard ratio (95% confidence interval): 0.88 (0.78–0.98), P = 0.03, adjusted for age, gender, Child-Pugh class, AJCC/mUICC stage, and initial treatment modality]. However, when divided according to the AJCC/mUICC stage, survival difference was observed only for those with AJCC/mUICC stage IV tumor, but not for AJCC/mUICC stage I, II or III tumors. The treatment outcome of each modality (resection, ablation, and transartherial chemoeombolization) was comparable between the two etiologies. Conclusion HBV-related and HCV-related HCC have clear differences in clinical manifestation, requiring different screening strategy according to etiology to optimize HCC surveillance in HBV-endemic area. However, etiology did not affect treatment outcomes and long-term survival within the same stage except for

  14. Differential association of STAT3 and HK-II expression in hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma.

    PubMed

    Li, Man; Wang, Weihua; Jin, Rui; Zhang, Tieying; Li, Na; Han, Qunying; Wei, Ping; Liu, Zhengwen

    2016-09-01

    STAT3 and hexokinase II (HK-II) are involved in viral infection and carcinogenesis of various cancers including hepatocellular carcinoma (HCC). The roles of STAT3 and HK-II in hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related HCC remain largely unclear. This study examined STAT3 and HK-II expression in HBV- and HCV-related HCC, HBV-related liver fibrosis, and normal control liver by using tissue microarray and immunohistochemical method. Results showed that STAT3 expression in HBV-related HCC, HCV-related HCC, and HBV-related liver fibrosis was significantly higher than in control liver (P < 0.001, P = 0.016, and P = 0.005, respectively) and had no significant differences between these three diseased liver tissues. The HK-II expression in HBV-related HCC was significantly higher than that in HCV-related HCC, HBV-related liver fibrosis, and control liver (P = 0.007, P = 0.029, and P = 0.008, respectively) but had no significant elevation in and no significant differences between HCV-related HCC, HBV-related liver fibrosis, and control liver. The HK-II expression was significantly correlated to STAT3 expression in HBV-related HCC (P = 0.022), but no correlation was observed in HCV-related HCC, HBV-related liver fibrosis, and control liver. In conclusion, STAT3 expression is upregulated in both HBV- and HCV-related HCC, while HK-II is predominantly upregulated and correlated to STAT3 in HBV-related HCC. These differential expression and association may suggest the distinct roles of STAT3 and HK-II in hepatocarcinogenesis of HBV and HCV infection. Studies are needed to confirm the relationship of STAT3 and HK-II and to examine the underlying mechanisms. J. Med. Virol. 88:1552-1559, 2016. © 2016 Wiley Periodicals, Inc. PMID:26889748

  15. Association of Hepatitis B Virus Covalently Closed Circular DNA and Human APOBEC3B in Hepatitis B Virus-Related Hepatocellular Carcinoma.

    PubMed

    Luo, Xuan; Huang, Yao; Chen, Yanmeng; Tu, Zeng; Hu, Jieli; Tavis, John E; Huang, Ailong; Hu, Yuan

    2016-01-01

    Chronic Hepatitis B Virus (HBV) infections can progresses to liver cirrhosis and hepatocellular carcinoma (HCC). The HBV covalently-closed circular DNA cccDNA is a key to HBV persistence, and its degradation can be induced by the cellular deaminase APOBEC3. This study aimed to measure the distribution of intrahepatic cccDNA levels and evaluate the association between levels of cccDNA and APOBEC3 in HCC patients. Among 49 HCC patients, 35 matched cancerous and contiguous noncancerous liver tissues had detectable cccDNA, and the median intrahepatic cccDNA in the cancerous tissues (CT) was significantly lower than in the contiguous noncancerous tissues (CNCT) (p = 0.0033). RCA (rolling circle amplification), followed by 3D-PCR identified positive amplification in 27 matched HCC patients. Sequence analysis indicated G to A mutations accumulated to higher levels in CT samples compared to CNCT samples, and the dinucleotide context showed preferred editing in the GpA context. Among 7 APOBEC3 genes, APOBEC3B was the only one up-regulated in cancerous tissues both at the transcriptional and protein levels (p < 0.05). This implies APOBEC3B may contribute to cccDNA editing and subsequent degradation in cancerous tissues. PMID:27310677

  16. Association of Hepatitis B Virus Covalently Closed Circular DNA and Human APOBEC3B in Hepatitis B Virus-Related Hepatocellular Carcinoma

    PubMed Central

    Chen, Yanmeng; Tu, Zeng; Hu, Jieli; Tavis, John E.; Huang, Ailong; Hu, Yuan

    2016-01-01

    Chronic Hepatitis B Virus (HBV) infections can progresses to liver cirrhosis and hepatocellular carcinoma (HCC). The HBV covalently-closed circular DNA cccDNA is a key to HBV persistence, and its degradation can be induced by the cellular deaminase APOBEC3. This study aimed to measure the distribution of intrahepatic cccDNA levels and evaluate the association between levels of cccDNA and APOBEC3 in HCC patients. Among 49 HCC patients, 35 matched cancerous and contiguous noncancerous liver tissues had detectable cccDNA, and the median intrahepatic cccDNA in the cancerous tissues (CT) was significantly lower than in the contiguous noncancerous tissues (CNCT) (p = 0.0033). RCA (rolling circle amplification), followed by 3D-PCR identified positive amplification in 27 matched HCC patients. Sequence analysis indicated G to A mutations accumulated to higher levels in CT samples compared to CNCT samples, and the dinucleotide context showed preferred editing in the GpA context. Among 7 APOBEC3 genes, APOBEC3B was the only one up-regulated in cancerous tissues both at the transcriptional and protein levels (p < 0.05). This implies APOBEC3B may contribute to cccDNA editing and subsequent degradation in cancerous tissues. PMID:27310677

  17. C type murine leukaemia virus particles in tetraparental AKR↔CBA chimaeras

    PubMed Central

    Wills, E. J.; Tuffrey, Maureen; Barnes, R. D.

    1975-01-01

    The incidence of lymphomas in a group of tetraparental AKR ↔ CBA/H-T6 mouse chimaeras derived by early embryo aggregation was less than that of the high leukaemic parental AKR strain. Earlier evidence had shown that the delay in onset and lower incidence of lymphomas in these chimaeras was not due to the absence of AKR cells. We report here that loss of the oncogenic virus carried by the AKR was also unlikely to explain the apparent lymphoma resistance of the chimaeras, since large numbers of C type virus particles were present in their tissues, usually in amounts comparable with the AKR. ImagesFIG. 1FIG. 2

  18. Serum zinc value in patients with hepatitis virus-related chronic liver disease: association with the histological degree of liver fibrosis and with the severity of varices in compensated cirrhosis

    PubMed Central

    Iwata, Kazunari; Enomoto, Hirayuki; Nishiguchi, Shuhei; Aizawa, Nobuhiro; Sakai, Yoshiyuki; Iwata, Yoshinori; Tanaka, Hironori; Ikeda, Naoto; Takashima, Tomoyuki; Saito, Masaki; Imanishi, Hiroyasu; Iijima, Hiroko; Tsuda, Yasuhiro; Higuchi, Kazuhide

    2014-01-01

    The relationships between the serum mineral concentrations and the endoscopic findings of esophageal varices have been poorly investigated. In this study, we investigated hepatitis virus-positive patients who had undergone a liver biopsy (n = 576) and 75 patients with compensated cirrhosis in order to evaluate the association of the zinc value with the severity of liver fibrosis and esophageal varices. The mean zinc values decreased with the progression of fibrosis (METAVIR score; F0–1: 71.3 ± 11.3, F2: 68.9 ± 11.7, F3: 66.3 ± 11.8, F4: 63.9 ± 15.0). In the hepatitis virus-related compensated cirrhosis, the mean zinc value decreased with the severity of varices (patients without varices: 66.3 ± 12.6, patients with low-risk varices: 62.5 ± 13.7, patients with high-risk varices: 55.6 ± 13.0). The zinc value was significantly lower in patients with varices than in those without varices (59.3 ± 13.6 vs 66.3 ± 12.6, p<0.05). The zinc value was also significantly lower in the patients with a high risk of bleeding than in those with a low risk (55.6 ± 13.0 vs 64.6 ± 13.1, p<0.01). These findings suggest that the zinc value is not only an indicator of an abnormal metal metabolism, but is also a simple parameter associated with hepatitis virus-related various conditions, including the degree of liver fibrosis and the severity of esophageal varices in compensated cirrhosis. PMID:25320463

  19. Is the optimal pH for membrane fusion in host cells by avian influenza viruses related to host range and pathogenicity?

    PubMed

    Okamatsu, Masatoshi; Motohashi, Yurie; Hiono, Takahiro; Tamura, Tomokazu; Nagaya, Kazuki; Matsuno, Keita; Sakoda, Yoshihiro; Kida, Hiroshi

    2016-08-01

    Influenza viruses isolated from wild ducks do not replicate in chickens. This fact is not explained solely by the receptor specificity of the hemagglutinin (HA) from such viruses for target host cells. To investigate this restriction in host range, the fusion activities of HA molecules from duck and chicken influenza viruses were examined. Influenza viruses A/duck/Mongolia/54/2001 (H5N2) (Dk/MNG) and A/chicken/Ibaraki/1/2005 (H5N2) (Ck/IBR), which replicate only in their primary hosts, were used. The optimal pH for membrane fusion of Ck/IBR was 5.9, higher than that of Dk/MNG at 4.9. To assess the relationship between the optimal pH for fusion and the host range of avian influenza viruses, the optimal pH for fusion of 55 influenza virus strains isolated from ducks and chickens was examined. No correlation was found between the host range and optimal pH for membrane fusion by the viruses, and this finding applied also to the H5N1 highly pathogenic avian influenza viruses. The optimal pH for membrane fusion for avian influenza viruses was shown to not necessarily be correlated with their host range or pathogenicity in ducks and chickens. PMID:27231009

  20. Eosinophilic leukaemia in a cat.

    PubMed

    Sharifi, Hassan; Nassiri, Seyed Mahdi; Esmaelli, Hossein; Khoshnegah, Javad

    2007-12-01

    A 14-year-old female domestic shorthair cat was presented to Tehran University Veterinary Teaching Hospital for a persistent fever, anorexia, intermittent vomiting, weight loss and weakness. The main clinical signs were pale mucous membranes, dehydration and splenomegaly. The complete blood count and serum biochemistry tests revealed non-regenerative anaemia, thrombocytopenia and increased alkaline phosphatase (ALP) activity. An enzyme-linked immunosorbent assay (ELISA) test for feline leukaemia virus was negative. Blood film and bone marrow examination revealed a large number of immature eosinophils with variable sizes and numbers of faintly azurophilic granules. Cytochemical staining of blood film demonstrated 70% positive cells for ALP activity. Four percent CD34 positive cells were detected by flow cytometry. As eosinophilic leukaemia is difficult to identify by light microscopy, well-defined diagnostic criteria and the use of flow cytometry and cytochemical staining can improve the ability to correctly diagnose this type of leukaemia in cats. PMID:17669677

  1. Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study

    PubMed Central

    van der Linden, Vanessa; Brainer-Lima, Alessandra Mertens; Coeli, Regina Ramos; Rocha, Maria Angela; Sobral da Silva, Paula; Durce Costa Gomes de Carvalho, Maria; van der Linden, Ana; Cesario de Holanda, Arthur; Valenca, Marcelo Moraes

    2016-01-01

    Objective To report radiological findings observed in computed tomography (CT) and magnetic resonance imaging (MRI) scans of the first cases of congenital infection and microcephaly presumably associated with the Zika virus in the current Brazilian epidemic. Design Retrospective study with a case series. Setting Association for Assistance of Disabled Children (AACD), Pernambuco state, Brazil. Participants 23 children with a diagnosis of congenital infection presumably associated with the Zika virus during the Brazilian microcephaly epidemic. Main outcome measures Types of abnormalities and the radiological pattern of lesions identified on CT and MRI brain scans. Results Six of the 23 children tested positive for IgM antibodies to Zika virus in cerebrospinal fluid. The other 17 children met the protocol criteria for congenital infection presumably associated with the Zika virus, even without being tested for IgM antibodies to the virus—the test was not yet available on a routine basis. Of the 23 children, 15 underwent CT, seven underwent both CT and MRI, and one underwent MRI. Of the 22 children who underwent CT, all had calcifications in the junction between cortical and subcortical white matter, 21 (95%) had malformations of cortical development, 20 (91%) had a decreased brain volume, 19 (86%) had ventriculomegaly, and 11 (50%) had hypoplasia of the cerebellum or brainstem. Of the eight children who underwent MRI, all had calcifications in the junction between cortical and subcortical white matter, malformations of cortical development occurring predominantly in the frontal lobes, and ventriculomegaly. Seven of the eight (88%) children had enlarged cisterna magna, seven (88%) delayed myelination, and six each (75%) a moderate to severe decrease in brain volume, simplified gyral pattern, and abnormalities of the corpus callosum (38% hypogenesis and 38% hypoplasia). Malformations were symmetrical in 75% of the cases. Conclusion Severe cerebral damage was

  2. Respiratory Syncytial Virus Related Readmission in Preterm Infants Less than 34 weeks' Gestation Following Discharge from a Neonatal Intensive Care Unit in Korea

    PubMed Central

    Lee, Jang Hoon; Kim, Chun Soo; Chang, Yun Sil

    2015-01-01

    This study was done to evaluate respiratory syncytial virus (RSV) related readmission (RRR) and risk factors of RRR in preterm infants < 34 weeks gestational age (GA) within 1 yr following discharge from the neonatal intensive care unit (NICU). Infants (n = 1,140) who were born and admitted to the NICUs of 46 hospitals in Korea from April to September 2012, and followed up for > 1 yr after discharge from the NICU, were enrolled. The average GA and birth weight of the infants was 30+5 ± 2+5 weeks and 1,502 ± 474 g, respectively. The RRR rate of enrolled infants was 8.4% (96/1,140), and RSV accounted for 58.2% of respiratory readmissions of infants who had laboratory tests confirming etiological viruses. Living with elder siblings (odd ratio [OR], 2.68; 95% confidence interval [CI], 1.68-4.28; P < 0.001), and bronchopulmonary dysplasia (BPD) (OR, 2.95; 95% CI, 1.44-6.04; P = 0.003, BPD vs. none) increased the risk of RRR. Palivizumab prophylaxis (OR, 0.06; 95% CI, 0.03-0.13; P < 0.001) decreased the risk of RRR. The risk of RRR of infants of 32-33 weeks' gestation was lower than that of infants < 26 weeks' gestation (OR, 0.11; 95% CI, 0.02-0.53; P = 0.006). This was a nationwide study that evaluated the rate and associated risk factors of RRR in Korean preterm infants. Preterm infants with BPD or living with siblings should be supervised, and administration of palivizumab to prevent RRR should be considered. PMID:26566351

  3. Negative regulatory element associated with potentially functional promoter and enhancer elements in the long terminal repeats of endogenous murine leukemia virus-related proviral sequences.

    PubMed Central

    Ch'ang, L Y; Yang, W K; Myer, F E; Yang, D M

    1989-01-01

    Three series of recombinant DNA clones were constructed, with the bacterial chloramphenicol acetyltransferase (CAT) gene as a quantitative indicator, to examine the activities of promoter and enhancer sequence elements in the 5' long terminal repeat (LTR) of murine leukemia virus (MuLV)-related proviral sequences isolated from the mouse genome. Transient CAT expression was determined in mouse NIH 3T3, human HT1080, and mink CCL64 cultured cells transfected with the LTR-CAT constructs. The 700-base-pair (bp) LTRs of three polytropic MuLV-related proviral clones and the 750-bp LTRs of four modified polytropic proviral clones, in complete structures either with or without the adjacent downstream sequences, all showed very little or negligible activities for CAT expression, while ecotropic MuLV LTRs were highly active. The MuLV-related LTRs were divided into three portions and examined separately. The 3' portion of the MuLV-related LTRs that contains the CCAAC and TATAA boxes was found to be a functional promoter, being about one-half to one-third as active as the corresponding portion of ecotropic MuLV LTRs. A MboI-Bg/II fragment, representing the distinct 190- to 200-bp inserted segment in the middle, was found to be a potential enhancer, especially when examined in combination with the simian virus 40 promoter in CCL64 cells. A PstI-MboI fragment of the 5' portion, which contains the protein-binding motifs of the enhancer segment as well as the upstream LTR sequences, showed moderate enhancer activities in CCL6 cells but was virtually inactive in NIH 3T3 cells and HT1080 cells; addition of this fragment to the ecotropic LTR-CAT constructs depressed CAT expression. Further analyses using chimeric LTR constructs located the presence of a strong negative regulatory element within the region containing the 5' portion of the enhancer and the immediate upstream sequences in the MuLV-related LTRs. Images PMID:2542587

  4. Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues

    PubMed Central

    He, Tianyu; Brocca-Cofano, Egidio; Gillespie, Delbert G.; Xu, Cuiling; Stock, Jennifer L.; Ma, Dongzhu; Policicchio, Benjamin B.; Raehtz, Kevin D.; Rinaldo, Charles R.; Apetrei, Cristian; Jackson, Edwin K.; Macatangay, Bernard J. C.

    2015-01-01

    ABSTRACT The role of the adenosine (ADO) pathway in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/SIV) infection remains unclear. We compared SIVsab-induced changes of markers related to ADO production (CD39 and CD73) and breakdown (CD26 and adenosine deaminase) on T cells from blood, lymph nodes, and intestine collected from pigtailed macaques (PTMs) and African green monkeys (AGMs) that experience different SIVsab infection outcomes. We also measured ADO and inosine (INO) levels in tissues by mass spectrometry. Finally, we assessed the suppressive effect of ADO on proinflammatory cytokine production after T cell receptor stimulation. The baseline level of both CD39 and CD73 coexpression on regulatory T cells and ADO levels were higher in AGMs than in PTMs. Conversely, high INO levels associated with dramatic increases in CD26 expression and adenosine deaminase activity were observed in PTMs during chronic SIV infection. Immune activation and inflammation markers in the gut and periphery inversely correlated with ADO and directly correlated with INO. Ex vivo administration of ADO significantly suppressed proinflammatory cytokine production by T cells in both species. In conclusion, the opposite dynamics of ADO pathway-related markers and contrasting ADO/INO levels in species with divergent proinflammatory responses to SIV infection support a key role of ADO in controlling immune activation/inflammation in nonprogressive SIV infections. Changes in ADO levels predominately occurred in the gut, suggesting that the ADO pathway may be involved in sparing natural hosts of SIVs from developing SIV-related gut dysfunction. Focusing studies of the ADO pathway on mucosal sites of viral replication is warranted. IMPORTANCE The mechanisms responsible for the severe gut dysfunction characteristic of progressive HIV and SIV infection in humans and macaques are not completely elucidated. We report that ADO may play a key role in controlling immune

  5. Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study

    PubMed Central

    Bellentani, S; Pozzato, G; Saccoccio, G; Crovatto, M; Croce, L; Mazzoran, L; Masutti, F; Cristianini, G; Tiribelli, C

    1999-01-01

    BACKGROUND—The severity, clinical course, and risk of hepatitis C virus (HCV) related chronic liver disease are still rather poorly defined.
AIMS—To investigate the prevalence, risk factors, and severity of HCV related liver disease in the general population, and investigate whether infection with a specific genotype is associated with an increased risk of cirrhosis or hepatocellular carcinoma.
METHODS—HCV RNA determination by polymerase chain reaction (PCR) and HCV genotyping were performed in all anti-HCV positive subjects belonging to the Dionysos study (6917 subjects). Diagnosis of cirrhosis and hepatocellular carcinoma was established by liver biopsy in all cases. All the data were analysed by univariate and multivariate statistics in all the cohort. To investigate the natural history of HCV infection, anti-HCV positive subjects were followed up every six months for three years with liver function tests and ultrasonograms.
RESULTS—The overall prevalence of HCV RNA positivity was 2.3%. Positivity increased progressively with age, and was higher in women (ratio of men to women = 0.7). Genotypes 1b and 2a were the most frequent (42 and 24% of HCV RNA positive patients), with a prevalence of 1 and 0.6% respectively. Intravenous drug use, blood transfusions received before 1990, history of previous hepatitis among the cohabiting, and history of animal (mainly dogs) bites were significantly (p<0.05) associated with HCV infection, independently of age and sex. Multivariate analysis showed that, independently of age, sex, and alcohol intake, genotype 1b infection, with or without coinfection with other genotypes, is the major risk factor associated with the presence of cirrhosis and/or hepatocellular carcinoma. During the three years of follow up, 57 (35%) of the HCV RNA positive subjects had consistently normal alanine aminotransferase and γ-glutamyltransferase values. Two of the 22 HCV RNA positive cirrhotic patients, all drinking more than 90

  6. Successful treatment of Epstein-Barr virus-related post-transplant lymphoproliferative disease with central nervous system involvement following allogeneic haematopoietic stem cell transplantation - a case study.

    PubMed

    Wróblewska, Małgorzata; Gil, Lidia A; Komarnicki, Mieczysław A

    2015-01-01

    Post-transplant lymphoproliferative disease (PTLD) is a rare but severe form of Epstein-Barr virus (EBV)-driven complication that develops in patients after haematopoietic stem cell transplantation. In rare cases it manifests as primary central nervous system (CNS) involvement, which is thought to be the most unfavourable localisation with respect to outcome. Disease confined to the CNS is much more challenging than systemic PTLD, and one of the contributing factors is the limited drug penetration across the blood-brain barrier. We describe the case of a 29-year-old woman who was successfully treated for PTLD with CNS involvement. The patient was diagnosed with T-cell lymphoblastic lymphoma and underwent the procedure of haematopoietic stem cell transplantation from an unrelated donor. Two months after transplantation she manifested severe headache and progressive mental deterioration accompanied by enlargement of the lymph nodes. Magnetic resonance imaging (MRI) scan revealed segmental, asymmetrical thickening of the meninges. Based on the clinical picture and the laboratory findings diagnosis of PTLD was made. The patient was effectively treated with reduction of immunosuppressive therapy and intravenous rituximab. Initially started intrathecal chemotherapy was stopped due to iatrogenic complications. We conclude that in this case the involvement of meninges in the course of the lymphoproliferative process might have compromised the blood-brain barrier. This factor probably improved rituximab's penetration to CNS, contributing to our patient's recovery. PMID:26155195

  7. Combined detection of liver stiffness and C-reactive protein in patients with hepatitis B virus-related liver cirrhosis, with and without hepatocellular carcinoma

    PubMed Central

    LIU, XIAO-YAN; MA, LI-NA; YAN, TING-TING; LU, ZHEN-HUI; TANG, YUAN-YUAN; LUO, XIA; DING, XIANG-CHUN

    2016-01-01

    The aim of the present study was to investigate the usefulness of combined detection of liver stiffness (LS) and serum C-reactive protein (CRP) level in patients with hepatitis B virus (HBV)-related liver cirrhosis (LC). A total of 156 cases of previously untreated patients with HBV-related LC were classified into the LC group [LC without hepatocellular carcinoma (HCC)] and the HCC group (LC with HCC). Comparative analyses of LS and serum CRP level were conducted between these two groups. LS values and serum CRP levels were found to be significantly higher in the HCC group compared with those in the LC group (P<0.01). The LS values and serum CRP levels were not significantly different between α-fetoprotein (AFP)-positive and -negative patients. A high LS value was a high-risk factor for HCC in patients with chronic hepatitis B. The CRP-positive rate was significantly higher in the HCC group compared with that in LC group in a subset of patients with high LS values (P<0.01). In conclusion, the combined detection of LS and serum CRP may complement the measurement of AFP in the diagnosis of HBV-related HCC, improve the identification of patients with AFP-negative HCC and help distinguish HCC from LC. PMID:27073669

  8. Recombinase polymerase amplification combined with a lateral flow dipstick for discriminating between infectious Penaeus stylirostris densovirus and virus-related sequences in shrimp genome.

    PubMed

    Jaroenram, Wansadaj; Owens, Leigh

    2014-11-01

    Penaeus stylirostris densovirus (PstDV) is an important shrimp pathogen that causes mortality in P. stylirostris and runt deformity syndrome (RDS) in Penaeus vannamei and Penaeus monodon. Recently, PstDV-related sequences were found in the genome of P. monodon and P. vannamei. This led to false positive results by PCR-based detection system. Here, a more efficient detection platform based on recombinase polymerase amplification (RPA) and a lateral flow dipstick (LFD) was developed for detecting PstDV. Under the optimal conditions, 30 min at 37°C for RPA followed by 5 min at room temperature for LFD, the protocol was 10 times more sensitive than the Saksmerphrome et al's interim 3-tube nested PCR and showed no cross-reaction with other shrimp viruses. It also reduced false positive results arising from viral inserts to ∼5% compared to 76-78% by the IQ2000™ nested PCR kit and the 309F/R PCR protocol currently recommended by World Organization for Animal Health (OIE) for PstDV detection. Together with simplicity and portability, the protocol serves as an alternative tool to PCR for primarily screening PstDV, which is suitable for both laboratory and field application. PMID:25152528

  9. Identification of novel subgroup A variants with enhanced receptor binding and replicative capacity in primary isolates of anaemogenic strains of feline leukaemia virus

    PubMed Central

    2012-01-01

    Background The development of anaemia in feline leukaemia virus (FeLV)-infected cats is associated with the emergence of a novel viral subgroup, FeLV-C. FeLV-C arises from the subgroup that is transmitted, FeLV-A, through alterations in the amino acid sequence of the receptor binding domain (RBD) of the envelope glycoprotein that result in a shift in the receptor usage and the cell tropism of the virus. The factors that influence the transition from subgroup A to subgroup C remain unclear, one possibility is that a selective pressure in the host drives the acquisition of mutations in the RBD, creating A/C intermediates with enhanced abilities to interact with the FeLV-C receptor, FLVCR. In order to understand further the emergence of FeLV-C in the infected cat, we examined primary isolates of FeLV-C for evidence of FeLV-A variants that bore mutations consistent with a gradual evolution from FeLV-A to FeLV-C. Results Within each isolate of FeLV-C, we identified variants that were ostensibly subgroup A by nucleic acid sequence comparisons, but which bore mutations in the RBD. One such mutation, N91D, was present in multiple isolates and when engineered into a molecular clone of the prototypic FeLV-A (Glasgow-1), enhanced replication was noted in feline cells. Expression of the N91D Env on murine leukaemia virus (MLV) pseudotypes enhanced viral entry mediated by the FeLV-A receptor THTR1 while soluble FeLV-A Env bearing the N91D mutation bound more efficiently to mouse or guinea pig cells bearing the FeLV-A and -C receptors. Long-term in vitro culture of variants bearing the N91D substitution in the presence of anti-FeLV gp70 antibodies did not result in the emergence of FeLV-C variants, suggesting that additional selective pressures in the infected cat may drive the subsequent evolution from subgroup A to subgroup C. Conclusions Our data support a model in which variants of FeLV-A, bearing subtle differences in the RBD of Env, may be predisposed towards enhanced

  10. Sociodemographic and Behavioral Correlates of Anogenital Warts and Human Papilloma Virus-Related Knowledge Among Men who have Sex with Men and Trans Women in Lima, Peru

    PubMed Central

    Brown, Brandon; Monsour, Emmi; Klausner, Jeffrey D.; Galea, Jerome T.

    2015-01-01

    Background Human papilloma virus (HPV) is the most common sexually transmitted infection (STI) globally, with a high burden of anogenital warts (AGW) among men who have sex with men (MSM) and transwomen (TW). Methods Six-hundred HIV negative MSM and TW (300 with AGW, 300 without) were recruited for a prospective cohort study to examine HPV outcomes and HPV vaccine knowledge. Participants completed a self-administered online questionnaire. Logistic regression was used to assess the association between sociodemographic and behavioral characteristics with HPV vaccine knowledge. Results The average participant age was 25.5 years. Most (67%) were single and 41.2% self-reported STI symptoms. The average age of first anal intercourse was 17 years, with self-reported sexual role as active (36%), passive (36%), and both (27%). Three quarters (77%) of participants reported engaging in condomless anal or oral sex up to six months prior to the study. Less than half (48%) of participants had heard of HPV. Participants with AGW were more likely to report that condoms helped prevent HPV (p=0.01) and that the absence of genital warts does not mean the absence of HPV (p<0.01). Conclusion Study participants had low levels of HPV knowledge but likely high HPV exposure due to condomless anal sex. The HPV knowledge gap may be explained in part by the stigma of sex work, underreporting of STIs, the high cost of the HPV vaccine in Peru, and misinformation about HPV vaccine. More work is needed to educate MSM and TW on HPV and the HPV vaccine. PMID:25763672

  11. Role of LncRNA-activated by transforming growth factor beta in the progression of hepatitis C virus-related liver fibrosis.

    PubMed

    Fu, Na; Niu, Xuemin; Wang, Yang; Du, Huijuan; Wang, Baoyu; Du, Jinghua; Li, Ya; Wang, Rongqi; Zhang, Yuguo; Zhao, Suxian; Sun, Dianxing; Qiao, Liang; Nan, Yuemin

    2016-08-01

    Long non-coding RNA (LncRNA)-activated by transforming growth factor-beta (LncRNA-ATB) is a key regulator of transforming growth factor-beta (TGF-β) signaling pathway, and is positively correlated with the development of liver cirrhosis and vascular invasion of hepatocellular carcinoma (HCC). However, the role of LncRNA-ATB in hepatitis C virus (HCV)-related liver fibrosis remains largely unknown. In the present study, we confirmed a high expression level of LncRNA-ATB in the liver tissues and plasma samples of patients with HCV-related hepatic fibrosis, and the plasma level of LncRNA-ATB was significantly correlated with liver fibrosis stages. Furthermore, increased expression level of LncRNA-ATB was also present in activated hepatic stellate cells (HSCs), and knockdown of LncRNA-ATB inhibited the expression of alpha-smooth muscle actin (α-SMA) and alpha-1 type I collagen (Col1A1). LncRNA-ATB was found to share the common miRNA responsive element of miR-425-5p with TGF-β type II receptor (TGF-βRII) and SMAD2. Ectopic expression of LncRNA-ATB in HSCs could upregulate the protein expression of TGF-βRII and SMAD2 by inhibiting the endogenous miR-425-5p. Moreover, overexpression of miR-425-5p could partly abrogate the expression of TGF-βRII and SMAD2 induced by LncRNA-ATB. Hence, we conclude that LncRNA-ATB promotes HCV-induced liver fibrogenesis by activating HSCs and increasing collagen I production through competitively binding to miR-425-5p. LncRNA-ATB may be a novel diagnostic biomarker and a potential therapeutic target for HCV-related hepatic fibrosis. PMID:27585228

  12. The value of serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein as a predictive marker for hepatitis C virus-related complications after systemic chemotherapy.

    PubMed

    Totani, Haruhito; Kusumoto, Shigeru; Tanaka, Yasuhito; Suzuki, Nana; Hagiwara, Shinya; Kinoshita, Shiori; Iio, Etsuko; Ito, Asahi; Ri, Masaki; Ishida, Takashi; Komatsu, Hirokazu; Iida, Shinsuke

    2016-09-01

    Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA(+)-M2BP) was developed recently as a predictive marker of progression to liver fibrosis and hepatocellular carcinoma (HCC) in patients seropositive for hepatitis C virus (HCV). We retrospectively analyzed 16 HCV-seropositive patients who received systemic chemotherapy for hematologic malignancies to evaluate the usefulness of WFA(+)-M2BP for predicting HCV-related complications. These were defined as the onset of significant liver damage (LD) with increased HCV RNA levels, leading to interrupted or discontinued chemotherapy or the occurrence of HCC after chemotherapy. Baseline WFA(+)-M2BP levels were determined using preserved serum samples. The median level of WFA(+)-M2BP was 1.59 [cutoff index (C.O.I.) value range 0.38-6.66]. With a median follow-up of 623 days (range 120-2404), LD and HCC were observed in three and two patients, respectively. Detectable HCV RNA and WFA(+)-M2BP ≥2.0 C.O.I. at baseline were identified as risk factors for these HCV-related complications (P = 0.034 and P = 0.005, respectively). The sensitivity, specificity, and positive and negative predictive values of the WFA(+)-M2BP level (cutoff point: 2.0 C.O.I.) for the occurrence of HCV-related complications were 100.0, 81.8, 71.4, and 100.0 %, respectively. WFA(+)-M2BP may be a useful marker for the prediction of HCV-related complications in HCV-seropositive patients following systemic chemotherapy. PMID:27255233

  13. Gastric adenocarcinoma microRNA profiles in fixed tissue and in plasma reveal cancer-associated and Epstein-Barr virus-related expression patterns.

    PubMed

    Treece, Amanda L; Duncan, Daniel L; Tang, Weihua; Elmore, Sandra; Morgan, Douglas R; Dominguez, Ricardo L; Speck, Olga; Meyers, Michael O; Gulley, Margaret L

    2016-06-01

    MicroRNA expression in formalin-fixed paraffin-embedded tissue (FFPE) or plasma may add value for cancer management. The GastroGenus miR Panel was developed to measure 55 cancer-specific human microRNAs, Epstein-Barr virus (EBV)-encoded microRNAs, and controls. This Q-rtPCR panel was applied to 100 FFPEs enriched for adenocarcinoma or adjacent non-malignant mucosa, and to plasma of 31 patients. In FFPE, microRNAs upregulated in malignant versus adjacent benign gastric mucosa were hsa-miR-21, -155, -196a, -196b, -185, and -let-7i. Hsa-miR-18a, 34a, 187, -200a, -423-3p, -484, and -744 were downregulated. Plasma of cancer versus non-cancer controls had upregulated hsa-miR-23a, -103, and -221 and downregulated hsa-miR-378, -346, -486-5p, -200b, -196a, -141, and -484. EBV-infected versus uninfected cancers expressed multiple EBV-encoded microRNAs, and concomitant dysregulation of four human microRNAs suggests that viral infection may alter cellular biochemical pathways. Human microRNAs were dysregulated between malignant and benign gastric mucosa and between plasma of cancer patients and non-cancer controls. Strong association of EBV microRNA expression with known EBV status underscores the ability of microRNA technology to reflect disease biology. Expression of viral microRNAs in concert with unique human microRNAs provides novel insights into viral oncogenesis and reinforces the potential for microRNA profiles to aid in classifying gastric cancer subtypes. Pilot studies of plasma suggest the potential for a noninvasive addition to cancer diagnostics. PMID:26950485

  14. Disparities in the Magnitude of Human Immunodeficiency Virus-related Opportunistic Infections Between High and Low/Middle-income Countries: Is Highly Active Antiretroviral Therapy Changing the Trend?

    PubMed

    Iroezindu, M O

    2016-01-01

    Opportunistic infections (OIs) cause significant morbidity/mortality in human immunodeficiency virus (HIV)-infected individuals globally. Disparities between high-income countries (HICs) and low/middle-income countries (LMICs) in the magnitude of HIV-related OIs in pre-highly active antiretroviral therapy (HAART) populations was reviewed, and HAART-induced decline in OIs was further compared between the two settings. Studies published in English from onset of HIV epidemic up to December 2013 were searched in PubMed, Google, Google Scholar, and African Journal online. An article was included if (a) the study was conducted in HIC or LMIC, (b) the age of the participants was ≥12 years, (c) the HAART status of the participants was stated, and (d) various types of OIs were investigated. In predominantly pre-HAART populations, the incidence and prevalence of overall HIV-related OIs in HIC ranged from 5.5 to 50.0 per 100 person-years (PY) and 27.4-56.7%, respectively. In LMIC, the respective overall incidence and prevalence of OIs were 12.2-93.9 per 100 PY and 32.0-77.7%. Pneumocystis jirovecii pneumonia, candidiasis, Cytomegalovirus disease, Mycobacterium avium complex disease, and Kaposi's sarcoma were the most frequent OIs in HICs while tuberculosis, candidiasis, chronic diarrhea, and cryptococcosis were predominant in LMICs. The introduction of HAART led to substantial reduction in the incidence of OIs with more impressive percentage decline in HICs (43-97%) compared to 30-79% in LMICs. Disparities in the magnitude of HIV-related OIs between HICs and LMICs are evident both in the pre-HAART and post-HAART era. Efforts to optimize HAART-induced decline in HIV-related OIs should become a global health priority irrespective of prevailing socioeconomic circumstances. PMID:27144071

  15. Inflammatory pseudotumor of the liver occurring during the course of hepatitis C virus-related hepatocellular carcinoma treatment: A case report

    PubMed Central

    Honmyo, Naruhiko; Kobayashi, Tsuyoshi; Tashiro, Hirotaka; Ishiyama, Kohei; Ide, Kentaro; Tahara, Hiroyuki; Ohira, Masahiro; Kuroda, Shintaro; Arihiro, Koji; Ohdan, Hideki

    2016-01-01

    Introduction Inflammatory pseudotumor (IPT) of the liver is a rare and benign disease that has a good prognosis. It is often difficult to distinguish IPT from hepatic malignancies, such as hepatocellular carcinoma (HCC), because specific clinical symptoms are absent and the diseases’ radiological findings can be similar. IPT is particularly difficult to distinguish from HCC in livers with hepatitis C virus (HCV)-related cirrhosis. We report a case of IPT of the liver that mimicked HCV-related HCC recurrence. Presentation of case A 78-year-old asymptomatic Japanese man who had undergone hepatectomy for HCV-related HCCs (moderately differentiated type) in segments 7 and 5 four and a half years previously was referred to our hospital for treatment of a 30-mm enhanced tumor in segment 5 (a typical HCC pattern). The tumor was identified via abdominal dynamic computed tomography (CT) and CT with hepatic arteriography and arterial portography. Thereafter, liver segmentectomy 5 was performed, and the histopathological diagnosis was a 10-mm IPT of the liver. After 1.5 years, magnetic resonance imaging revealed two new enhanced lesions in segment 8, which showed the typical pattern of HCC. Because these lesions grew in size for 3 months, liver segmentectomy 8 was performed for HCC recurrence. Histopathological examination showed that both lesions were HCCs. Conclusion HCV-related HCC has a high rate of multicentric recurrence. Our experience suggests that, when a hepatic lesion is suspected to be HCC, surgical resection should be considered for curative treatment and to rule out malignancy, even if the lesion may be an IPT. PMID:26826935

  16. miR-29c targets TNFAIP3, inhibits cell proliferation and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma

    SciTech Connect

    Wang, Chun-Mei; Wang, Yan; Fan, Chun-Guang; Xu, Fei-Fei; Sun, Wen-Sheng; Liu, Yu-Gang; Jia, Ji-Hui

    2011-08-05

    Highlights: {yields} miR-29c was significantly downregulated in HBV-related HCC. {yields} TNFAIP3 was found to be inversely correlated with miR-29c levels and identified as a target of miR-29c. {yields} Overexpression of miR-29c suppressed TNFAIP3. {yields} miR-29c inhibited HBV DNA replication, cell proliferation and induced apoptosis. -- Abstract: Recent studies have revealed that microRNA-29c (miR-29c) is involved in a variety of biological processes including carcinogenesis. Here, we report that miR-29c was significantly downregulated in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) cell lines as well as in clinical tissues compared with their corresponding controls. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3), a key regulator in inflammation and immunity, was found to be inversely correlated with miR-29c levels and was identified as a target of miR-29c. Overexpression of miR-29c in HepG2.2.15 cells effectively suppressed TNFAIP3 expression and HBV DNA replication as well as inhibited cell proliferation and induced apoptosis. We conclude that miR-29c may play an important role as a tumor suppressive microRNA in the development and progression of HBV-related HCC by targeting TNFAIP3. Thus miR-29c and TNFAIP3 represent key diagnostic markers and potential therapeutic targets for the prevention and treatment of HBV infection.

  17. Clinical implication of the preoperative GSA index in ⁹⁹mTc-GSA scintigraphy in hepatitis C virus-related hepatocellular carcinoma.

    PubMed

    Nishikawa, Hiroki; Osaki, Yukio; Komekado, Hideyuki; Sakamoto, Azusa; Saito, Sumio; Nishijima, Norihiro; Nasu, Akihiro; Arimoto, Akira; Kita, Ryuichi; Kimura, Toru

    2015-03-01

    We aimed to examine the relationship between the preoperative GSA index [uptake ratio of the liver to the liver plus heart at 15 min (LHL15) to uptake ratio of the heart at 15 min to that at 3 min (HH15) ratio] calculated from 99mTc‑labeled diethylene triamine pentaacetate-galactosyl human serum albumin (99mTc-GSA) scintigraphy and background liver fibrosis and to investigate whether the GSA index can be a useful predictor in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) patients treated with surgical resection (SR). A total of 213 HCV-related HCC patients were analyzed. Receiver operating characteristic (ROC) curve analysis was performed for calculating the area under the ROC (AUROC) for nine noninvasive parameters including GSA index, indocyanine green retention at 15 min, aspartate aminotransferase (AST) to platelet ratio index, FIB-4 index, AST to alanine aminotransferase ratio, serum albumin, total bilirubin, platelet count and prothrombin time for cirrhosis. We also examined predictive factors associated with overall survival (OS) and recurrence-free survival (RFS) after SR in univariate and multivariate analyses. There were 153 males and 60 females with the mean age of 69.9 years. The median observation periods were 2.8 years. The mean maximum tumor size was 4.1 cm. HH15 ranged from 0.452 to 0.897. LHL15 ranged from 0.669 to 0.982. The mean value of the GSA index was 1.41. Among the nine parameters, the GSA index yielded the highest AUROC for cirrhosis with a level of 0.786 at an optimal cut-off value of 1.37 (sensitivity, 65.9%; specificity, 79.0%). In multivariate analyses, the GSA index was an independent predictor (P<0.001) linked to RFS and it had a marginal significance in terms of OS (P=0.074). In conclusion, the preoperative GSA index can be a useful predictor in HCV-related HCC patients treated with SR. PMID:25528990

  18. Nine susceptibility loci for hepatitis B virus-related hepatocellular carcinoma identified by a pilot two-stage genome-wide association study

    PubMed Central

    QU, LI-SHUAI; JIN, FEI; GUO, YAN-MEI; LIU, TAO-TAO; XUE, RU-YI; HUANG, XIAO-WU; XU, MIN; CHEN, TAO-YANG; NI, ZHENG-PING; SHEN, XI-ZHONG

    2016-01-01

    Previous studies have indicated that complex interactions among viral, environmental and genetic factors lead to hepatocellular carcinoma (HCC). To identify susceptibility alleles for hepatitis B virus (HBV)-related HCC, the present study conducted a pilot two-phase genome-wide association study (GWAS) in 660 Han Chinese individuals. In phase 1, a total of 500,447 single-nucleotide polymorphisms (SNPs) were genotyped in 50 HCC cases and 50 controls using Affymetrix GeneChip 500k Array Set. In phase 2, 1,152 SNPs were selected from phase 1 and genotyped in 282 cases and 278 controls using the Illumina GoldenGate platform. The prior probability of HCC in control subjects was assigned at 0.01, and false-positive report probability (FPRP) was utilized to evaluate the statistical significance. In phase 1, one SNP (rs2212522) showed a significant association with HCC (Pallele=5.23×10−8; ORallele=4.96; 95% CI, 2.72–9.03). In phase 2, among 27 SNPs with unadjusted Pallele<0.05, 9 SNPs were associated with HCC based on FPRP criteria (FPRP <0.20). The strongest statistical evidence for an association signal was with rs2120243 (combined ORallele=1.76; 95% CI, 1.39–2.22; P=2.00×10−6), which maps within the fourth intron of VEPH1. The second strongest statistical evidence for an association was identified for rs1350171 (combined ORallele=1.66; 95% CI, 1.33–2.07; P=6.48×10−6), which maps to the region downstream of the FZD4 gene. The other potential susceptibility genes included PCDH9, PRMT6, LHX1, KIF2B and L3MBTL4. In conclusion, this pilot two-phase GWAS provides the evidence for the existence of common susceptibility loci for HCC. These genes involved various signaling pathways, including those associated with transforming growth factor β, insulin/phosphoinositide 3 kinase, Wnt and epidermal growth factor receptor. These associations must be replicated and validated in larger studies. PMID:26870257

  19. Serum MicroRNAs as Potential Biomarkers for Early Diagnosis of Hepatitis C Virus-Related Hepatocellular Carcinoma in Egyptian Patients.

    PubMed

    Motawi, Tarek K; Shaker, Olfat G; El-Maraghy, Shohda A; Senousy, Mahmoud A

    2015-01-01

    Circulating microRNAs are deregulated in liver fibrosis and hepatocellular carcinoma (HCC) and are candidate biomarkers. This study investigated the potential of serum microRNAs; miR-19a, miR-296, miR-130a, miR-195, miR-192, miR-34a, and miR-146a as early diagnostic biomarkers for hepatitis C virus (HCV)-related HCC. As how these microRNAs change during liver fibrosis progression is not clear, we explored their serum levels during fibrosis progression in HCV-associated chronic liver disease (CLD) and if they could serve as non-invasive biomarkers for fibrosis progression to HCC. 112 Egyptian HCV-HCC patients, 125 non-malignant HCV-CLD patients, and 42 healthy controls were included. CLD patients were subdivided according to Metavir fibrosis-scoring. Serum microRNAs were measured by qRT-PCR custom array. Serum microRNAs were deregulated in HCC versus controls, and except miR-130a, they were differentially expressed between HCC and CLD or late fibrosis (F3-F4) subgroup. Serum microRNAs were not significantly different between individual fibrosis-stages or between F1-F2 (early/moderate fibrosis) and F3-F4. Only miR-19a was significantly downregulated from liver fibrosis (F1-F3) to cirrhosis (F4) to HCC. Individual microRNAs discriminated HCC from controls, and except miR-130a, they distinguished HCC from CLD or F3-F4 patients by receiver-operating-characteristic analysis. Multivariate logistic analysis revealed a panel of four microRNAs (miR-19a, miR-195, miR-192, and miR-146a) with high diagnostic accuracy for HCC (AUC = 0.946). The microRNA panel also discriminated HCC from controls (AUC = 0.949), CLD (AUC = 0.945), and F3-F4 (AUC = 0.955). Studied microRNAs were positively correlated in HCC group. miR-19a and miR-34a were correlated with portal vein thrombosis and HCC staging scores, respectively. In conclusion, studied microRNAs, but not miR-130a, could serve as potential early biomarkers for HCC in high-risk groups, with miR-19a as a biomarker for liver fibrosis

  20. Genomic losses at 5q13.2 and 8p23.1 in dysplastic hepatocytes are common events in hepatitis B virus-related hepatocellular carcinoma

    PubMed Central

    ZHAO, ZHANG; CHEN, GUANG-YONG; LONG, JIANG; LI, HAI; HUANG, JIAN

    2015-01-01

    Chromosomal loci with genomic imbalances are frequently identified in hepatocellular carcinoma (HCC). Greater than two-thirds of hepatitis B virus (HBV)-related HCCs originate from liver cirrhosis following a duration of up to two decades. However, it is unclear whether these genomic imbalances occur and accumulate in dysplastic hepatocytes of the cirrhotic liver during the progression from regenerated nodules to preneoplastic lesions, including dysplastic nodules (DN). In the present study, high-grade DNs (HGDNs) of HBV-related liver cirrhosis were screened to identify loci with genomic imbalances, and the frequency of the identified loci in a group of HCCs was analyzed in order to determine whether there may be a genetic link between liver cirrhosis and HCC. Genomic DNA was extracted from six HGDNs of two cases of HBV-related liver cirrhosis and subjected to array comparative genomic hybridization (CGH) analysis with a NimbleGen 720K microarray. Loci with the most frequently observed genomic imbalances in DNs were further analyzed in 83 cases of HCC by differential polymerase chain reaction (PCR) and quantitative PCR. The array CGH analysis revealed that the majority of genomic imbalances in the HGDNs were genomic losses of small segments, with loss of heterozygosity (LOH) at 5q13.2 and 8p23.1 identified most frequently. Of the 83 HCC cases, 30 (36.1%) cases were identified with LOH at 5q13.2, where known tumor-associated genes are located, including general transcription factor IIH subunit 2 (GTF2H2), baculoviral IAP repeat-containing protein 1 (BIRC1) and occludin (OCLN). LOH frequency at 8p23.1 in HCC was 61.29% (D8S1130) and 68.4% (D8S503) respectively, similar to the results obtained in previous studies. In conclusion, the results of the present study provided evidence that genomic losses at 5q13.2 and 8p23.1 identified in dysplastic hepatocytes of the cirrhotic liver are common events in HCC. HCC-associated chromosomal abnormalities may occur and accumulate

  1. Prognostic value of M30/M65 for outcome of hepatitis B virus-related acute-on-chronic liver failure

    PubMed Central

    Zheng, Su-Jun; Liu, Shuang; Liu, Mei; McCrae, Malcolm A; Li, Jun-Feng; Han, Yuan-Ping; Xu, Chun-Hui; Ren, Feng; Chen, Yu; Duan, Zhong-Ping

    2014-01-01

    AIM: To determine the prognostic value of circulating indicators of cell death in acute-on-chronic liver failure (ACLF) patients with chronic hepatitis B virus (HBV) infection as the single etiology. METHODS: Full length and caspase cleaved cytokeratin 18 (detected as M65 and M30 antigens) represent circulating indicators of necrosis and apoptosis. M65 and M30 were identified by enzyme-linked immunosorbent assay in 169 subjects including healthy controls (n = 33), patients with chronic hepatitis B (CHB, n = 55) and patients with ACLF (n = 81). According to the 3-mo survival period, ACLF patients were defined as having spontaneous recovery (n = 33) and non-spontaneous recovery which included deceased patients and those who required liver transplantation (n = 48). RESULTS: Both biomarker levels significantly increased gradually as liver disease progressed (for M65: P < 0.001 for all; for M30: control vs CHB, P = 0.072; others: P < 0.001 for all). In contrast, the M30/M65 ratio was significantly higher in controls compared with CHB patients (P = 0.010) or ACLF patients (P < 0.001). In addition, the area under receiver operating characteristic curve (AUC) analysis demonstrated that both biomarkers had diagnostic value (AUC ≥ 0.80) in identifying ACLF from CHB patients. Interestingly, it is worth noting that the M30/M65 ratio was significantly different between spontaneous and non-spontaneous recovery in ACLF patients (P = 0.032). The prognostic value of the M30/M65 ratio was compared with the Model for End-Stage Liver Disease (MELD) and Child-Pugh scores at the 3-mo survival period, the AUC of the M30/M65 ratio was 0.66 with a sensitivity of 52.9% and the highest specificity of 92.6% (MELD:AUC = 0.71; sensitivity, 79.4%; specificity, 63.0%; Child-Pugh: AUC = 0.77; sensitivity, 61.8%; specificity, 88.9%). CONCLUSION: M65 and M30 are strongly associated with liver disease severity. The M30/M65 ratio may be a potential prognostic marker for spontaneous recovery in

  2. NKP30-B7-H6 Interaction Aggravates Hepatocyte Damage through Up-Regulation of Interleukin-32 Expression in Hepatitis B Virus-Related Acute-On-Chronic Liver Failure

    PubMed Central

    Pan, Xingfei; Lu, Ying; Liao, Sihong; Wang, Xicheng; Wang, Guoying; Lin, Dongjun

    2015-01-01

    Background and Aims Previous work conducted by our group has shown that the accumulation of hepatic natural killer (NK) cells and the up-regulation of natural cytotoxicity receptors (NKP30 and NKP46) on NK cells from patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) were correlated with disease progression in HBV-ACLF. The natural cytotoxicity receptors expressed on NK cells are believed to be probable candidates involved in the NK cell-mediated hepatocyte damage in HBV-ACLF. However, the underlying mechanisms remain to be elucidated. In the present study, we aimed to discover the role of NKP30-B7-H6 interaction in NK cells-mediated hepatocyte damage in HBV-ACLF. Methods Hepatic expressions of B7-H6 and interleukin-32 (IL-32) were examined by immunochemistry staining in samples from patients with HBV-ACLF or mild chronic hepatitis B (CHB). The cytotoxicity of NK-92 cell against target cells (Huh-7 and LO2) was evaluated by CCK8 assay. Expression of IL-32 in liver NK cell, T cells and NK-92 cell line was detected by the flow cytometric analysis. The effect of IL-32 on the apoptosis of Huh7 cells was evaluated using Annexin V/PI staining analysis. Results An enhancement of hepatic B7-H6 and IL-32 expression was associated with the severity of liver injury in HBV-ACLF. And there was a positive association between hepatic B7-H6 and IL-32 expression. Expressions of IL-32 in liver NK cells and T cells were increased in HBV-ACLF patients. In vitro NK-92 cells are highly capable of killing the high B7-H6 expressing Huh7 cells and B7-H6-tansfected hepatocyte line LO2 cells dependent on NKP30 and B7-H6 interaction. Furthermore, NK-92 cells exhibited elevated IL-32 expression when stimulated with anti-NKP30 antibodies or when co-cultured with Huh7 cells. IL-32 can induce the apoptosis of Huh7 cells in a dose-dependent manner. Conclusion Our results suggest that NKP30-B7-H6 interaction can aggravate hepatocyte damage, probably through up

  3. Identification of a novel overlapping sequential E epitope (E') on the bovine leukaemia virus SU glycoprotein and analysis of immunological data.

    PubMed

    Forti, Katia; Rizzo, Giorgia; Cagiola, Monica; Ferrante, Giovanna; Marini, Carla; Feliziani, Francesco; Pezzotti, Giovanni; De Giuseppe, Antonio

    2014-08-01

    Bovine leukaemia virus (BLV), an oncogenic C-type retrovirus, is the causative agent of enzootic bovine leucosis. Binding of BLV to its cellular receptor is mediated by the surface envelope glycoprotein subunit (SU). Previous studies have identified eight different epitopes (A through H) on the BLV SU. In this study, a new sequential epitope was identified using the monoclonal antibody 2G7 (MAb 2G7) on the C-terminal region of the BLV SU. To localise and refine the map of this epitope, a series of deleted forms in the C and N-terminal ends of the glycoprotein were made and synthesised in baculovirus and Escherichia coli expression systems. The synthetic proteins were analysed both in Western blot and MAb-capture ELISA assays. MAb 2G7 recognised a stretch of 11 amino acids, named epitope E', corresponding to residues 189-SDWVPSVRSWA-199 (comprising the 33 amino acids signal peptide) overlapping with the E epitope of the SU. The data obtained by Enzyme-Linked Immunosorbent Assay (ELISA) revealed that the E' epitope was hidden on whole BLV particles and that the variation in reactivity between epitope E' and MAb 2G7 depends on the glycosylation state of SU. Similarly, the analysis of immunological data evidenced that the failure of interaction between the MAb anti-DD' and its epitope was also due to a steric hindrance of the glycosylation. Finally, the ELISA assay analysis performed with the deleted and mutated forms of rSU evidenced that the conformational epitopes F, G and H lied into in the 34-173 amino-acids residues of N-terminal region of SU. PMID:24916842

  4. No association found between the detection of either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus and chronic fatigue syndrome in a blinded, multi-site, prospective study by the establishment and use of the SolveCFS BioBank

    PubMed Central

    2014-01-01

    Background In 2009, a retrospective study reported the detection of xenotropic murine leukemia virus-related virus (XMRV) in clinical isolates derived from individuals with chronic fatigue syndrome or myalgic encephalomyelitis (CFS). While many efforts to confirm this observation failed, one report detected polytropic murine leukemia virus (pMLV), instead of XMRV. In both studies, Polymerase Chain Reaction (PCR)-based methods were employed which could provide the basis for the development of a practical diagnostic tool. To confirm these studies, we hypothesized that the ability to detect these viruses will not only depend upon the technical details of the methods employed but also on the criteria used to diagnose CFS and the availability of well characterized clinical isolates. Methods A repository of clinical isolates from geographically distinct sites was generated by the collection of fresh blood samples from well characterized CFS and healthy subjects. Molecular techniques were used to generate assay positive controls and to determine the lower limit of detection (LLOD) for murine retroviral and Intracisternal A particle (Cell 12(4):963-72, 1977) detection methods. Results We report the establishment of a repository of well-defined, clinical isolates from five, geographically distinct regions of the US, the comparative determination of the LLODs and validation efforts for the previously reported detection methods and the results of an effort to confirm the association of these retroviral signatures in isolates from individuals with CFS in a blinded, multi-site, prospective study. We detected various, murine retroviral DNA signatures but were unable to resolve a difference in the incidence of their detection between isolates from CFS (5/72; 6.7%) and healthy (2/37; 5.4%) subjects (Fisher’s Exact Test, p-value = 1). The observed sequences appeared to reflect the detection of endogenous murine retroviral DNA, which was not identical to either XMRV or p

  5. Gene profiling of the erythro- and megakaryoblastic leukaemias induced by the Graffi murine retrovirus

    PubMed Central

    2010-01-01

    Background Acute erythro- and megakaryoblastic leukaemias are associated with very poor prognoses and the mechanism of blastic transformation is insufficiently elucidated. The murine Graffi leukaemia retrovirus induces erythro- and megakaryoblastic leukaemias when inoculated into NFS mice and represents a good model to study these leukaemias. Methods To expand our understanding of genes specific to these leukaemias, we compared gene expression profiles, measured by microarray and RT-PCR, of all leukaemia types induced by this virus. Results The transcriptome level changes, present between the different leukaemias, led to the identification of specific cancerous signatures. We reported numerous genes that may be potential oncogenes, may have a function related to erythropoiesis or megakaryopoiesis or have a poorly elucidated physiological role. The expression pattern of these genes has been further tested by RT-PCR in different samples, in a Friend erythroleukaemic model and in human leukaemic cell lines. We also screened the megakaryoblastic leukaemias for viral integrations and identified genes targeted by these integrations and potentially implicated in the onset of the disease. Conclusions Taken as a whole, the data obtained from this global gene profiling experiment have provided a detailed characterization of Graffi virus induced erythro- and megakaryoblastic leukaemias with many genes reported specific to the transcriptome of these leukaemias for the first time. PMID:20102610

  6. The Molecular Characterization of Bovine Leukaemia Virus Isolates from Eastern Europe and Siberia and Its Impact on Phylogeny

    PubMed Central

    Rola-Łuszczak, Marzena; Pluta, Aneta; Olech, Monika; Donnik, Irina; Petropavlovskiy, Maxim; Gerilovych, Anton; Vinogradova, Irina; Choudhury, Bhudipa; Kuźmak, Jacek

    2013-01-01

    Recent studies have shown that bovine leukemia virus (BLV) sequences can be classified into seven distinct genotypes based on full gp51 sequence. This classification was based on available sequence data that mainly represented the BLV population that is circulating in cattle from the US and South America. In order to aid with a global perspective inclusion of data from Eastern Europe is required. In this study we examined 44 BLV isolates from different geographical regions of Poland, Belarus, Ukraine, and Russia. Phylogenetic analysis based on a 444bp fragment of env gene revealed that most of isolates belonged to genotypes 4 and 7. Furthermore, we confirmed the existence of a new genotype, genotype 8, which was highly supported by phylogenetic computations. A significant number of amino acid substitutions were found in the sequences of the studied Eastern European isolates, of which 71% have not been described previously. The substitutions encompassed mainly the C-part of the CD4+ epitope, zinc binding peptide region, CD8+ T cell epitope, and overlapping linear epitope E. These observations highlight the use of sequence data to both elucidate phylogenetic relationships and the potential effect on serological detection of geographically diverse isolates. PMID:23527009

  7. A novel mutant 10Ala/Arg together with mutant 144Ser/Arg of hepatitis B virus X protein involved in hepatitis B virus-related hepatocarcinogenesis in HepG2 cell lines.

    PubMed

    Shi, Ying; Wang, Junwei; Wang, Yuhe; Wang, Anna; Guo, Hongliang; Wei, Feili; Mehta, Sanjay R; Espitia, Stephen; Smith, Davey M; Liu, Longgen; Zhang, Yulin; Chen, Dexi

    2016-02-28

    Hepatitis B virus (HBV) infection-related hepatocellular carcinoma (HCC) represents a major health problem worldwide. HBV X (HBx) protein is the most common open reading frame that may undergo mutations, resulting in the development of HCC. This study aimed to determine specific HBx mutations that differentiate the central- and para-tumor tissues, and identify their association with HCC development. HBx gene from HCC tumor and para-tumor tissues of 47 HCC patients was amplified, sequenced and statistically analyzed. A novel combination of 2 mutations at residues 10 and 144 was identified which might play a significant role in HCC development. Expression vectors carrying HBx with the specific mutations were constructed and transfected into HepG2 and p53-null HepG2 cells. Compared to wild type (WT) and single mutation of HBx at residue 10 or 144, the 10/144 double mutations strongly up-regulated p21 expression and prolonged G1/S transition in WT- and p53-null HepG2 cells. Apoptosis was also inhibited by HBx harboring 10/44 double-mutation. Binding of 10/144 double-mutant HBx to p53 was lower than WT HBx. Conclusively, the 10/144 double mutation of HBx might play a crucial role in HCC formation. PMID:26706415

  8. The rapamycin sensitivity of human T-cell leukaemia virus type I-induced T-cell proliferation is mediated independently of the polypyrimidine motifs in the 5' long terminal repeat.

    PubMed

    Rose, N; Lever, A

    2001-02-01

    The immunosuppressant rapamycin can regulate the translation of a subset of messenger RNAs, a phenotype which has been linked to the presence of a polypyrimidine motif [C(N)(4-14)] downstream of the mRNA cap structure. T-cell clones naturally infected with transcriptionally active human T-cell leukaemia virus, type I (HTLV-I) undergo autologous proliferation; this phenotype is inhibited by rapamycin but not FK506, which reverses the rapamycin effect. Within the R region of the HTLV-I 5' long terminal repeat (LTR) there are seven polypyrimidine motifs. We sought to determine if these were involved in the sensitivity of proliferation to the presence of rapamycin. Here we illustrate the generation of an in vitro model of this rapamycin-sensitivity and the analysis of LTR mutants which were created to determine the importance of the polypyrimidine motifs. Reporter gene assays suggest the effect is independent of the polypyrimidine motifs in the virus leader sequence. PMID:11161283

  9. Chronic lymphocytic leukaemia.

    PubMed

    Scarfò, Lydia; Ferreri, Andrés J M; Ghia, Paolo

    2016-08-01

    Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among the adults in the Western World. CLL (and the corresponding nodal entity small lymphocytic lymphoma, SLL) is classified as a lymphoproliferative disorder characterised by the relentless accumulation of mature B-lymphocytes showing a peculiar immunophenotype in the peripheral blood, bone marrow, lymph nodes and spleen. CLL clinical course is very heterogeneous: the majority of patients follow an indolent clinical course with no or delayed treatment need and with a prolonged survival, while others experience aggressive disease requiring early treatment followed by frequent relapses. In the last decade, the improved understanding of CLL pathogenesis shed light on premalignant conditions (i.e., monoclonal B-cell lymphocytosis, MBL), defined new prognostic and predictive markers, improving patient stratification, but also broadened the therapeutic armamentarium with novel agents, targeting fundamental signaling pathways. PMID:27370174

  10. Chilblain-like leukaemia cutis.

    PubMed

    Tran, Chi; McEwen, Gary; Fraga, Garth Robert

    2016-01-01

    Chilblain, also known as pernio, is an abnormal inflammatory response to cold, moist environmental conditions. Persistent or atypical lesions should prompt investigation to exclude underlying systemic illness. We describe a case of acute myeloid leukaemia that presented with chilblain-like leukaemia cutis. PMID:27095810

  11. Lymphoid leukaemia in a cow.

    PubMed

    Johnstone, A C

    1982-10-01

    An 18-month old Friesian heifer which had lost condition and had diarrhoea for several weeks was diagnosed by haematological and pathological examinations as having lymphocytic leukaemia. True lymphatic leukaemia has not previously been described in cattle and does not readily fit into presently accepted classifications of bovine leukosis. PMID:16030823

  12. Suppression of development of glomerulonephritis in NZB x NZWF1 mice by persistent infection with lactic dehydrogenase virus: relations between intercellular adhesion molecule-1 expression on endothelial cells and leucocyte accumulation in glomeruli.

    PubMed Central

    Kameyama, Y.; Hayashi, T.

    1994-01-01

    The development of glomerulonephritis (GN) in autoimmune NZB x NZWF1 mice was suppressed by persistent lactic dehydrogenase virus (LDV) infection. In this study the expression of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells in glomeruli was examined during the development of GN. ICAM-1 expression on endothelial cells preceded the accumulation of leucocytes within glomeruli. The uninfected mice exhibited an age-related and profound increase in ICAM-1 expression associated with the development of a GN as evidenced by deposits of IgG and C3. Uninfected mice also showed increased accumulation of leucocytes, such as polymorphonuclear leucocytes (PMNs), macrophages, T and CD4+ cells, which express the lymphocyte function-associated antigen-1 (LFA-1) within glomeruli during the development of GN. These changes were strongly suppressed by LDV infection. Our findings suggest that the expression of ICAM-1 in glomerular endothelial cells may, at least in part, contribute to the development of GN. Suppressed expression of ICAM-1 in LDV-infected mice may be responsible for the suppression of GN seen in these animals. Thus there may be a pathogenetic role for ICAM-1 expression and for intraglomerular accumulation of leucocytes, especially PMNs, which express LFA-1 in the development of GN. Images Figure 1 Figure 2 Figure 7 Figure 9 Figure 11 PMID:7947231

  13. Current preventive strategies and management of Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplantation in Europe. Results of the ESGICH Questionnaire-based Cross-sectional Survey.

    PubMed

    San-Juan, R; Manuel, O; Hirsch, H H; Fernández-Ruiz, M; López-Medrano, F; Comoli, P; Caillard, S; Grossi, P; Aguado, J M

    2015-06-01

    There is limited clinical evidence on the utility of the monitoring of Epstein-Barr virus (EBV) DNAemia in the pre-emptive management of post-transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients. We investigated current preventive measures against EBV-related PTLD through a web-based questionnaire sent to 669 SOT programmes in 35 European countries. This study was performed on behalf of the ESGICH study group from the European Society of Clinical Microbiology and Infectious Diseases. A total of 71 SOT programmes from 15 European countries participated in the study. EBV serostatus of the recipient is routinely obtained in 69/71 centres (97%) and 64 (90%) have access to EBV DNAemia assays. EBV monitoring is routinely used in 85.9% of the programmes and 77.4% reported performing pre-emptive treatment for patients with significant EBV DNAemia levels. Pre-emptive treatment for EBV DNAemia included reduction of immunosuppression in 50.9%, switch to mammalian target of rapamycin inhibitors in 30.9%, and use of rituximab in 14.5% of programmes. Imaging by whole-body 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) is used in 60.9% of centres to rule out PTLD and complemented computer tomography is used in 50%. In 10.9% of centres, FDG-PET is included in the first-line diagnostic workup in patients with high-risk EBV DNAemia. Despite the lack of definitive evidence, EBV load measurements are frequently used in Europe to guide diagnostic workup and pre-emptive reduction of immunosuppression. We need prospective and controlled studies to define the impact of EBV monitoring in reducing the risk of PTLD in SOT recipients. PMID:25686696

  14. Association of the miR-196a2 C>T and miR-499 A>G polymorphisms with hepatitis B virus-related hepatocellular carcinoma risk: an updated meta-analysis

    PubMed Central

    Zhu, Shao-Liang; Zhong, Jian-Hong; Gong, Wen-Feng; Li, Hang; Li, Le-Qun

    2016-01-01

    Background This study meta-analyzed data on the possible association of the miR-196a2 C>T (rs11614913) and miR-499 A>G (rs3746444) polymorphisms with risk of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods Databases in PubMed, EMBASE, Web of Science, China BioMedicine, and Google Scholar were systematically searched to identify relevant studies. Meta-analyses were performed to examine the association of the miR-196a2 C>T and miR-499 A>G polymorphisms with HBV-related HCC risk. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results A total of 13 studies involving 3,964 cases and 5,875 healthy controls were included. Random-effect meta-analysis showed that the T allele and TT genotype of miR-196a2 C>T were associated with significantly lower HBV-related HCC risk (allelic model, OR =0.84, 95% CI =0.71–0.99, P=0.04; homozygous model, OR =0.68, 95% CI =0.47–0.98, P=0.04). In contrast, miR-499 A>G showed no significant association with HBV-related HCC risk in either overall pooled analysis or ethnic subgroup analysis according to any of the four genetic models. Based on analysis of ethnic subgroups, neither miR-196a2 C>T nor miR-499 A>G was significantly associated with risk of HBV-related HCC in Chinese population. Conclusion The polymorphism miR-196a2 C>T, but not miR-499 A>G, may be associated with decreased HBV-related HCC risk. These conclusions should be verified in large, well-designed studies. PMID:27143913

  15. The CD8+ T-Cell Response to an Epstein-Barr Virus-Related Gammaherpesvirus Infecting Rhesus Macaques Provides Evidence for Immune Evasion by the EBNA-1 Homologue

    PubMed Central

    Fogg, Mark H.; Kaur, Amitinder; Cho, Young-Gyu; Wang, Fred

    2005-01-01

    Epstein-Barr virus (EBV) infection persists for life in humans, similar to other gammaherpesviruses in the same lymphocryptovirus (LCV) genus that naturally infect Old World nonhuman primates. The specific immune elements required for control of EBV infection and potential immune evasion strategies essential for persistent EBV infection are not well defined. We evaluated the cellular immune response to latent infection proteins in rhesus macaques with naturally and experimentally acquired rhesus LCV (rhLCV) infection. RhLCV EBNA-1 (rhEBNA-1) was the most frequently targeted latent infection protein and induced the most robust responses by peripheral blood mononuclear cells tested ex vivo using the gamma interferon ELISPOT assay. In contrast, although in vitro stimulation and expansion of rhLCV-specific T lymphocytes demonstrated cytotoxic T-lymphocyte (CTL) activity against autologous rhLCV-infected B cells, rhEBNA-1-specific CTL activity could not be detected. rhEBNA-1 CTL epitopes were identified and demonstrated that rhEBNA-1-specific CTL were stimulated and expanded in vitro but did not lyse targets expressing rhEBNA-1. Similarly, rhEBNA-1-specific CTL clones were able to lyse targets pulsed with rhEBNA-1 peptides or expressing rhEBNA-1 deleted for the glycine-alanine repeat (GAR) but not full-length rhEBNA-1 or rhLCV-infected B cells. These studies show that the rhLCV-specific immune response to latent infection proteins is similar to the EBV response in humans, and a potential immune evasion mechanism for EBNA-1 has been conserved in rhLCV. Thus, the rhLCV animal model can be used to analyze the immune responses important for control of persistent LCV infection and the role of the EBNA-1 GAR for immune evasion in vivo. PMID:16188971

  16. The Transforming Growth Factor β1/Interleukin-31 Pathway Is Upregulated in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure and Is Associated with Disease Severity and Survival

    PubMed Central

    Yu, Xueping; Guo, Ruyi; Ming, Desong; Deng, Yong; Su, Milong; Lin, Chengzu; Li, Julan; Lin, Zhenzhong

    2015-01-01

    The transforming growth factor β1/interleukin-31 (TGF-β1/IL-31) pathway plays an important role in the process of cell injury and inflammation. The purpose of this work was to explore the role of the TGF-β1/IL-31 pathway in the cytopathic process of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). The quantitative serum levels of TGF-β1, IL-9, IL-10, IL-17, IL-22, IL-23, IL-31, IL-33, and IL-35 were analyzed among chronic hepatitis B (CHB) patients (n = 17), ACLF patients (n = 18), and normal control (NC) subjects (n = 18). Disease severity in patients with ACLF was assessed using the model for end-stage liver disease (MELD) and Child-Pugh scores. Serum TGF-β1 levels were strongly positively correlated with IL-31 in all subjects, and both of them were positively correlated with IL-17, IL-22, and IL-33. In CHB and ACLF patients, serum levels of TGF-β1 and IL-31 were both increased significantly compared with those in NC subjects and positively correlated with total bilirubin (TBil) and alpha-fetoprotein (AFP) levels. ACLF patients showed the highest levels of TGF-β1 and IL-31, which were positively correlated with Child-Pugh scores. Furthermore, the recovery from the liver injury in CHB was accompanied by decreased TGF-β1 and IL-31 levels. More importantly, serum levels of TGF-β1 and IL-31 were markedly upregulated in ACLF nonsurvivors, and IL-31 displayed the highest sensitivity and specificity (85.7% and 100.0%, respectively) in predicting nonsurvival of ACLF patients. Increasing activity of the TGF-β1/IL-31 pathway is well correlated with the extent of liver injury, disease severity, and nonsurvival of ACLF patients, while reducing activity is detected along the recovery from liver injury in CHB, suggesting its potential role in the pathogenesis of liver injury during chronic HBV infection. PMID:25716231

  17. Association of Hypoxia-Inducible Factor-2 Alpha Gene Polymorphisms with the Risk of Hepatitis B Virus-Related Liver Disease in Guangxi Chinese: A Case-Control Study

    PubMed Central

    Deng, Yan; Liu, Yanqiong; Zhao, Jiangyang; Huang, Xiuli; Tang, Wenjun; Sun, Yifan; Qin, Xue; Li, Shan

    2016-01-01

    Objective Hypoxia-inducible factor-2 alpha (HIF-2a) plays a major role in the progression of disease, although the role of HIF-2α gene polymorphisms in hepatitis B virus (HBV)-related diseases remains elusive. The aim of this study is to determine whether HIF-2a rs13419896 and rs6715787 single-nucleotide polymorphisms (SNPs) are associated with susceptibility to chronic hepatitis B (CHB), liver cirrhosis (LC), or hepatocellular carcinoma (HCC). Method A case-control study of 107 patients with CHB, 83 patients with LC, 234 patients with HCC, and 224 healthy control subjects was carried out, and the HIF-2a rs13419896 and rs6715787 SNPs were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Results No significant differences were observed in the genotype or allele frequency of two HIF-2a SNPs between the cases and controls (all p>0.05). However, in subgroup analysis by gender, the HIF-2a rs13419896 GA and AA genotypes were significantly associated with a risk of CHB (odds ratio [OR] = 3.565, 95% confidence interval [CI] = 1.123–11.314, p = 0.031 and OR = 12.506, 95% CI = 1.329–117.716, p = 0.027) in females, and the A allele of rs13419896 was associated with a risk of CHB (OR = 2.624, 95% CI = 1.244–5.537, p = 0.011) and LC (OR = 2.351, 95% CI = 1.002–5.518, p = 0.050) in females. The rs6715787 CG genotype polymorphism may contribute to a reduced risk of LC in the Guangxi Zhuang Chinese population (OR = 0.152, 95% CI = 0.028–0.807, p = 0.027), as determined via subgroup analysis by ethnicity. Moreover, binary logistic regression analyses that were adjusted by drinking status indicated that the AA genotype of rs13419896 may contribute to an increased risk of LC in the non-alcohol-drinking population (OR = 3.124, 95% CI = 1.091–8.947, p = 0.034). In haplotype analysis, GG haplotype was significantly associated with a reduced risk of LC (OR = 0.601, 95% CI = 0.419–0.862, p = 0.005). Conclusions The HIF-2a rs

  18. Association between catalase gene polymorphisms and risk of chronic hepatitis B, hepatitis B virus-related liver cirrhosis and hepatocellular carcinoma in Guangxi population: a case-control study.

    PubMed

    Liu, Yanqiong; Xie, Li; Zhao, Jiangyang; Huang, Xiuli; Song, Liuying; Luo, Jingrong; Ma, Liping; Li, Shan; Qin, Xue

    2015-04-01

    Reactive oxygen species (ROS) play critical roles in hepatocarcinogenesis. The catalase (CAT) enzyme is involved in the repair of ROS. Therefore, we investigate the association between CAT gene polymorphisms and the risk of hepatocellular carcinoma (HCC). A total of 715 subjects were divided into 4 groups: 111 chronic hepatitis B (CHB) patients, 90 hepatitis B virus (HBV)-related liver cirrhosis (LC) patients, 266 HBV-HCC patients, and 248 healthy controls. The polymerase chain reaction-restriction fragment length polymorphism strategy was used to detect CAT gene rs1001179, rs769217, and rs7943316 polymorphisms. Binary logistic regression analyses adjusting for sex, age, ethnicity, smoking and alcohol consumption, and body mass index suggested that subjects carrying the rs769217 T allele were at marginally increased risk of CHB, LC, and HCC, with adjusted odds ratios (ORs) of 1.51 (95% confidence interval [CI] = 1.04-2.20, P = 0.029), 1.48 (95% CI = 1.03-2.14, P = 0.035), and 1.51 (95% CI = 1.14-1.98, P = 0.004), respectively. Similarly, those individuals carrying the rs769217 TT genotype had a moderately increased risk of CHB, LC, and HCC, with adjusted ORs of 2.11 (95% CI = 1.05-4.22, P = 0.035), 2.00 (95% CI, 1.01-3.95, P = 0.047), and 1.93 (95% CI = 1.14-3.28, P = 0.015), respectively. Moreover, subjects carrying the rs769217 CT genotype and at least 1 copy of the T allele (dominant model) were 1.78 times and 1.83 times more likely to develop HCC, respectively (OR = 1.78, 95% CI = 1.16-2.73, P = 0.009 and OR = 1.83, 95% CI = 1.23-2.71, P = 0.003). This association between CAT rs769217 T alleles and HCC risk is significantly strengthened among men, nonsmokers, nondrinkers, and among individuals <50 years of age. Furthermore, we found 1 high-risk haplotype GTA for CHB (OR = 1.45, 95% CI = 1.05-2.01) and 1 protective haplotype GCA for HCC risk (OR = 0.67, 95% CI = 0.52-0.87). We

  19. Childhood leukaemia in Ireland.

    PubMed

    Herity, B; Daly, L; Breatnach, F; Buttimer, J; Egan, E; Fennelly, J; McCann, S; Walsh, J H

    1992-06-01

    In response to professional and public concern about health consequences, in particular cancer risk, from previous and current levels of ionising radiation in the Irish Sea, a study of incidence and mortality from acute lymphoid leukaemia (ALL) and other lymphoid malignancies in children was undertaken. Overall rates were similar to those found in other western populations and distribution of high rates was quite random over the country as a whole. There was a small but significant excess in incidence of ALL for the years 1974-76 in a narrow three mile wide strip along the east coast. It is not possible in the context of this study to postulate aetiological factors which might explain this finding. PMID:1628939

  20. Acute lymphoblastic leukaemia

    PubMed Central

    Inaba, Hiroto; Greaves, Mel; Mullighan, Charles G.

    2013-01-01

    Summary Acute lymphoblastic leukaemia (ALL) is seen in both children and adults, but its incidence peaks between ages 2 and 5 years. The causation of ALL is considered to be multi-factorial, including exogenous or endogenous exposures, genetic susceptibility, and chance. The survival rate of paediatric ALL has improved to approximately 90% in recent trials with risk stratification by biologic features of leukaemic cells and response to therapy, therapy modification based on patient pharmacodynamics and pharmacogenomics, and improved supportive care. However, innovative approaches are needed to further improve survival while reducing adverse effects. While most children can be cured, the prognosis of infants and adults with ALL remains poor. Recent genome-wide profiling of germline and leukaemic cell DNA has identified novel submicroscopic structural genetic alterations and sequence mutations that contribute to leukaemogenesis, define new ALL subtypes, influence responsiveness to treatment, and may provide novel prognostic markers and therapeutic targets for personalized medicine. PMID:23523389

  1. Acute myeloid leukaemia.

    PubMed

    Khwaja, Asim; Bjorkholm, Magnus; Gale, Rosemary E; Levine, Ross L; Jordan, Craig T; Ehninger, Gerhard; Bloomfield, Clara D; Estey, Eli; Burnett, Alan; Cornelissen, Jan J; Scheinberg, David A; Bouscary, Didier; Linch, David C

    2016-01-01

    Acute myeloid leukaemia (AML) is a disorder characterized by a clonal proliferation derived from primitive haematopoietic stem cells or progenitor cells. Abnormal differentiation of myeloid cells results in a high level of immature malignant cells and fewer differentiated red blood cells, platelets and white blood cells. The disease occurs at all ages, but predominantly occurs in older people (>60 years of age). AML typically presents with a rapid onset of symptoms that are attributable to bone marrow failure and may be fatal within weeks or months when left untreated. The genomic landscape of AML has been determined and genetic instability is infrequent with a relatively small number of driver mutations. Mutations in genes involved in epigenetic regulation are common and are early events in leukaemogenesis. The subclassification of AML has been dependent on the morphology and cytogenetics of blood and bone marrow cells, but specific mutational analysis is now being incorporated. Improvements in treatment in younger patients over the past 35 years has largely been due to dose escalation and better supportive care. Allogeneic haematopoietic stem cell transplantation may be used to consolidate remission in those patients who are deemed to be at high risk of relapse. A plethora of new agents - including those targeted at specific biochemical pathways and immunotherapeutic approaches - are now in trial based on improved understanding of disease pathophysiology. These advances provide good grounds for optimism, although mortality remains high especially in older patients. PMID:27159408

  2. Gene therapy for paediatric leukaemia.

    PubMed

    Rousseau, R F; Bollard, C M; Heslop, H E

    2001-07-01

    Improvements in the chemotherapeutic and transplant regimens have had a significant impact in improving survival rates for paediatric leukaemia. However, there are still important problems to address including what options are available for patients with chemoresistant disease and what strategies are available to avoid the concerns regarding the toxicity associated with highly cytotoxic treatment regimens. Gene therapy and immunotherapy protocols hold great promise. Using gene transfer of a marker gene, a number of biological issues in the therapy of leukaemia have been addressed. For example, by gene marking autologous bone marrow grafts it has been possible to demonstrate that infused marrow contributes to relapse in acute and chronic myeloid leukaemias. In the allogeneic transplant setting, genetically modified T-cells have proven valuable for the prophylaxis and treatment of viral diseases and may have an important role in preventing or treating disease relapse. Gene transfer is also being used to modify tumour function, enhance immunogenicity, and confer drug-resistance to normal haematopoietic stem cells. With the continued scientific advancements in this field, gene therapy will almost certainly have a major impact on the treatment of paediatric leukaemia in the future. PMID:11727502

  3. Haemophagocytic syndrome complicating acute lymphoblastic leukaemia.

    PubMed Central

    Stark, R.; Manoharan, A.

    1989-01-01

    A 41 year old female developed reactive haemophagocytic histiocytosis secondary to herpes simplex infection, during remission induction for acute lymphoblastic leukaemia. She recovered fully with acyclovir and supportive treatment. Previous publications on the association between acute lymphoblastic leukaemia and haemophagocytic syndrome are reviewed, and the nature of the haemophagocytic disorder is discussed. Images Figure 1 PMID:2687829

  4. Avian Influenza A Virus Infections in Humans

    MedlinePlus

    ... Research Making a Candidate Vaccine Virus Related Links Influenza Types Seasonal Avian Swine Variant Pandemic Other Get ... Submit What's this? Submit Button Past Newsletters Avian Influenza A Virus Infections in Humans Language: English Españ ...

  5. Ferritinaemia in Leukaemia and Hodgkin's Disease

    PubMed Central

    Jones, P. A. E.; Miller, F. M.; Worwood, M.; Jacobs, A.

    1973-01-01

    The serum ferritin concentration is increased in both acute myeloblastic leukaemia and Hodgkin's disease. In acute leukaemia the mean concentration is about ten times the normal level and is associated with a high concentration of transferrin-bound iron. In Hodgkin's disease abnormal ferritinaemia is associated with a low concentration of transferrin-bound iron and appears to result from a block of reticuloendothelial iron release. Increased concentrations of circulating ferritin have also been observed in a few cases of chronic leukaemia and myelomatosis. PMID:4511989

  6. Acute myelogenous leukaemia in Hurler's syndrome.

    PubMed

    Chen, K T; McKenna, R W; Desnick, R J

    1978-06-01

    The occurrence of the Hurler syndrome and acute myelogenous leukaemia in a 2 1/2-year-old girl is described. This represents the first published report of the concurrence of these two diseases. PMID:97385

  7. In utero origins of childhood leukaemia.

    PubMed

    Greaves, Mel

    2005-01-01

    Chimaeric fusion genes derived by chromosome translocation are common molecular abnormalities in paediatric leukaemia and provide unique markers for the malignant clone. They have been especially informative in studies with twins concordant for leukaemia and in retrospective scrutiny of archived neonatal blood spots. These data have indicated that, in paediatric leukaemia, the majority of chromosome translocations arise in utero during foetal haemopoiesis. Chromosomal translocations and preleukaemic clones arise at a substantially higher frequency ( approximately 100x) before birth than the cumulative incidence or risk of disease, reflecting the requirement for complementary and secondary genetic events that occur postnatally. A consequence of the latter is a very variable and occasionally protracted postnatal latency of disease (1-15 years). These natural histories provide an important framework for consideration of key aetiological events in paediatric leukaemia. PMID:15707724

  8. How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)?

    PubMed Central

    Bangham, Charles RM; Ratner, Lee

    2016-01-01

    A typical person infected with the retrovirus human T-lymphotropic virus type 1 (HTLV-1) carries tens of thousands of clones of HTLV-1-infected T lymphocytes, each clone distinguished by a unique integration site of the provirus in the host genome. However, only 5% of infected people develop the malignant disease adult T cell leukaemia/lymphoma, usually more than 50 years after becoming infected. We review the host and viral factors that cause this aggressive disease. PMID:26414684

  9. Fr-MLV infection induces erythroleukaemia instead of lymphoid leukaemia in mice given pituitary grafts.

    PubMed Central

    Fontanini, G.; Basolo, F.; Garzelli, C.; Squartini, F.; Toniolo, A.

    1990-01-01

    Here we report that the slow-transforming helper component of Friend murine leukaemia virus (Fr-MLV), which produces lymphoid leukaemias in normal mice, induces erythroleukaemia in mice given syngeneic pituitary grafts (SPG). Newborn mice were infected with Fr-MLV and, at one month of age, were transplanted with two pituitary glands under the kidney capsule. Sham-operated infected mice and uninfected transplanted mice served as controls. SPG selectively reduced the mean survival times of infected mice. Histopathology showed that, while most infected non-transplanted mice developed lymphoid leukaemias, virtually all Fr-MLF-infected mice given SPG developed erythroleukaemias. Experiments in vitro showed that Fr-MLV infection markedly depressed concanavalin A induced DNA synthesis in cells from spleen, thymus and lymph nodes. Addition of prolactin or growth hormone further suppressed lectin-induced mitogenesis of lymphoid cells from infected mice, but failed to influence the response of uninfected controls. These experiments indicate that, in mice, pituitary hormones modulate the development and the histological features of Fr-MLV induced leukaemias, and suggest that endocrine-immunological interactions play a role in retrovirus induced tumorigenesis. Images Figure 2 PMID:2372485

  10. Significance of Phi bodies in acute leukaemia.

    PubMed Central

    Cardullo, L de S; Morilla, R; Catovsky, D

    1981-01-01

    Material from 39 patients with acute leukaemia was investigated with the peroxidase cytochemical reaction using 3,3'diaminobenzidine (DAB) and other substrates in order to test their sensitivity in detecting myeloid differentiation. The proportion of positive blasts and of cases with Auer rods in acute myeloid leukaemia (AML) was significantly greater with DAB than with benzidine. In addition, Phi bodies were demonstrated in AML blasts only when DAB was used; Phi bodies were also observed in two out of seven cases of chronic granulocytic leukaemia in "myeloid" blast crisis but were not seen in any case of acute lymphoblastic leukaemia. Phi bodies were more numerous when the reaction was carried out at pH 9.7, and their number was significantly reduced in the presence of 3-amino 1,2,4-triazole. Both findings suggest that the Phi bodies derive from catalase-containing granules (microperoxisomes) and are distinct from Auer rods, which derive from peroxidase-containing (primary) granules. Like Auer rods, Phi bodies appear to be characteristics of immature myeloid cells in leukaemia but are seen with a higher frequency than Auer rods in acute myeloid leukemia. Images p154-a PMID:6262384

  11. Prevention and Treatment of Avian Influenza A Viruses in People

    MedlinePlus

    ... Research Making a Candidate Vaccine Virus Related Links Influenza Types Seasonal Avian Swine Variant Pandemic Other Get ... Button Past Newsletters Prevention and Treatment of Avian Influenza A Viruses in People Language: English Español ...

  12. Leukaemia mortality around French nuclear sites.

    PubMed Central

    Hattchouel, J. M.; Laplanche, A.; Hill, C.

    1995-01-01

    This study was designed to investigate leukaemia mortality in the population under the age of 25 residing around the 13 French nuclear sites operating in 1985. In four geographical zones defined according to the distance from the site, 503 exposed communes were identified and followed up between 1968 and 1989. A total of 4,132,000 person-years of observation were accumulated. The number of leukaemia deaths observed (69) did not differ from the expected number (86.15) estimated according to national mortality statistics. There was no difference in the risks of leukaemia mortality according to sex, age, type of installation and no trend with an increasing distance from installations. PMID:7880754

  13. Stem cell origins of leukaemia and curability.

    PubMed Central

    Greaves, M. F.

    1993-01-01

    It is suggested that most childhood acute lymphoblastic leukaemias and some other paediatric cancers are chemo-curable because they arise in stem cell populations that are functionally transient, chemosensitive and programmed for apoptosis. Most adult acute leukaemias are chemo-incurable at least in part because they originate in relatively drug resistant stem cells with extensive self-renewal capacity. The latter property in turn increases the probability of clones evolving with multi-drug resistance. Particular mutations may superimpose additional adverse features on leukaemic cells. PMID:8439493

  14. Cytogenetic findings in acute leukaemias of infants.

    PubMed Central

    Lampert, F.; Harbott, J.; Ritterbach, J.

    1992-01-01

    Of 706 children, 528 with acute lymphoblastic leukaemia (ALL) and 178 with acute myelocytic leukaemia (AML), whose leukaemia karyotypes could be successfully analysed, 48 were infants less than 1 year of age, 28 with ALL (5% of ALL patients) and 20 with AML (11% of AML patients). In contrast to older children. ALL-leukaemocytogenetics in infants was characterised by lack of hyperdiploidy with over 50 chromosomes and higher incidence of pseudodiploidy. Thirteen (= 46%) infants had an 11q23 aberration, and 11 of them had t(4;11). In AML, nine (= 45%) infants also had an 11q23 abnormality, e.g. t(9;11). Thus, the 11q23 aberration was present in almost 50% of all leukaemia karyotypes of infants. In ALL of infants, the CALLA negative, pre-pre-B immunophenotype prevailed. In AML of infants, the monocytic subtype dominated. A biphenotypic morphology (lymphoid-monocytic) with the expression of lymphoid and myeloid antigens was seen in several ALL and AML cases. In conclusion, leukaemogenesis in infants is a rare event, arising in stem cells of very early hematopoietic differentiation (probably due to gene rearrangement errors, most frequently at FRA11B), and differs from leukaemogenesis in older age groups by unique clinical and cellular features. PMID:1503922

  15. An algorithm for leukaemia immunophenotype pattern recognition.

    PubMed

    Petrovecki, M; Marusić, M; Dezelić, G

    1993-01-01

    Since leukaemia-specific leucocyte antigen has not been identified to date, the immunological diagnosis of leukaemia is achieved through the application of a wide set of monoclonal antibodies specific for surface markers on leukaemic cells. Thus, the interpretation of leukaemia immunophenotype seems to be a mathematically determined comparison of 'what we found' and 'what we know' about it. The objective of this study was to establish an algorithm for transformation of empirical rules into mathematical values to achieve proper decisions. Recognition of leukaemia phenotype was performed by comparison of phenotyping data with reference data, followed by scoring of such comparisons. Systematic scoring resulted in the formation of new numerical variables allocated to each state, whereas a most significant variable was described as a complex measure of compatibility. A system of recognized states was described by mathematical variables measuring the confidence of information systems, i.e. maximal, total and relative entropy. The entire algorithm was derived by matrix algebra and coded in a high-level program language. The list of the states recognized appeared to be especially helpful in differential diagnosis, occasionally pointing to states that had not been in the scientist's mind at the start of the analysis. PMID:8366688

  16. Rhinocerebral zygomycosis in acute lymphoblastic leukaemia.

    PubMed

    Sica, S; Morace, G; La Rocca, L M; Etuk, B; Di Mario, A; Pagano, L; Zini, G; Rutella, S; Leone, G

    1993-01-01

    We describe a patient with acute lymphoblastic leukaemia who developed rhinocerebral zygomycosis during the aplastic phase induced by antineoplastic chemotherapy. The patient was treated with fluconazole intravenously (400 mg daily) for 30 days and underwent surgical debridement. As a result of this treatment a complete remission of the zygomycosis-associated symptoms was observed. The possibility of treating zygomycosis with fluconazole is discussed. PMID:8015558

  17. Acute myeloid leukaemia after treatment for acute lymphoblastic leukaemia in girl with Bloom syndrome

    PubMed Central

    Adams, Madeleine; Jenney, Meriel; Lazarou, Laz; White, Rhian; Birdsall, Sanda; Staab, Timo; Schindler, Detlev; Meyer, Stefan

    2014-01-01

    Bloom syndrome (BS) is an inherited genomic instability disorder caused by disruption of the BLM helicase and confers an extreme cancer predisposition. Here we report on a girl with BS who developed acute lymphoblastic leukaemia (ALL) at age nine, and treatment-related acute myeloid leukaemia (t-AML) aged 12. She was compound heterozygous for the novel BLM frameshift deletion c.1624delG and the previously described c.3415C>T nonsense mutation. Two haematological malignancies in a child with BS imply a fundamental role for BLM for normal haematopoiesis, in particular in the presence of genotoxic stress. PMID:24932421

  18. Acute myeloid leukaemia after treatment for acute lymphoblastic leukaemia in girl with Bloom syndrome.

    PubMed

    Adams, Madeleine; Jenney, Meriel; Lazarou, Laz; White, Rhian; Birdsall, Sanda; Staab, Timo; Schindler, Detlev; Meyer, Stefan

    2013-09-18

    Bloom syndrome (BS) is an inherited genomic instability disorder caused by disruption of the BLM helicase and confers an extreme cancer predisposition. Here we report on a girl with BS who developed acute lymphoblastic leukaemia (ALL) at age nine, and treatment-related acute myeloid leukaemia (t-AML) aged 12. She was compound heterozygous for the novel BLM frameshift deletion c.1624delG and the previously described c.3415C>T nonsense mutation. Two haematological malignancies in a child with BS imply a fundamental role for BLM for normal haematopoiesis, in particular in the presence of genotoxic stress. PMID:24932421

  19. Time space distribution of childhood leukaemia in the Netherlands.

    PubMed Central

    van Steensel-Moll, H A; Valkenburg, H A; Vandenbroucke, J P; van Zanen, G E

    1983-01-01

    In the western part of the Netherlands during 1973-80 leukaemia was diagnosed in 293 patients aged under 15 years. An overall incidence rate of 2.91 per 100000 person years was calculated. No seasonal influence on months of birth or months of diagnosis of these patients could be traced by the method of Edwards. Time space clustering was looked for by both methods of Mantel and Knox. No significant time space clustering of date and place of diagnosis of childhood leukaemia was found in all types of leukaemia, acute lymphocytic leukaemia (ALL), ALL in boys and girls, ALL in children under 6 years at diagnosis, and in acute non-lymphocytic leukaemia. PMID:6577127

  20. Intravenous immune globulin in chronic lymphocytic leukaemia.

    PubMed Central

    Gamm, H; Huber, C; Chapel, H; Lee, M; Ries, F; Dicato, M A

    1994-01-01

    The most common complication of chronic lymphocytic leukaemia (CLL) is infection, which occurs mainly in advanced stages of disease or in those patients with hypogammaglobulinaemia. Intravenous immune globulin (IVIG) has been shown to be a useful prophylactic therapy against infections in such patients. A randomized, double-blind study on 36 patients receiving either 500 mg/kg or 250 mg/kg IVIG every 4 weeks was undertaken to determine the dose regimen required. There was no significant difference in the two treatment groups and we found that CLL patients were equally protected with low-dose IVIG. PMID:8033428

  1. Childhood leukaemia, nuclear sites, and population mixing.

    PubMed

    Kinlen, L

    2011-01-01

    The excess of childhood leukaemia (CL) in Seascale, near the Sellafield nuclear reprocessing site in rural NW England, suggested that an epidemic of an underlying infection, to which CL is a rare response, is promoted by marked population mixing (PM) in rural areas, in which the prevalence of susceptibles is higher than average. This hypothesis has been confirmed by 12 studies in non-radiation situations. Of the five established CL excesses near nuclear sites, four are associated with significant PM; in the fifth, the Krummel power station in Germany, the subject has not been thoroughly investigated. PMID:21063418

  2. Childhood leukaemia, nuclear sites, and population mixing

    PubMed Central

    Kinlen, L

    2011-01-01

    The excess of childhood leukaemia (CL) in Seascale, near the Sellafield nuclear reprocessing site in rural NW England, suggested that an epidemic of an underlying infection, to which CL is a rare response, is promoted by marked population mixing (PM) in rural areas, in which the prevalence of susceptibles is higher than average. This hypothesis has been confirmed by 12 studies in non-radiation situations. Of the five established CL excesses near nuclear sites, four are associated with significant PM; in the fifth, the Krummel power station in Germany, the subject has not been thoroughly investigated. PMID:21063418

  3. Distribution of ABO blood groups in acute leukaemias and lymphomas.

    PubMed

    Vadivelu, Murali K; Damodaran, Senthilkumar; Solomon, John; Rajaseharan, Annabelle

    2004-09-01

    We studied the distribution of ABO blood groups in Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukaemia and acute lymphoblastic leukaemia, in children up to the age of 12 years, in a hospital-based retrospective study. Blood group data were recorded from the case records of all the patients in a tertiary care centre with the diagnosis of Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukaemia and acute lymphoblastic leukaemia, during the period 1987-1997. There were 63 Hodgkin's lymphoma, 78 non-Hodgkin's lymphoma, 116 acute myeloid leukaemia and 522 acute lymphoblastic leukaemia patients. We assessed the distribution of ABO blood groups and the difference in the distribution from the source population. In Hodgkin's lymphoma, there were 45.6% [95% confidence interval (CI): 6.8-84.5] more patients with B blood group. In acute lymphoblastic leukaemia, there were 14.3% (95% CI: 3.2-25.2) more patients with O blood group. In Hodgkin's lymphoma and non-Hodgkin's lymphoma patients, there were 56.5% (95% CI: 19.9-85.4) and 52.9% (95% CI: 18.1-82.6) less patients with A blood group, respectively. This shows that the relationship between the ABO blood groups and haematological malignancies merits further investigation in a population-based prospective study. This is the first study of its kind in any Indian population. PMID:15175895

  4. Late relapses in acute promyelocytic leukaemia.

    PubMed

    Latagliata, Roberto; Carmosino, Ida; Breccia, Massimo; Minni, Antonio; Testi, Anna; Iorio, Nicol; Lo-Coco, Francesco; Avvisati, Giuseppe; Petti, Maria Concetta; Mandelli, Franco; Cimino, Giuseppe

    2007-01-01

    From January 1988 to December 1997, among 53 acute promyelocytic leukaemia patients in 1st complete remission (CR) after 5 years from diagnosis, we observed 5 late relapses (9.4%) after 60, 61, 71, 101 and 155 months from diagnosis; 3 of those late relapses (7.7%) occurred among 39 patients previously treated with all-trans-retinoic acid. An involvement of the mastoid occurred in 3/5 patients (60%), compared with 2/32 patients (6.3%) at an early relapse (p < 0.02). As to the treatment of the late relapse, 1 patient received all-trans-retinoic acid alone followed by allogeneic transplantation and 4 patients were treated according to the GIMEMA 0191 protocol. All patients achieved a 2nd CR and are still alive: 4 in the 2nd molecular CR after 6, 33, 34 and 115 months; 1 relapsed after 15 months and is now in the 3rd CR. In conclusion, a late relapse occurred in a sizeable fraction of acute promyelocytic leukaemia patients: the high rate of ear involvement might be explained considering the ear as a 'disease sanctuary'. PMID:17135723

  5. Maxillo-ethmoidal chloroma in acute myeloid leukaemia: Case report

    PubMed Central

    Ferri, E; Minotto, C; Ianniello, F; Cavaleri, S; Armato, E; Capuzzo, P

    2005-01-01

    Summary Chloroma, also called Granulocytic Sarcoma or Myeloid Sarcoma, is a rare malignant extra-medullary neoplasm of myeloid precursor cells. It is usually associated with myeloproliferative disorders but its appearance may precede the onset of leukaemia. Chloroma may be found in several extracranial sites. Involvement of the head and neck region is uncommon. Differential diagnosis is often difficult and includes acute lymphoblastic leukaemia, large cell NHL, lymphoblastic lymphoma and Ewing’s sarcoma. The case is presented of a maxillo-ethmoidal chloroma occurring in a case of poor prognosis acute myeloid leukaemia, emphasizing the clinical and cyto-histological features and problems concerning differential diagnosis. PMID:16450777

  6. Acute myeloid leukaemia (M6B: pure acute erythroid leukaemia) in a Thoroughbred foal.

    PubMed

    Forbes, G; Feary, D J; Savage, C J; Nath, L; Church, S; Lording, P

    2011-07-01

    A 10-week-old Thoroughbred filly was referred for anaemia of 4 weeks' duration. Haematology revealed severe anaemia and panleucopenia. Cytological examination of bone marrow smears revealed a myeloid to erythroid ratio <0.02:1 (reference range 0.5-2.4:1.0) and an abundance of erythroid precursor cells. The erythroid cell population included rubriblasts, prorubricytes and rubricytes, with only scant numbers of metarubricytes present. There were numerous mitotic erythroid cells, some of which were atypical and megaloblastic. These cytomorphological changes are consistent with pure acute erythroid leukaemia. No treatment was instituted and the filly died three days after presentation. This case illustrates the need to consider both haematology and bone marrow findings to establish a diagnosis of pure erythroid leukaemia. To our knowledge, there is no documented case of acute myeloproliferative disease in horses involving cells of erythroid lineage, but this condition should be considered a differential diagnosis for horses presenting with anaemia. PMID:21696377

  7. Gene Therapy in Treating Patients With Human Immunodeficiency Virus-Related Lymphoma Receiving Stem Cell Transplant

    ClinicalTrials.gov

    2016-06-08

    HIV Infection; Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Plasmablastic Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Burkitt Lymphoma; Recurrent Follicular Lymphoma; Stage III Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  8. Herpes simplex virus-related oral mucositis in patients with lymphoma.

    PubMed

    Guerrero, Maria D; Swenson, Karen K

    2014-05-01

    A 58-year-old man named J.S. was diagnosed with non-Hodgkin lymphoma and underwent treatment with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. He presented to his local outpatient clinic for evaluation and laboratory tests on day 10 after cycle 3. During this visit, J.S. reported great difficulty opening his mouth with significant gingival and lingual pain when eating and drinking in spite of prophylactic oral care. Laboratory test results revealed a white blood cell count of 0.9 k/ul, hemoglobin level of 8.9 g/dl, platelets of 100 k/ul, serum creatinine level of 1 mg/dl, and blood urea nitrogen level of 29 mg/dl. PMID:24769598

  9. Non-invasive diagnosis of hepatitis B virus-related cirrhosis

    PubMed Central

    Lee, Sangheun; Kim, Do Young

    2014-01-01

    Chronic hepatitis B (CHB) infection is a major public health problem associated with significant morbidity and mortality worldwide. Twenty-three percent of patients with CHB progress naturally to liver cirrhosis, which was earlier thought to be irreversible. However, it is now known that cirrhosis can in fact be reversed by treatment with oral anti-nucleotide drugs. Thus, early and accurate diagnosis of cirrhosis is important to allow an appropriate treatment strategy to be chosen and to predict the prognosis of patients with CHB. Liver biopsy is the reference standard for assessment of liver fibrosis. However, the method is invasive, and is associated with pain and complications that can be fatal. In addition, intra- and inter-observer variability compromises the accuracy of liver biopsy data. Only small tissue samples are obtained and fibrosis is heterogeneous in such samples. This confounds the two types of observer variability mentioned above. Such limitations have encouraged development of non-invasive methods for assessment of fibrosis. These include measurements of serum biomarkers of fibrosis; and assessment of liver stiffness via transient elastography, acoustic radiation force impulse imaging, real-time elastography, or magnetic resonance elastography. Although significant advances have been made, most work to date has addressed the diagnostic utility of these techniques in the context of cirrhosis caused by chronic hepatitis C infection. In the present review, we examine the advantages afforded by use of non-invasive methods to diagnose cirrhosis in patients with CHB infections and the utility of such methods in clinical practice. PMID:24574713

  10. Epidemiological Evidence of Childhood Leukaemia Around Nuclear Power Plants

    PubMed Central

    Janiak, Marek K.

    2014-01-01

    A few reports of increased numbers of leukaemia cases (clusters) in children living in the vicinity of nuclear power plants (NPP) and other nuclear installations have triggered a heated debate over the possible causes of the disease. In this review the most important cases of childhood leukaemia clusters around NPPs are described and analyzed with special emphasis on the relationship between the environmental exposure to ionizing radiation and the risk of leukaemia. Since, as indicated, a lifetime residency in the proximity of an NPP does not pose any specific health risk to people and the emitted ionizing radiation is too small to cause cancer, a number of hypotheses have been proposed to explain the childhood leukaemia clusters. The most likely explanation for the clusters is ‘population mixing’, i.e., the influx of outside workers to rural regions where nuclear installations are being set up and where local people are not immune to pathogens brought along with the incomers. PMID:25249830

  11. Leukaemia cutis after starting bendamustine: cause or coincidence?

    PubMed

    Mawri, Sagger; Nabi, Shahzaib; Jallad, Bassel; Won, Joseph

    2015-01-01

    A 55-year-old man with a history of chronic lymphocytic leukaemia presented with diffuse skin lesions that began 1 week after starting a new chemotherapy regimen with bendamustine and rituximab. The lesions appeared as erythematous papules that were neither itchy nor tender, and did not blanch with pressure. Initially, they began on his scalp and flanks and, over the next few days, spread diffusely throughout his body, becoming darker in colour. Skin biopsy showed atypical clonal B-cell proliferation in a perivascular, periadnexal and dermal band-like distribution, which was further characterised by immunohistochemical evaluation. These findings were suggestive of leukaemia cutis and consistent with the patient's chronic lymphocytic leukaemia, which was previously confirmed by bone marrow biopsy. The bendamustine was stopped and the patient's chemotherapy regimen was switched to fludarabine, cyclophosphamide and rituximab. Shortly thereafter, the leukaemia cutis regressed significantly. PMID:26392439

  12. Acute myelomonocytic leukaemia presenting as xanthomatous skin eruption

    PubMed Central

    O'Donnell, JR; Tansey, P; Chung, P; Burnett, AK; Thomson, J; McDonald, GA

    1982-01-01

    A case of acute myelomonocytic leukaemia (AMMOL) is reported in which skin infiltration with xanthomatous nodules was the presenting feature. The histological, including ultrastructural, appearances are described. Images PMID:6958680

  13. Adult T-cell leukaemia lymphoma in an aborigine.

    PubMed

    Kirkland, M A; Frasca, J; Bastian, I

    1991-10-01

    A 44-year-old Aborigine with Adult T-cell Leukaemia/Lymphoma (ATLL) due to HTLV-I is reported. He presented with transverse myelitis of subacute onset, and subsequently developed frank T-cell leukaemia complicated by splenomegaly and hypercalcaemia. Cell surface marker studies showed a phenotype of CD3+ CD4+ CD8- CD25+, and serological and molecular studies confirmed HTLV-I infection. This is the first report of ATLL in an Australian Aborigine. PMID:1759923

  14. Viruses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lytic bacteriophages, viruses which infect and lyse bacterial cells, can provide a natural method to reduce bacterial pathogens on produce commodities. The use of multi-phage cocktails is most likely to be effective against bacterial pathogens on produce commodities, and minimize the development of...

  15. Immunotherapy in Chronic Lymphocytic Leukaemia (CLL).

    PubMed

    Freeman, Ciara L; Gribben, John G

    2016-02-01

    Chronic lymphocytic leukaemia (CLL) is well known to generate impaired immune responses in the host, with the malignant clone residing in well-vascularized tissues and circulating in peripheral blood but also in close proximity to effector cells that are capable, if activated appropriately, of eliciting a cytotoxic response. These, combined with the fact that this is frequently a condition affecting older patients with co-morbidities often unfit for many "traditional" cytotoxic agents with their significant associated toxicities, make CLL an ideal candidate for the development of immunotherapy. The impressive results seen with the addition of a monoclonal antibody, rituximab, to a chemotherapy backbone, for example, is testament to how effective harnessing an immune-mediated response in CLL can be. This review serves to outline the available arsenal of immunotherapies-past and present-demonstrated to have potential in CLL with some perspectives on how the landscape in this disease may evolve in the future. PMID:26857283

  16. Sexuality of young women surviving leukaemia

    PubMed Central

    Puukko, L; Hirvonen, E; Aalberg, V; Hovi, L; Rautonen, J; Siimes, M

    1997-01-01

    Accepted 7 December 1996
 This study was designed to assess the sexuality of young women surviving acute leukaemia in childhood or early adolescence. Thirty of 31 survivors were compared with 50 healthy age matched controls. Three methods were used: a self report questionnaire, a face to face interview conducted by a psychiatrist, and a projective psychological test. The age at initiation of dating and sexual activity, the frequency of sexual intercourse, and opinions on sexual behaviour were similar in the two groups. With regard to inner sexuality, however, the survivors differed significantly from the healthy controls. Their images of sexuality were more restrictive, and their attitudes, especially those concerning sexual pleasure, were more negative than those of the controls. Sexual identity among the survivors was less often feminine and more often infantile as compared with the controls. The findings obtained with the three methods of assessment were concordant.

 PMID:9135258

  17. Incidence of childhood leukaemia in The Netherlands (1973-1980).

    PubMed Central

    van Steensel-Moll, H. A.; Valkenburg, H. A.; van Zanen, G. E.

    1983-01-01

    The childhood leukaemia incidence rate for the Netherlands was estimated at 3.11 per 100.000 children (aged 0-15 year) per year, based on a complete nation-wide childhood leukaemia registry comprising the period 1973-1980. Acute lymphocytic leukaemia (ALL) accounted for 82.4% of the patients, acute non-lymphocytic leukaemia for 13.6% and chronic myeloid leukaemia for 2.9%. ALL occurred more frequently in boys (sex ratio 1.2). The highest ALL rate was observed in the 3-4 year age group. These figures corresponded with the data of the Manchester Children's Tumour Registry. Neither the incidence rates according to year of diagnosis nor the incidence rates according to year of birth showed a significant trend with time. The total leukaemia incidence rate in urban areas was somewhat higher than in rural areas. While the direct comparison of the incidence rate between these areas is not significant, the trend over the three categories of urbanisation is significant. PMID:6573905

  18. Leukaemia incidence in the Techa River Cohort: 1953–2007

    PubMed Central

    Krestinina, L Y; Davis, F G; Schonfeld, S; Preston, D L; Degteva, M; Epifanova, S; Akleyev, A V

    2013-01-01

    Background: Little is known about leukaemia risk following chronic radiation exposures at low dose rates. The Techa River Cohort of individuals residing in riverside villages between 1950 and 1961 when releases from the Mayak plutonium production complex contaminated the river allows quantification of leukaemia risks associated with chronic low-dose-rate internal and external exposures. Methods: Excess relative risk models described the dose–response relationship between radiation dose on the basis of updated dose estimates and the incidence of haematological malignancies ascertained between 1953 and 2007 among 28 223 cohort members, adjusted for attained age, sex, and other factors. Results: Almost half of the 72 leukaemia cases (excluding chronic lymphocytic leukaemia (CLL)) were estimated to be associated with radiation exposure. These data are consistent with a linear dose response with no evidence of modification. The excess relative risk estimate was 0.22 per 100 mGy. There was no evidence of significant dose effect for CLL or other haematopoietic malignancies. Conclusion: These analyses demonstrate that radiation exposures, similar to those received by populations exposed as a consequence of nuclear accidents, are associated with long-term dose-related increases in leukaemia risks. Using updated dose estimates, the leukaemia risk per unit dose is about half of that based on previous dosimetry. PMID:24129230

  19. Frequency of adult T-cell leukaemia/lymphoma and HTLV-I in Ibadan, Nigeria.

    PubMed Central

    Williams, C. K.; Alexander, S. S.; Bodner, A.; Levine, A.; Saxinger, C.; Gallo, R. C.; Blattner, W. A.

    1993-01-01

    Sera from a small sample of adult blood donors, healthy school children and patients with lymphoma, leukaemia, non-haematologic cancer, congenital and inflammatory disorders from Ibadan, Nigeria were screened for HTLV-I antibody by an enzyme-linked immunoabsorbent assay and confirmed by investigational Western blot. Seventy-nine of 236 positively screened samples could not be tested for confirmation. Seropositive reactivity was observed in nine of 123 blood donors, and 3 of 46 healthy school children but banding patterns on Western blot were often sparse. Among non-Burkitt's non Hodgkin's lymphoma patients six of 30 were HTLV-I positive including four of four with clinical features of adult T-cell leukaemia (ATL). Other clinical conditions had a frequency of positivity indistinguishable from healthy donors. Western blot patterns ranged from strong with multiple bands, which were uncommon, to those with only p24 and p21 envelope positive which were frequent. Given the relative paucity of clinical ATL and the unusual Western blot patterns the true rate of HTLV-I infection may be lower than estimated. It is possible that a cross-reactive HTLV-I-like virus accounts for this pattern. PMID:8471436

  20. Inhibition of proliferation by agricultural plant extracts in seven human adult T-cell leukaemia (ATL)-related cell lines.

    PubMed

    Kai, Hisahiro; Akamatsu, Ena; Torii, Eri; Kodama, Hiroko; Yukizaki, Chizuko; Sakakibara, Yoichi; Suiko, Masahito; Morishita, Kazuhiro; Kataoka, Hiroaki; Matsuno, Koji

    2011-07-01

    Adult T-cell leukaemia (ATL) is caused by human T-cell leukaemia virus type I (HTLV-I) infection and is resistant to conventional chemotherapy. We evaluated the inhibitory effects of agricultural plants on the proliferation of seven ATL-related human leukaemia cells, using three ATL cell lines (ED, Su9T01 and S1T), two human T-cell lines transformed by HTLV-I infection (HUT-102 and MT-2) and two HTLV-I-negative human T-cell acute lymphoblastic leukaemia cell lines (Jurkat and MOLT-4). A total of 52 samples of 80% ethanol extracts obtained from 30 types of agricultural plants were examined. On the basis of IC(50) values, we selected samples with greater activity than genistein, which was used as a positive control. The highest inhibitory effect was observed with extracts from leaves of Vaccinium virgatum Aiton (blueberry) on four cell lines (ED, Su9T01, HUT-102 and Jurkat); seeds of Momordica charantia L. (bitter gourd) exhibited the second highest activity. The bitter gourd seeds suppressed the proliferation of three cell lines (Su9T01, HUT-102 and Jurkat). The extracts from edible parts of Ipomea batatas LAM. (sweet potato), edible parts of Colocasia esculenta (L.) Schott (taro), skin of taro and seeds of Prunus mume Sieb. et Zucc. (mume) showed markedly greater inhibitory effects on Su9T01 than genistein. These findings suggest that ATL-preventative bioactive compounds may exist in these agricultural plants, which are considered to be functional foods. PMID:21293936

  1. Mortality from brain cancer and leukaemia among electrical workers.

    PubMed Central

    Loomis, D P; Savitz, D A

    1990-01-01

    The relation of brain cancer and mortality from leukaemia to electrical occupations was investigated in a case-control study based on all deaths in 1985 and 1986 in the 16 states in the United States that report occupational data from death certificates to the national vital statistics registry. The case series comprised all 2173 men who died of primary brain cancer (International Classification of Diseases-9 ((ICD-9) code 191) and all 3400 who died of leukaemia (ICD-9 codes 204-208). Each was matched with 10 controls who died of other causes in the same year. Men employed in any electrical occupation had age race adjusted odds ratios (ORs) of 1.4 (95% confidence interval (CI) 1.1-1.7) for brain cancer and 1.0 (95% CI 0.8-1.2) for leukaemia, compared with men in all other occupations. Brain cancer odds ratios were larger for electrical engineers and technicians (OR 2.7, 95% CI 2.1-3.4), telephone workers (OR 1.6, 95% CI 1.1-2.4), electric power workers (OR 1.7, 95% CI 1.1-2.7), and electrical workers in manufacturing industries (OR 2.1, 95% CI 1.3-3.4). There was some evidence of excess leukaemia among the same groups (ORs of 1.1-1.5) despite absence of an association for all electrical workers. The excess of deaths from brain cancer was concentrated among men aged 65 or older, whereas leukaemia was associated with electrical work only among younger decedents and those with acute lymphocytic leukaemia. These results from a large and geographically diverse population corroborate reports of increased mortality from brain cancer among electrical workers, but gives only limited support to suggestions of excess deaths from leukaemia. PMID:2207035

  2. Maternal and birth characteristics in relation to childhood leukaemia.

    PubMed

    Podvin, Danise; Kuehn, Carrie M; Mueller, Beth A; Williams, Michelle

    2006-07-01

    Our objective was to investigate the association of childhood leukaemia with selected maternal and birth characteristics by conducting a population-based case-control study using linked cancer registry and birth certificate records for Washington State. We compared maternal and infant characteristics of 595 Washington-born residents <20 years old with leukaemia diagnosed during 1981-2003, and 5,950 control children, using stratified analysis and logistic regression. Maternal age 35+ years (odds ratio [OR] 1.5; 95% confidence interval [CI] 1.1, 2.0), infant birthweight 4,000+ g (OR 1.4; 95% CI 1.1, 1.8), neonatal jaundice (OR 1.5; 95% CI 1.1, 2.1), and Down's syndrome (OR 31.3; 95% CI 6.4, 153.4) were associated with an increased risk of leukaemia. Among women with 2+ pregnancies, having at least two prior early (<20 weeks' gestation) fetal deaths was also associated with an increased risk (OR 1.5; 95% CI 0.97, 2.1). Maternal unmarried status (OR 0.7; 95% CI 0.6, 0.9) and African American race (OR 0.5; 95% CI 0.3, 0.9) were associated with a decreased risk. These results were more marked for acute lymphocytic leukaemia (ALL) than for acute myeloid leukaemia (AML), and for leukaemia diagnosed <5 years of age. These results may provide clues to the aetiology of childhood leukaemia. Genetic epidemiological studies are needed to expand our knowledge of inherent and possibly prenatal influences on the occurrence of this disease. PMID:16879503

  3. Genetic susceptibility in childhood acute leukaemias: a systematic review

    PubMed Central

    Brisson, Gisele D; Alves, Liliane R; Pombo-de-Oliveira, Maria S

    2015-01-01

    Acute leukaemias (AL) correspond to 25–35% of all cancer cases in children. The aetiology is still sheltered, although several factors are implicated in causality of AL subtypes. Childhood acute leukaemias are associated with genetic syndromes (5%) and ionising radiation as risk factors. Somatic genomic alterations occur during fetal life and are initiating events to childhood leukaemia. Genetic susceptibility has been explored as a risk factor, since environmental exposure of the child to xenobiotics, direct or indirectly, can contribute to the accumulation of somatic mutations. Hence, a systematic review was conducted in order to understand the association between gene polymorphisms and childhood leukaemia risk. The search was performed in the electronic databases PubMed, Lilacs, and Scielo, selecting articles published between 1995 and 2013. This review included 90 case-control publications, which were classified into four groups: xenobiotic system (n = 50), DNA repair (n = 16), regulatory genes (n = 15), and genome wide association studies (GWAS) (n = 9). We observed that the most frequently investigated genes were: NQO1, GSTM1, GSTT1, GSTP1, CYP1A1, NAT2, CYP2D6, CYP2E1, MDR1 (ABCB1), XRCC1, ARID5B, and IKZF1. The collected evidence suggests that genetic polymorphisms in CYP2E1, GSTM1, NQO1, NAT2, MDR1, and XRCC1 are capable of modulating leukaemia risk, mainly when associated with environmental exposures, such as domestic pesticides and insecticides, smoking, trihalomethanes, alcohol consumption, and x-rays. More recently, genome wide association studies identified significant associations between genetic polymorphisms in ARID5B e IKZF1 and acute lymphoblastic leukaemia, but only a few studies have replicated these results until now. In conclusion, genetic susceptibility contributes to the risk of childhood leukaemia through the effects of gene–gene and gene–environment interactions. PMID:26045716

  4. Sequence heterogeneity of murine acquired immunodeficiency syndrome virus: the role of endogenous virus.

    PubMed

    Gayama, S; Vaupel, B A; Kanagawa, O

    1995-05-01

    A defective murine leukemia virus is the causative agent of murine acquired immunodeficiency syndrome (MAIDS). We have cloned cDNAs from both virus infected and non-infected cells using the PCR methods with primers corresponding to the franking sequence of the unique p12 gag gene. Sequence analysis of these cDNA clones revealed: (i) the presence of endogenous virus related to MAIDS virus in C57BL/6 mice, (ii) B cell lineage specific expression of endogenous virus and (iii) extensive heterogeneity of MAIDS virus recovered from virus infected cells due to the recombination of the related viruses (defective pathogenic virus, ecotropic virus and endogenous virus). These findings suggest that the creation of virus variants in infected cells may play an important role in virus pathogenesis and escape from immune attack during the development of MAIDS. PMID:7547712

  5. Heterogeneity of T cell lymphoblastic leukaemias.

    PubMed Central

    Gómez, E; San Miguel, J F; González, M; Orfao, A; López-Berges, C; Ríos, A; López Borrasca, A

    1991-01-01

    Twenty eight out of 170 consecutive cases of acute lymphoblastic leukaemia (ALL) were examined. They were of T cell origin, with the following distribution: seven (28%) cases had pre-T or prothymic features; nine (36%) cases showed early thymocytic features, six (24%) had cortical features; and three (12%) had a "mature" phenotype. The remaining three cases could not be sub-classified. A striking finding was that pre-T ALL differed from intrathymic ALL not only in the absence of both E rosettes and intrathymic differentiation antigens, but also in the expression of two non-lineage specific antigens HLA-DR and CD10. Both antigens appear in the bone marrow from the very first stages of lymphoid differentiation, implying that the origin for pre-T ALL is bone marrow. A comparison of the clinical features of pre-T and thymic ALL showed that pre-T ALL disease showed a pattern more similar to non-T ALL disease: a lower incidence of mediastinal mass, absence of extrahaematopoietic disease, lower white cell counts and haemoglobin concentrations, and a higher incidence of bone pain. No obvious difference in response to treatment was apparent. The results show that T-ALL is not only a heterogeneous immunological group but also suggest that it may have different origins: bone marrow for pre-T ALL and the thymus for thymic ALL. PMID:1890194

  6. Molecular therapy for acute myeloid leukaemia.

    PubMed

    Coombs, Catherine C; Tallman, Martin S; Levine, Ross L

    2016-05-01

    Acute myeloid leukaemia (AML) is a heterogeneous disease that is, in general, associated with a very poor prognosis. Multiple cytogenetic and molecular abnormalities that characterize different forms of AML have been used to better prognosticate patients and inform treatment decisions. Indeed, risk status in patients with this disease has classically been based on cytogenetic findings; however, additional molecular characteristics have been shown to inform risk assessment, including FLT3, NPM1, KIT, and CEBPA mutation status. Advances in sequencing technology have led to the discovery of novel somatic mutations in tissue samples from patients with AML, providing deeper insight into the mutational landscape of the disease. The majority of patients with AML (>97%) are found to have a clonal somatic abnormality on mutational profiling. Nevertheless, our understanding of the utility of mutation profiling in clinical practice remains incomplete and is continually evolving, and evidence-based approaches to application of these data are needed. In this Review, we discuss the evidence-base for integrating mutational data into treatment decisions for patients with AML, and propose novel therapeutic algorithms in the era of molecular medicine. PMID:26620272

  7. Epidemiology of chronic myeloid leukaemia: an update.

    PubMed

    Höglund, Martin; Sandin, Fredrik; Simonsson, Bengt

    2015-04-01

    National and regional population-based registries are, provided diagnostic accuracy and full coverage of the target population, indispensible tools for epidemiological research. Chronic myeloid leukaemia (CML) registries with more comprehensive reporting may also provide complementary data on treatment outcome to those obtained from clinical trials. Reports from several European CML registries consistently show a crude annual incidence of 0.7-1.0/100,000, a median age at diagnosis of 57-60 years and a male/female ratio of 1.2-1.7. The incidence of CML has been stable over time. Worldwide, variations in the reported incidence of CML may be due to methodological issues, but a true difference between different geographical areas and/or ethnical subgroups cannot be excluded. The prevalence of CML is not well known but has been estimated to be 10-12/100,000 inhabitants with a steady increase due to the dramatic improvement in survival of these patients. In recent population-based studies, CML patients have an overall survival that is comparable to that shown in large clinical trials, though relative survival in patients >70 years is still decreased. The importance of socio-economic factors and health-care setting for outcome and the possible increased risk of secondary cancer in CML are areas of ongoing research. PMID:25814090

  8. Structural studies on leukaemia inhibitory factor

    SciTech Connect

    Norton, R.S.; Maurer, T.; Smith, D.K.; Nicola, N.A.

    1994-12-01

    Leukaemia Inhibitory Factor (LIF) is a pleiotropic cytokine that acts on a wide range of target cells, including mega-karyocytes, osteoblasts, hepatocytes, adipocytes, neurons, embryonic stem cells, and primordial germ cells. Many of its activities are shared with other cytokines, particularly interleukin-6, oncostatin-M, ciliary neurotrophic factor, and granulocyte colony-stimulating factor (G-CSF). Although secreted in vivo as a glycoprotein, nonglycosylated recombinant protein expressed in E. coli is fully active and has been used in our nuclear magnetic resonance (NMR) studies of the three-dimensional structure and structure-function relationships of LIF. With 180 amino acids and a molecular mass of about 20 kDa, OF is too large for direct structure determination by two-dimensional and three-dimensional {sup 1}HNMR. It is necessary to label the protein with the stable isotopes {sup 15}N and {sup 13}C and employ heteronuclear three-dimensional NMR in order to resolve and interpret the spectral information required for three-dimensional structure determination. This work has been undertaken with both human LIF and a mouse-human chimaera that binds to the human LIF receptor with the same affinity as the human protein and yet expresses in E. coli at much higher levels. Sequence-specific resonance assignments and secondary structure elements for these proteins will be presented and progress towards determination of their three-dimensional structures described.

  9. Leucapheresis for management of retinopathy in chronic myeloid leukaemia.

    PubMed

    Mohamed, Muhajir; Oakley, Carmen; McEwen, Fiona; Connelley, Georgina

    2015-01-01

    Chronic myeloid leukaemia is a myeloproliferative neoplasm characterised by granulocytic hyperplasia in the bone marrow and the presence of a specific cytogenetic abnormality known as Philadelphia chromosome with fusion of breakpoint cluster region (BCR) and ableson (ABL) genes. Retinopathy is a rare sight-threatening complication of chronic myeloid leukaemia, which occurs due to leucostasis in retinal blood vessels. We report a case of a patient who presented with visual impairment due to leucostasis, who was successfully managed by leucapheresis along with BCR-ABL tyrosine kinase inhibitor. PMID:26628310

  10. The seroepidemiology of human herpesvirus-6 (HHV-6) from a case-control study of leukaemia and lymphoma.

    PubMed

    Clark, D A; Alexander, F E; McKinney, P A; Roberts, B E; O'Brien, C; Jarrett, R F; Cartwright, R A; Onions, D E

    1990-05-15

    Sera from an epidemiological case-control study of leukaemias and lymphomas conducted between 1980 and 1986 were examined for reactivity to human herpesvirus-6 (HHV-6) by an indirect immunofluorescence assay. Statistical analyses of the data revealed higher HHV-6 seroprevalence and antibody titres in the cases, particularly evident in the disease subtypes acute myeloid leukaemia, Hodgkin's disease (HD), and low-grade non-Hodgkin's lymphoma. Within the control group alone, HHV-6 seroprevalence was placed at 55% at a serum dilution of 1:40. The controls also displayed higher seropositivity in females as compared with males. Further analyses suggest an association of increased HHV-6 seropositivity and geometric mean titre ratio with HD among young adults lacking social contact in the family group. This finding might indicate late exposure to HHV-6 in such persons and could possibly signify late exposure to a number of viruses, including those hypothesized as playing a role in the aetiology of HD. Previous reports have nominated Epstein-Barr virus as a possible candidate. Our results suggest that HHV-6 should be included in further investigations of the aetiology of HD. PMID:2159435

  11. Plasma fibronectin deficiency during chemotherapy of acute myeloid leukaemia.

    PubMed

    Brodin, B; Liedén, G; Malm, C; Vikrot, O

    1983-03-01

    Plasma fibronectin was determined using a laser nephelometric method in 10 patients with acute myeloid leukaemia undergoing chemotherapy. There was a continuous fall during the first 3 weeks to about 50% of the normal level. The decrease of fibronectin may contribute to the lowered resistance against infection characteristic of these patients. PMID:6574587

  12. Pulmonary function after treatment for acute lymphoblastic leukaemia in childhood.

    PubMed Central

    Nysom, K.; Holm, K.; Olsen, J. H.; Hertz, H.; Hesse, B.

    1998-01-01

    The aim of this study was to examine pulmonary function after acute lymphoblastic leukaemia in childhood and identify risk factors for reduced pulmonary function. We studied a population-based cohort of 94 survivors of acute lymphoblastic leukaemia in childhood who were in first remission after treatment without spinal irradiation or bone marrow transplantation. Pulmonary function test results were compared with reference values for our laboratory, based on 348 healthy subjects who had never smoked from a local population study. A median of 8 years after cessation of therapy (range 1-18 years) the participants had a slight, subclinical, restrictive ventilatory insufficiency and reduced transfer factor and transfer coefficient. The changes in lung function were related to younger age at treatment and to more dose-intensive treatment protocols that specified more use of cranial irradiation and higher cumulative doses of anthracyclines, cytosine arabinoside and intravenous cyclophosphamide than previous protocols. We conclude that, 8 years after treatment without bone marrow transplantation or spinal irradiation, survivors of childhood acute lymphoblastic leukaemia in first remission were without pulmonary symptoms but had signs of slight restrictive pulmonary disease including reduced transfer factor. The increased dose intensity of many recent protocols for childhood acute lymphoblastic leukaemia may lead to increased late pulmonary toxicity. PMID:9662245

  13. Immunological and ultrastructural studies in acute biphenotypic leukaemia.

    PubMed Central

    Shetty, V; Chitale, A; Matutes, E; Buccheri, V; Morilla, R; Catovsky, D

    1993-01-01

    AIMS--To compare the sensitivity of the ultrastructural method to detect myeloperoxidase (MPO) with light microscopy and immunocytochemistry using an anti-MPO antibody; to examine the expression of lymphoid antigens in relation to MPO activity in blast cells from cases of biphenotypic leukaemia. METHODS--Blast cells from 14 cases of biphenotypic acute leukaemia were analysed. Immunological markers were performed by single or double immunofluorescence staining on a flow cytometer. The presence of MPO was determined by light microscopy, electron microscopy on fixed and unfixed cells, and by immunoalkaline phosphatase with an anti-MPO antibody. The immunogold method was applied at the ultrastructural level to assess the expression of lymphoid and myeloid antigens at the same time as the MPO activity. RESULTS--Six of the 14 cases were initially classified as acute lymphoblastic leukaemia (ALL) and eight as acute myeloid leukaemia (AML). MPO activity was shown at the ultrastructural level in 4-99% blasts from all cases. Six of the 14 were MPO negative by light microscopy and three of these were negative with the antibody anti-MPO. Coexpression of lymphoid antigens (CD19, CD10, or CD2) and MPO was shown by the immunogold method in four out of 11 cases; in seven cases the blasts coexpressed myeloid antigens (CD13, CD33) and MPO. CONCLUSIONS--Electron microscopy is more sensitive for showing MPO than light microscopy and immunocytochemistry; the immunogold method combined with MPO used at the ultrastructural level can help to define the cell lineage involved in biphenotypic leukaemia by highlighting the myeloid component defined by MPO. Images PMID:8227405

  14. Time Trends and Geographical Distribution of Childhood Leukaemia in Basrah, Iraq, from 2004 to 2009

    PubMed Central

    Alrudainy, Laith A; Hassan, Jenan G; Salih, Hussam M; Abbas, Mohammed K; Majeed, Athar AS

    2011-01-01

    Objectives: This study aimed to assess the incidence and trend of childhood leukaemia in Basrah. Methods: This was a hospital-based cancer registry study carried out at the Pediatric Oncology Ward, Maternity & Children’s Hospital and other institutes in Basrah, Iraq. All children with leukaemia, aged 0 to 14 years diagnosed and registered in Basrah from January 2004 to December 2009 were included in the study. Their records were retrieved and studied. The pattern of childhood leukaemia by year of diagnosis, age at diagnosis, morphological subtypes, and geographical distribution was analysed. Rates of childhood leukaemia over time were calculated for six years using standard linear regression. Results: The total number of cases of childhood leukaemia was 181. The number of cases ranged from 21 in year 1, to 31 in the final year reaching a peak of 39 in 2006. Leukaemia rates did not change over the study period (test for trend was not significant, P = 0.81). The trend line shows a shift towards younger children (less than 5 years). The commonest types of leukaemia were acute lymphoblastic leukaemia (ALL), then acute myeloid leukaemia (AML) and finally chronic myeloid leukaemia (CML). Conclusion: Annual rates of childhood leukaemia in Basrah were similar to those in other countries with a trend towards younger children. This raises the question about the effect of environmental catastrophes in the alteration of some specific rates of childhood leukaemia, rather than the overall incidence rate. There is a need for further epidemiological studies to understand the aetiology of childhood leukaemia in Basrah. PMID:21969893

  15. Managing pregnancy in chronic myeloid leukaemia.

    PubMed

    Palani, Renuka; Milojkovic, Dragana; Apperley, Jane F

    2015-04-01

    Over the past decade, we have witnessed significant advances in knowledge of the biology and treatment of chronic myeloid leukaemia (CML). The development of molecular-targeted therapy with tyrosine kinase inhibitors (TKIs) has fundamentally changed the outcome of this disease. Treatment with TKIs is now the standard of care in patients with CML and has dramatically improved long-term survival in the majority of patients. Patients who achieve major molecular response (MMR) after 2 years of treatment with imatinib have survival rates comparable to those of the general population. The success of TKIs has led to durable molecular response and possibility of normal life expectancies, such that it is now timely to address quality of life aspects such as fertility, pregnancy and family planning. Pregnancy in CML presents specific management and therapeutic challenges for the patient and the physician. Despite the recent treatment advances, we still have limited data on the safety of TKIs in pregnancy and its effect on fertility. However, there is a cause for concern and heightened awareness following the occurrence of a constellation of rare congenital malformations and spontaneous abortions in association with imatinib therapy. When a patient becomes pregnant whilst receiving TKI therapy, the difficulty lies in balancing the risk to the foetus of continuing therapy versus the risk to the patient of treatment interruption and potentially losing optimal disease response. All couples should be counselled on the risks associated with pregnancy whilst receiving TKI therapy. This is an essential aspect in patient care and frequently not emphasized enough by physicians. At the time of diagnosis, fertility preservation should be discussed with both male and female patients of childbearing potential. They should be made aware of fertility options which are available such as semen cryopreservation, ovarian or oocyte retrieval and storage and embryo cryopreservation in view of the

  16. Phase I/II study of vaccination with dendritic-like leukaemia cells for the immunotherapy of acute myeloid leukaemia.

    PubMed

    Roddie, H; Klammer, M; Thomas, C; Thomson, R; Atkinson, A; Sproul, A; Waterfall, M; Samuel, K; Yin, J; Johnson, P; Turner, M

    2006-04-01

    Twenty-two patients with acute myeloid leukaemia were recruited into a phase I/II clinical trial investigating the vaccination of patients in complete remission (CR) with autologous dendritic-like leukaemia cells (DLLC). At trial entry, leukaemia cells were harvested and tested for their ability to undergo cytokine-induced dendritic cell differentiation. Patients were then treated with intensive chemotherapy. Five patients achieved both CR and had leukaemia cells that successfully underwent differentiation and therefore proceeded to vaccination. Four escalating doses of DLLC were administered weekly by subcutaneous injection. Vaccination was generally well tolerated although one patient developed extensive eczema and an increased antinuclear factor titre possibly indicating induction of autoimmunity. Development of anti-leukaemic T-cell responses was assessed by enzyme-linked immunospot analysis of gamma-interferon secreting T lymphocytes and by human leucocyte antigen tetramer analysis for WT1-specific T cells. Increases in anti-leukaemic T-cell responses were demonstrated in four patients, but only two of the five remained in remission more than 12 months postvaccination. The study has demonstrated that generation of DLLC is feasible in only a subgroup of patients and is currently neither broadly applicable or clinically effective. PMID:16611305

  17. Childhood leukaemia and population movements in France, 1990–2003

    PubMed Central

    Bellec, S; Baccaïni, B; Goubin, A; Rudant, J; Ripert, M; Hémon, D; Clavel, J

    2007-01-01

    In a national study, we investigated the incidence of childhood leukaemia (CL) over a 14-year period in France in relation to several measures based on the proportion of individuals who changed address between the last two national censuses. A positive association was found with the proportion of migrants who came from a distant place. The further the migrants came, the higher was the incidence of leukaemia, particularly among children aged 0–4 years in ‘isolated' communes at the time of diagnosis (RR=1.4, 95% CI: 1.1,1.8 in the highest category of migration distance). Although the role of the population density was less obvious, a more marked association was found above a certain threshold. No association with the proportion of commuters was observed. PMID:18087281

  18. Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview.

    PubMed

    Manola, Kalliopi N

    2013-10-01

    Acute leukaemia of ambiguous lineage (ALAL) is a rare complex entity with heterogeneous clinical, immunophenotypic, cytogenetic and molecular genetic features and adverse outcome. According to World Health Organization 2008 classification, ALAL encompasses those leukaemias that show no clear evidence of differentiation along a single lineage. The rarity of ALAL and the lack of uniform diagnostic criteria have made it difficult to establish its cytogenetic features, although cytogenetic analysis reveals clonal chromosomal abnormalities in 59-91% of patients. This article focuses on the significance of cytogenetic analysis in ALAL supporting the importance of cytogenetic analysis in the pathogenesis, diagnosis, prognosis, follow up and treatment selection of ALAL. It reviews in detail the types of chromosomal aberrations, their molecular background, their correlation with immunophenotype and age distribution and their prognostic relevance. It also summarizes some novel chromosome aberrations that have been observed only once. Furthermore, it highlights the ongoing and future research on ALAL in the field of cytogenetics. PMID:23888868

  19. Neuropsychological and neurological outcome after relapse of lymphoblastic leukaemia.

    PubMed

    Christie, D; Battin, M; Leiper, A D; Chessells, J; Vargha-Khadem, F; Neville, B G

    1994-04-01

    Fourteen children who relapsed after initial remission of leukaemia were studied. Six received a second course of cranial radiotherapy, while the remaining eight children were given total body irradiation before bone marrow transplantation. The postirradiation somnolence syndrome was common after cranial radiotherapy. All children had mild/soft neurological signs, mostly of coordination. None had a major motor disability. All but the youngest child had cataracts; two children required an operation for these. All children were growth hormone deficient. Verbal IQ, attention, and concentration were selectively reduced (with respect to normative levels). The time between the two treatments, age at relapse, and higher doses of radiotherapy all correlated with cognitive outcome, with girls showing greater impairments than boys. Only two children were performing at age appropriate levels on measures of academic achievement. It is concluded that neurological and neuropsychological morbidity is significantly increased by the current treatments prescribed after the relapse of leukaemia. PMID:7514391

  20. Encephalopathy in Acute Leukaemia Associated with Methotrexate Therapy

    PubMed Central

    Kay, H. E. M.; Knapton, P. J.; O'Sullivan, J. P.; Wells, D. G.; Harris, Ruth F.; Innes, Elizabeth M.; Stuart, J.; Schwartz, F. C. M.; Thompson, Eileen N.

    1972-01-01

    Seven patients are described in whom dementia developed during treatment with methotrexate for meningeal leukaemia. The patients presented with confusion, tremor, ataxia, irritability, and somnolence. There were major epileptic fits in two cases and in one case there was progression to coma and death. Necropsy findings in the latter showed infarcted areas in the temporal and parietal lobes, with no evidence of active leukaemic disease or of viral encephalitis. The condition has not responded to radiotherapy and no positive evidence of viral encephalitis has been obtained. On the other hand, when treated with folinic and folic acid the deterioration has been arrested and there has been some improvement; thus the condition appears to be due to methotrexate. The occurrence of so many cases within the past year of a condition not previously described is probably attributable to the introduction of intensive cytotoxic therapy directed against meningeal leukaemia. ImagesFIG. 2.FIG. 3.FIG. 4FIG. 5 PMID:4504035

  1. The genetics and mechanisms of T cell acute lymphoblastic leukaemia.

    PubMed

    Belver, Laura; Ferrando, Adolfo

    2016-07-25

    T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy derived from early T cell progenitors. In recent years genomic and transcriptomic studies have uncovered major oncogenic and tumour suppressor pathways involved in T-ALL transformation and identified distinct biological groups associated with prognosis. An increased understanding of T-ALL biology has already translated into new prognostic biomarkers and improved animal models of leukaemia and has opened opportunities for the development of targeted therapies for the treatment of this disease. In this Review we examine our current understanding of the molecular mechanisms of T-ALL and recent developments in the translation of these results to the clinic. PMID:27451956

  2. CCR4 frameshift mutation identifies a distinct group of adult T cell leukaemia/lymphoma with poor prognosis.

    PubMed

    Yoshida, Noriaki; Miyoshi, Hiroaki; Kato, Takeharu; Sakata-Yanagimoto, Mamiko; Niino, Daisuke; Taniguchi, Hiroaki; Moriuchi, Yukiyoshi; Miyahara, Masaharu; Kurita, Daisuke; Sasaki, Yuya; Shimono, Joji; Kawamoto, Keisuke; Utsunomiya, Atae; Imaizumi, Yoshitaka; Seto, Masao; Ohshima, Koichi

    2016-04-01

    Adult T cell leukaemia/lymphoma (ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next-generation sequencing-based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense (NS) and frameshift (FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell-surface CCR4 positivity. Semi-quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild-type (WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WT CCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology. PMID:26847489

  3. Novel small-molecule SIRT1 inhibitors induce cell death in adult T-cell leukaemia cells

    PubMed Central

    Kozako, Tomohiro; Suzuki, Takayoshi; Yoshimitsu, Makoto; Uchida, Yuichiro; Kuroki, Ayako; Aikawa, Akiyoshi; Honda, Shin-ichiro; Arima, Naomichi; Soeda, Shinji

    2015-01-01

    Adult T-cell leukaemia/lymphoma (ATL) is an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukaemia virus (HTLV)-1. The identification of new molecular targets for ATL prevention and treatment is desired. SIRT1, a nicotinamide adenine dinucleotide+ -dependent histone/protein deacetylase, plays crucial roles in various physiological processes, including aging and apoptosis. We previously reported that ATL patients had significantly higher SIRT1 protein levels than healthy controls. Here, we demonstrate that two novel small-molecule SIRT1 inhibitors, NCO-01/04, reduced cell viability and enhanced apoptotic cells in peripheral blood monocyte cells of patients with acute ATL, which has a poor prognosis. NCO-01/04 also reduced the cell viability with DNA fragmentation, Annexin V-positive cells, and caspase activation. However, a caspase inhibitor did not inhibit this caspase-dependent cell death. NCO-01/04 enhanced the endonuclease G level in the nucleus with loss of the mitochondrial transmembrane potential, which can promote caspase-independent death. Interestingly, NCO-01/04 increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation as well as autophagy. Thus, NCO-01/04 simultaneously caused caspase activation and autophagy. These results suggest that NCO-01/04 is highly effective against ATL cells in caspase-dependent or -independent manners with autophagy, and that its clinical application might improve the prognosis of patients with this fatal disease. PMID:26091232

  4. Leukaemia clusters in childhood: geographical analysis in Britain.

    PubMed Central

    Knox, E G

    1994-01-01

    STUDY OBJECTIVE--To validate previously demonstrated spatial clustering of childhood leukaemias by showing relative proximities of selected map features to cluster locations, compared with control locations. If clusters are real, then they are likely to be close to a determining hazard. DESIGN--Cluster postcode loci and partially matched control postcodes were compared in terms of distances to railways, main roads, churches, surface water, woodland areas, and railside industrial installations. Further supporting comparisons between non-clustered cases and random postcode controls with those map features representable as single grid points were made. SETTING--England, Wales, and Scotland 1966-83. SUBJECTS--Grid referenced registrations of 9406 childhood leukaemias and non-Hodgkin's lymphomas, including 264 pairs (or more) separated by < 150 m, and grid references of random postcodes in equal numbers. MAIN RESULTS--The 264 clusters showed relative proximities (or the inverse) to several map features, of which the most powerful was an association with railways. The non-railway associations seemed to be statistically indirect. Some railside industrial installations, identified from a railway atlas, also showed relative proximities to leukaemia clusters, as well as to non-clustered cases, but did not "explain" the railway effect. These installations, with seemingly independent geographical associations, included oil refineries, petrochemical plants, oil storage and oil distribution depots, power stations, and steelworks. CONCLUSIONS--The previously shown childhood leukaemia clusters are confirmed to be non-random through their systematic associations with certain map features when compared with the control locations. The common patterns of close association of clustered and non-clustered cases imply a common aetiological component arising from a common environmental hazard--namely the use of fossil fuels, especially petroleum. PMID:7964336

  5. Ebola Virus Disease: A Review of Its Past and Present.

    PubMed

    Murray, Michael J

    2015-09-01

    Ebola virus, the virus responsible for Ebola virus disease, has spawned several epidemics during the past 38 years. In 2014, an Ebola epidemic spread from Africa to other continents, becoming a pandemic. The virus's relatively unique structure, its infectivity and lethality, the difficulty in stopping its spread, and the lack of an effective treatment captured the world's attention. This article provides a brief review of the known history of Ebola virus disease, its etiology, epidemiology, and pathophysiology and a review of the limited information on managing patients with Ebola virus disease. PMID:26287303

  6. Genetic variegation of clonal architecture and propagating cells in leukaemia.

    PubMed

    Anderson, Kristina; Lutz, Christoph; van Delft, Frederik W; Bateman, Caroline M; Guo, Yanping; Colman, Susan M; Kempski, Helena; Moorman, Anthony V; Titley, Ian; Swansbury, John; Kearney, Lyndal; Enver, Tariq; Greaves, Mel

    2011-01-20

    Little is known of the genetic architecture of cancer at the subclonal and single-cell level or in the cells responsible for cancer clone maintenance and propagation. Here we have examined this issue in childhood acute lymphoblastic leukaemia in which the ETV6-RUNX1 gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or 'driver' copy number alterations. By multiplexing fluorescence in situ hybridization probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of subclones identified and a composite picture of subclonal architecture and putative ancestral trees assembled. Subclones in acute lymphoblastic leukaemia have variegated genetics and complex, nonlinear or branching evolutionary histories. Copy number alterations are independently and reiteratively acquired in subclones of individual patients, and in no preferential order. Clonal architecture is dynamic and is subject to change in the lead-up to a diagnosis and in relapse. Leukaemia propagating cells, assayed by serial transplantation in NOD/SCID IL2Rγ(null) mice, are also genetically variegated, mirroring subclonal patterns, and vary in competitive regenerative capacity in vivo. These data have implications for cancer genomics and for the targeted therapy of cancer. PMID:21160474

  7. Identification of novel Notch target genes in T cell leukaemia

    PubMed Central

    Chadwick, Nicholas; Zeef, Leo; Portillo, Virginia; Fennessy, Carl; Warrander, Fiona; Hoyle, Sarah; Buckle, Anne-Marie

    2009-01-01

    Background Dysregulated Notch signalling is believed to play an important role in the development and maintenance of T cell leukaemia. At a cellular level, Notch signalling promotes proliferation and inhibits apoptosis of T cell acute lymphoblastic leukaemia (T-ALL) cells. In this study we aimed to identify novel transcriptional targets of Notch signalling in the T-ALL cell line, Jurkat. Results RNA was prepared from Jurkat cells retrovirally transduced with an empty vector (GFP-alone) or vectors containing constitutively active forms of Notch (N1ΔE or N3ΔE), and used for Affymetrix microarray analysis. A subset of genes found to be regulated by Notch was chosen for real-time PCR validation and in some cases, validation at the protein level, using several Notch-transduced T-ALL and non-T-ALL leukaemic cell lines. As expected, several known transcriptional target of Notch, such as HES1 and Deltex, were found to be overexpressed in Notch-transduced cells, however, many novel transcriptional targets of Notch signalling were identified using this approach. These included the T cell costimulatory molecule CD28, the anti-apoptotic protein GIMAP5, and inhibitor of DNA binding 1 (1D1). Conclusion The identification of such downstream Notch target genes provides insights into the mechanisms of Notch function in T cell leukaemia, and may help identify novel therapeutic targets in this disease. PMID:19508709

  8. Chapter A7. Section 7.2. Fecal Indicator Viruses

    USGS Publications Warehouse

    Bushon, Rebecca N.

    2003-01-01

    More than 100 types of human pathogenic viruses may be present in fecal-contaminated waters. Coliphages are used as indicators of virus-related fecal contamination and of the microbiological quality of waters. This report provides information on the equipment, sampling protocols, and laboratory methods that are in standard use by U.S. Geological Survey (USGS) personnel for the collection of data on fecal indicator viruses.

  9. Adenovirus detection in Guthrie cards from paediatric leukaemia cases and controls

    PubMed Central

    Vasconcelos, G M; Kang, M; Pombo-de-Oliveira, M S; Schiffman, J D; Lorey, F; Buffler, P; Wiemels, J L

    2008-01-01

    Archived neonatal blood cards (Guthrie cards) from children who later contracted leukaemia and matched normal controls were assayed for adenovirus (AdV) C DNA content using two highly sensitive methods. In contrast to a previous report, AdV DNA was not detected at a higher frequency among neonates who later developed leukaemia, when compared with controls. PMID:19002185

  10. Chronic lymphocytic leukaemia in pregnancy: a case report and literature review

    PubMed Central

    Maxwell, Cynthia; Grady, Rosheen; Crump, Michael

    2009-01-01

    Chronic lymphocytic leukaemia is a rare condition reported in pregnancy. We review a case of a woman presenting for pregnancy care with active disease and review the literature on this condition. This case raises several important issues with regard to managing complex medical diseases such as leukaemia in pregnant women, including the role of multidisciplinary care.

  11. Acute leukaemia after exposure to a weed killer, 2-methyl-4-chlorphenoxyacetic acid.

    PubMed

    Timonen, T T; Palva, I P

    1980-01-01

    Acute leukaemia is known to develop in many cases of benzene-induced pancytopenia [1]. This is a report of the development of acute leukaemia in a patient who had apparently recovered from pancytopenia after chronic exposure to a weed killer, 2-methyl-4-chlorphenoxyacetic acid. PMID:6769284

  12. The risk of childhood leukaemia following exposure to ionising radiation--a review.

    PubMed

    Wakeford, Richard

    2013-03-01

    Since the early years of follow-up of the Japanese atomic-bomb survivors, it has been apparent that childhood leukaemia has a particular sensitivity to induction by ionising radiation, the excess relative risk (ERR) being expressed as a temporal wave with time since exposure. This pattern has been generally confirmed by studies of children treated with radiotherapy. Case-control studies of childhood leukaemia and antenatal exposure to diagnostic x-rays, a recent large cohort study of leukaemia following CT examinations of young people, and a recent large case-control study of natural background γ-radiation and childhood leukaemia have found evidence of raised risks following low-level exposure. These findings indicate that an ERR/Sv for childhood leukaemia of ~50, which may be derived from risk models based upon the Japanese atomic-bomb survivors, is broadly applicable to low dose or low dose-rate exposure circumstances. PMID:23296257

  13. Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer.

    PubMed Central

    Hawkins, M. M.; Wilson, L. M.; Stovall, M. A.; Marsden, H. B.; Potok, M. H.; Kingston, J. E.; Chessells, J. M.

    1992-01-01

    OBJECTIVE--To investigate the incidence and aetiology of secondary leukaemia after childhood cancer in Britain. DESIGN--Cohort study and a case-control study. SETTING--Britain and population based National Register of Childhood Tumours. SUBJECTS--Cohort of 16,422 one year survivors of childhood cancer diagnosed in Britain between 1962 and 1983, among whom 22 secondary leukaemias were observed. A case-control study of 26 secondary leukaemias observed among survivors of childhood cancer diagnosed in Britain between 1940 and 1983; 96 controls were selected matched for sex, type of first cancer, age at first cancer, and interval to diagnosis of secondary leukaemia. MAIN OUTCOME MEASURES--Dose of radiation averaged over patients' active bone marrow and total accumulated dose of epipodophyllotoxins, alkylating agents, vinca alkaloids, antimetabolites, and antibiotics (mg/m2) given for the original cancer. RESULTS--Cumulative risk of secondary leukaemia within the cohort did not exceed 0.5% over the initial five years beyond one year survival, except that after non-Hodgkin's lymphomas 1.4% of patients developed secondary leukaemia. Corresponding figure for patients treated for non-Hodgkin's lymphomas in the early 1980s was 4%. The relative risk of secondary leukaemia increased significantly with exposure to epipodophyllotoxins and dose of radiation averaged over patients' active bone marrow. Ten patients developed leukaemia after having an epipodophyllotoxin-teniposide in nine cases, etoposide in one. Chromosomal translocations involving 11q23 were observed relating to two secondary leukaemias from a total of six for which there were successful cytogenetic studies after administration of an epipodophyllotoxin. CONCLUSIONS--Epipodophyllotoxins acting alone or together with alkylating agents or radiation seem to be involved in secondary leukaemia after childhood cancer. PMID:1581717

  14. Uranium-235 and childhood leukaemia around Greenham Common airfield.

    PubMed

    Bithell, J F; Draper, G J

    1999-09-01

    There has been considerable publicity recently concerning the possible release of enriched uranium from the Greenham Common USAF base near Newbury in Berkshire. Evidence for the release relies on an internal report of the Atomic Weapons Research Establishment at Aldermaston, the authors of which postulated that it resulted from a fire in 1958 involving a B47 bomber standing on the runway. Their report contained a much publicised contour map of excess 235U levels estimated from the ratio of 235U to 238U in 26 evergreen leaf samples examined. The current concern of the inhabitants of Newbury centres mostly on the incidence of leukaemia, which was known beforehand to be slightly elevated in parts of West Berkshire, at least for young children. A number of cases have received considerable press publicity, with suggestions that their homes are located close to the base or the flight-path. The reports are, however, anecdotal and are not based on a complete register of cases. We have examined the evidence for this putative association by re-analysing the uranium data and determining the spatial relationship to the base of cases of childhood leukaemia diagnosed in the years 1966-87. We conclude that, although the excess uranium found has a non-random distribution, it does not support the pattern depicted by the contours and bears no relation to the incidence of childhood leukaemia for the period we examined. In any case, the increase in level of environmental radiation as a result of the putative release must be very small and is at variance with the reporting in some of the national press. PMID:10503703

  15. Acute leukaemias in adult Ethiopians in a teaching hospital.

    PubMed

    Shamebo, M

    1994-01-01

    Eighty-two consecutive cases of acute leukaemias in adult Ethiopians were admitted to the Tikur Anbessa (Black Lion) Hospital, a teaching and referral hospital in Addis Abeba, Ethiopia, from January 1982 to December 1992. These cases were studied to describe the clinical and haematological findings, response to therapy and prognosis. The age range was 13-78 (mean 29.6) years. The male to female ratio was 1.6:1. Acute myeloblastic (AML) and acute lymphoblastic (ALL) leukaemias occurred in 53.7% and 46.3%, respectively. The commonest symptoms were anaemia, fever and bleeding tendencies. The commonest signs were pallor, fever, sternal tenderness and purpura. Splenomegaly was more commonly seen in ALL patients. The haematological findings were anaemia (mean Hgb 6.35 g%), leucocytosis (mean WBC count 88,507/mm3) and thrombocytopenia (mean platelet count 31,700/mm3). Of the patients eligible for evaluation treated with chemotherapeutic agents, only 38.4% of ALL and 6.2% of AML achieved complete remission. Twenty-seven patients with ALL died from one day to 84 (median 1.0) months after diagnosis. Ten are lost to follow-up from two weeks to 36 (median 2.5) months, one is still alive 40 months after diagnosis. Thirty-nine of the AML patients died from one day to nine (median 0.3) months after diagnosis. Five are lost to follow-up from two weeks to two and a half (median 2.0) months. The causes of death were sepsis and bleeding, separately or in combination. Increasing numbers of acute leukaemia patients are being referred to this centre. Therefore, attempts should be made to equip it for the treatment of such cases. PMID:8187778

  16. Bone marrow fibrosis in childhood acute lymphoblastic leukaemia.

    PubMed Central

    Wallis, J P; Reid, M M

    1989-01-01

    Bone marrow trephine biopsy specimens were obtained at diagnosis from 63 of 76 consecutively presenting children with acute lymphoblastic leukaemia (ALL). The association between marrow fibrosis and presenting features, including immunophenotype, was analysed. Reticulin was increased in 45 of 56 cases in which blasts expressed B lineage markers, but in only one of seven with T-ALL. A weak association was also found between marrow fibrosis and splenomegaly in those with common ALL. Marrow fibrosis is apparently associated with some examples of ALL of B cell lineage, but precisely which subtypes and whether the phenomenon is clinically important remain to be determined. PMID:2613918

  17. Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia

    PubMed Central

    Ceccacci, Elena; Minucci, Saverio

    2016-01-01

    Histone deacetylases (HDACs) are a key component of the epigenetic machinery regulating gene expression, and behave as oncogenes in several cancer types, spurring the development of HDAC inhibitors (HDACi) as anticancer drugs. This review discusses new results regarding the role of HDACs in cancer and the effect of HDACi on tumour cells, focusing on haematological malignancies, particularly acute myeloid leukaemia. Histone deacetylases may have opposite roles at different stages of tumour progression and in different tumour cell sub-populations (cancer stem cells), highlighting the importance of investigating these aspects for further improving the clinical use of HDACi in treating cancer. PMID:26908329

  18. The Effects of Herbs and Fruits on Leukaemia

    PubMed Central

    Saedi, Tayebeh Azam; Md Noor, Sabariah; Ismail, Patimah; Othman, Fauziah

    2014-01-01

    In developing countries, herbal therapy is the first and basis form of treatment for most types of diseases. About 75–80% of the world's population prefers herbal therapy as a major treatment due to its better adequacy and satisfactoriness, which enhance human body's symmetry with minimal side effects. Fruits and plants have been presented from the past as promising tools in becoming a natural anticancer agents. Many of these plant extracts are currently used in cancer therapy and prevention. This review paper will particularly explore and emphasize on herbs and fruits used in the treatment of the leukaemia. PMID:25250054

  19. Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia.

    PubMed

    Ceccacci, Elena; Minucci, Saverio

    2016-03-15

    Histone deacetylases (HDACs) are a key component of the epigenetic machinery regulating gene expression, and behave as oncogenes in several cancer types, spurring the development of HDAC inhibitors (HDACi) as anticancer drugs. This review discusses new results regarding the role of HDACs in cancer and the effect of HDACi on tumour cells, focusing on haematological malignancies, particularly acute myeloid leukaemia. Histone deacetylases may have opposite roles at different stages of tumour progression and in different tumour cell sub-populations (cancer stem cells), highlighting the importance of investigating these aspects for further improving the clinical use of HDACi in treating cancer. PMID:26908329

  20. Antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after surgery: A comment for moving forward

    PubMed Central

    Zhong, Jian-Hong; Yang, Tian; Xiang, Bang-De; Li, Le-Qun; Ma, Liang

    2016-01-01

    Recurrence rate of hepatocellular carcinoma remains quite high even after surgery, and no postoperative therapies have been definitively shown to prevent hepatocellular carcinoma recurrence. A previous study showed that therapy with nucleos(t)ide analogues given to such patients after surgery significantly improved survival. However, many questions still exist about the usage of nucleos(t)ide analogues for patients with hepatocellular carcinoma after surgery. PMID:27168873

  1. Traffic-related air pollution and risk for leukaemia of an adult population.

    PubMed

    Raaschou-Nielsen, Ole; Ketzel, Matthias; Harbo Poulsen, Aslak; Sørensen, Mette

    2016-03-01

    Air pollution causes lung cancer, but associations with other cancers have not been established. We investigated whether long-term exposure to traffic-related air pollution is associated with the risk of the general population for leukaemia. We identified 1,967 people in whom leukaemia was diagnosed in 1992-2010 from a nation-wide cancer registry and selected 3,381 control people at random, matched on sex and year of birth, from the entire Danish population. Residential addresses since 1971 were traced in a population registry, and outdoor concentrations of NOx and NO2 , as indicators of traffic-related air pollution, were calculated at each address in a dispersion model. We used conditional logistic regression to estimate the risk for leukaemia after adjustment for income, educational level, cohabitation status and co-morbidity. In linear analyses, we found odds ratios for acute myeloid leukaemia of 1.20 (95% confidence interval: 1.04-1.38) per 20 µg/m(3) increase in NOx and 1.31 (1.02-1.68) per 10 µg/m(3) increase in NO2 , calculated as time-weighted average exposure at all addresses since 1971. We found no association with chronic myeloid or lymphocytic leukaemia. This study indicates an association between long-term exposure to traffic-related air pollution and acute myeloid leukaemia in the general population, but not for other subtypes of leukaemia. PMID:26415047

  2. Current standard treatment of adult acute promyelocytic leukaemia.

    PubMed

    Lo-Coco, Francesco; Cicconi, Laura; Breccia, Massimo

    2016-03-01

    The outcome of patients with acute promyelocytic leukaemia (APL) has dramatically improved over the last two decades, due to the introduction of combined all-trans retinoic acid (ATRA) and chemotherapy regimens and, more recently, to the advent of arsenic trioxide (ATO). ATRA and anthracycline-based chemotherapy remains a widely used strategy, providing cure rates above 80%, but it is associated with risk of severe infections and occurrence of secondary leukaemias. ATO is the most effective single agent in APL and, used alone or in combination with ATRA or ATRA and reduced-intensity chemotherapy, results in greater efficacy with considerably less haematological toxicity. The toxic profile of ATO includes frequent, but manageable, QTc prolongation and increase of liver enzymes. Two large randomized studies have shown that ATRA + ATO is superior to ATRA + chemotherapy for newly diagnosed low-risk APL resulting in 2-4 year event-free survival rates above 90% and very few relapses. According to real world data, the spectacular progress in APL outcomes reported in clinical trials has not been paralleled by a significant improvement in early death rates, this remains the most challenging issue for the final cure of the disease. PMID:26687281

  3. Immunophenotypic characterisation of acute leukaemia after polycythemia vera.

    PubMed Central

    Hernández, J M; Orfao, A; González, M; Cuesta, B; López-Berges, M C; Cañizo, M C; Ciudad, J; San Miguel, J F

    1993-01-01

    AIMS--To analyze the immunophenotype of blast cells in patients with acute leukaemia after polycythemia vera, together with the most relevant clinical and haematological disease characteristics. METHODS--The immunophenotype was analysed in nine patients by immunofluorescence flow cytometry using a panel of 15 monoclonal antibodies. The DNA content of blast cells was determined using Vindelov's technique. RESULTS--The most relevant clinical and haematological disease characteristics included: the presence of enlarged spleen and liver by 56% and 67%, respectively; a moderate degree of leucocytosis with thrombocytopenia while haemoglobin was normal in 50% of patients. All patients received alkylating agents or hydroxyurea, or both. Interestingly, the chronic phase in patients receiving this latter drug was shorter. All cases showed a myeloid phenotype, four of them reactive only to early myeloid antigens (CD13/33); in the remaining cases the blast cells displayed granulomonocytic (CD14+, CD15+), erythroid (CD71 ), or megakaryocytic (CD61+, CD41+) markers. Coexpression of lymphoid related antigens (CD7, TdT, or CD19) was also detected. The morphological assessment of blast cells agreed with the immunophenotyping in five out of the nine cases. Blast cells from all six patients analysed displayed a diploid DNA content and the proportion of S-phase cells ranged from 0.4% to 4%. CONCLUSIONS--These findings suggest a pluripotential stem cell with myeloid commitment as the target cell of acute leukaemia after polycythemia vera. PMID:8157758

  4. Antibody-based treatment of acute myeloid leukaemia.

    PubMed

    Mulford, Deborah A; Jurcic, Joseph G

    2004-01-01

    Monoclonal antibodies have become an important treatment modality in cancer therapy. Genetically engineered chimaeric and humanised antibodies have demonstrated activity against a variety of tumours. Whereas the humanised anti-CD33 monoclonal antibody HuM195 has only modest activity against overt acute myeloid leukaemia (AML), it can eliminate minimal residual disease detectable by reverse transcription-polymerase chain reaction in acute promyelocytic leukaemia. High-dose radioimmunotherapy with beta-particle-emitting isotopes targeting CD33, CD45 and CD66 can potentially allow intensification of antileukaemic therapy before bone marrow transplantation. Conversely, alpha-particle immunotherapy with isotopes such as bismuth-213 or actinium-225 offers the possibility of selective tumour cell kill while sparing surrounding normal cells. Targeted chemotherapy with the anti-CD33-calicheamicin construct gemtuzumab ozogamicin has produced remissions as a single agent in patients with relapsed AML and appears promising when used in combination with standard chemotherapy in the treatment of newly diagnosed AML. PMID:14680472

  5. Life span, leukaemia and amyloid incidences of untreated and polycation-treated AKR mice.

    PubMed Central

    Ebbesen, P.

    1978-01-01

    AKR mice, which have a short mean survival time and usually die with leukaemia, were studied from one month of age for correlation between these two parameters. For untreated animals we found the same mean survival time whether or not leukaemia occurred. By treating sucklings with the polycations diethylaminoethyl-dextran or hexadimethrine bromide the leukaemia incidence was significantly reduced. However, the mean survival time was unchanged, and remained the same in leukaemic and non-leukaemic animals. It is therefore suggested that the early death of AKR mice results from an ageing process and does not require leukaemia for implementation. Our prophylactic polycation treatment was furthermore found to induce spleen amyloid in some but not all of the mice that remained non-leukaemic. PMID:619959

  6. Bone marrow and splenic histology in hairy cell leukaemia.

    PubMed

    Wotherspoon, Andrew; Attygalle, Ayoma; Mendes, Larissa Sena Teixeira

    2015-12-01

    Hairy cell leukaemia is a rare chronic neoplastic B-cell lymphoproliferation that characteristically involves blood, bone marrow and spleen with liver, lymph node and skin less commonly involved. Histologically, the cells have a characteristic appearance with pale/clear cytoplasm and round or reniform nuclei. In the spleen, the infiltrate involves the red pulp and is frequently associated with areas of haemorrhage (blood lakes). The cells stain for B-cell related antigens as well as with antibodies against tartrate-resistant acid phosphatase, DBA44 (CD72), CD11c, CD25, CD103, CD123, cyclin D1 and annexin A1. Mutation of BRAF -V600E is present and antibody to the mutant protein can be used as a specific marker. Bone marrow biopsy is essential in the initial assessment of disease as the bone marrow may be inaspirable or unrepresentative of degree of marrow infiltration as a result of the tumour associated fibrosis preventing aspiration of the tumour cell component. Bone marrow biopsy is important in the assessment of therapy response but in this context staining for CD11c and Annexin A1 is not helpful as they are also markers of myeloid lineage and identification of low level infiltration may be obscured. In this context staining for CD20 may be used in conjunction with morphological assessment and staining of serial sections for cyclin D1 and DBA44 to identify subtle residual infiltration. Staining for CD79a and CD19 is not recommended as these antibodies will identify plasma cells and can lead to over-estimation of disease. Staining for CD20 should not be used in patients following with anti-CD20 based treatments. Down regulation of cyclin D1 and CD25 has been reported in patients following BRAF inhibitor therapy and assessment of these antigens should not be used in this context. Histologically, hairy cell leukaemia needs to be distinguished from other B-cell lymphoproliferations associated with splenomegaly including splenic marginal zone lymphoma, splenic

  7. Acute myeloid leukaemia as a cause of acute ischaemic heart disease

    PubMed Central

    van Haelst, P.L.; Schot, B.; Hoendermis, E.S.; van den Berg, M.P.

    2006-01-01

    Ischaemic heart disease is almost invariably the result of atherosclerotic degeneration of the coronary arteries. However, other causes of ischaemic heart disease should always be considered. Here we describe two patients with a classic presentation of ischaemic heart disease resulting from acute leukaemia. The pathophysiological mechanisms of acute leukaemia leading to ischaemic heart disease are discussed. ImagesFigure 1AFigure 1BFigure 2 PMID:25696595

  8. Harnessing the immune system in acute myeloid leukaemia.

    PubMed

    Austin, Rebecca; Smyth, Mark J; Lane, Steven W

    2016-07-01

    Acute myeloid leukaemia (AML) is an aggressive blood cancer caused by the proliferation of immature myeloid cells. The genetic abnormalities underlying AML affect signal transduction pathways, transcription factors and epigenetic modifiers. In solid tumours, it is emerging that the genetic landscape of the tumour has a direct effect on the anti-tumour immune responses and response to immunotherapeutic treatment. However, there remains little information as to whether genetic abnormalities affect anti-leukemic immune responses. This review discusses current knowledge of AML antigens and immune responses to AML with a particular focus on the role of T cells and natural killer cells. Understanding immune responses to AML has implications for the development and use of immunotherapies to treat AML patients with distinct genetic abnormalities. PMID:27247119

  9. Orbital mass secondary to infantile acute lymphoblastic leukaemia.

    PubMed

    Hossain, Ibtesham Tausif; Moosajee, Mariya; Abou-Rayyah, Yassir; Pavasovic, Vesna

    2016-01-01

    An 8-month-old Asian infant girl was referred with a 1-week history of left periorbital swelling on a background of a narrowed left palpebral aperture over the preceding 8 weeks. There was no history of chronic illness, fever or other systemic features. Examination revealed a tender and fluctuant medial canthal swelling with associated periorbital haematoma. There were no other ophthalmic findings and neurological examination was normal. A MRI scan of the brain and orbit demonstrated abnormal soft tissue with features of an aggressive tumour in the left orbital region with no globe invasion. Peripheral blood smear revealed blast cells, confirmed by bone marrow aspirate. A diagnosis of infant acute lymphoblastic leukaemia was made. The patient was started on risk-stratified chemotherapy according to the Interfant-06 Protocol The periorbital swelling resolved by day eight following a course of prednisolone, the patient continues on chemotherapy and is currently in molecular remission. PMID:27143162

  10. Metabolic syndrome in the survivors of childhood acute lymphoblastic leukaemia.

    PubMed

    Abu-Ouf, Noran M; Jan, Mohammed M

    2015-01-01

    Metabolic syndrome is a common complication encountered in children surviving acute lymphoblastic leukaemia (ALL). Affected patients develop obesity, insulin resistance, hypertension, and hyperlipidemia. Metabolic syndrome is a consequence of multiple factors, particularly hormonal imbalance induced by various ALL treatments. This review aims to evaluate the risk factors and mechanisms leading to the development of metabolic syndrome. Further research is needed to improve our understanding of the mechanisms leading to insulin resistance and the associated endothelial and adipose tissue dysfunction. Future studies should also examine other possible contributing factors, such as environmental and genetic factors. Understanding these factors will help in guiding modifications of the current ALL treatment protocols in order to prevent the development of this syndrome and hence improve the quality of life of ALL survivors. Until this is achieved, clinicians should continue to identify patients at risk early and use a therapeutic approach that combines dietary restrictions and enhanced physical activity. PMID:25081809

  11. Skin nodules in a patient with acute lymphoblastic leukaemia

    PubMed Central

    Le Clech, Lenaïg; Hutin, Pascal; Le Gal, Solène; Guillerm, Gaëlle

    2014-01-01

    Opportunistic infections cause a significant morbidity and mortality in immunocompromised patients. We describe the case of a patient with skin fusariosis and a probable cerebral toxoplasmosis after UCB stem cell transplantation for B-cell acute lymphoblastic leukaemia. Fusarium species (spp) infections are difficult to treat. To date, there has been no consensus on the treatment of fusariosis and the management of its side effects. Given the negative pretransplant Toxoplasma serology in this case, identifying the origin of the Toxoplasma infection was challenging. All usual transmission routes were screened for and ruled out. The patient's positive outcome was not consistent with that of the literature reporting 60% mortality due to each infection. PMID:24408938

  12. SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation.

    PubMed

    Xu, Shuang-Nian; Wang, Tian-Shi; Li, Xi; Wang, Yi-Ping

    2016-01-01

    Like most other types of cancer cells, leukaemia cells undergo metabolic reprogramming to support rapid proliferation through enhancing biosynthetic processes. Pentose phosphate pathway (PPP) plays a pivotal role in meeting the anabolic demands for cancer cells. However, the molecular mechanism by which PPP contributes to leukaemia remains elusive. Here, we report that leukaemia cell proliferation is dependent on the oxidative branch of PPP, in particular the first and rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of G6PD reduces NADPH level in acute myeloid leukaemia (AML) cell lines. Exogenous lipid supplements partially restore the proliferation of G6PD-depleted cells. Deacetylase SIRT2 promotes NADPH production through deacetylating G6PD at lysine 403 (K403). Activation of G6PD by SIRT2 supports the proliferation and clonogenic activity of leukaemia cells. Chemical inhibitors against SIRT2 suppress G6PD activity, leading to reduced cell proliferation of leukaemia cells, but not normal hematopoietic stem and progenitor cells. Importantly, SIRT2 is overexpressed in clinical AML samples, while K403 acetylation is downregulated and G6PD catalytic activity is increased comparing to that of normal control. Together, our study reveals that acetylation regulation of G6PD is involved in the metabolic reprogramming of AML, and SIRT2 serves as a promising target for further therapeutic investigations. PMID:27586085

  13. A case–control study of risk of leukaemia in relation to mobile phone use

    PubMed Central

    Cooke, R; Laing, S; Swerdlow, A J

    2010-01-01

    Background: Mobile phone use is now ubiquitous, and scientific reviews have recommended research into its relation to leukaemia risk, but no large studies have been conducted. Methods: In a case–control study in South East England to investigate the relation of acute and non-lymphocytic leukaemia risk to mobile phone use, 806 cases with leukaemia incident 2003–2009 at ages 18–59 years (50% of those identified as eligible) and 585 non-blood relatives as controls (provided by 392 cases) were interviewed about mobile phone use and other potentially aetiological variables. Results: No association was found between regular mobile phone use and risk of leukaemia (odds ratio (OR)=1.06, 95% confidence interval (CI)=0.76, 1.46). Analyses of risk in relation to years since first use, lifetime years of use, cumulative number of calls and cumulative hours of use produced no significantly raised risks, and there was no evidence of any trends. A non-significantly raised risk was found in people who first used a phone 15 or more years ago (OR=1.87, 95% CI=0.96, 3.63). Separate analyses of analogue and digital phone use and leukaemia subtype produced similar results to those overall. Conclusion: This study suggests that use of mobile phones does not increase leukaemia risk, although the possibility of an effect after long-term use, while biologically unlikely, remains open. PMID:20940717

  14. SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation

    PubMed Central

    Xu, Shuang-Nian; Wang, Tian-Shi; Li, Xi; Wang, Yi-Ping

    2016-01-01

    Like most other types of cancer cells, leukaemia cells undergo metabolic reprogramming to support rapid proliferation through enhancing biosynthetic processes. Pentose phosphate pathway (PPP) plays a pivotal role in meeting the anabolic demands for cancer cells. However, the molecular mechanism by which PPP contributes to leukaemia remains elusive. Here, we report that leukaemia cell proliferation is dependent on the oxidative branch of PPP, in particular the first and rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of G6PD reduces NADPH level in acute myeloid leukaemia (AML) cell lines. Exogenous lipid supplements partially restore the proliferation of G6PD-depleted cells. Deacetylase SIRT2 promotes NADPH production through deacetylating G6PD at lysine 403 (K403). Activation of G6PD by SIRT2 supports the proliferation and clonogenic activity of leukaemia cells. Chemical inhibitors against SIRT2 suppress G6PD activity, leading to reduced cell proliferation of leukaemia cells, but not normal hematopoietic stem and progenitor cells. Importantly, SIRT2 is overexpressed in clinical AML samples, while K403 acetylation is downregulated and G6PD catalytic activity is increased comparing to that of normal control. Together, our study reveals that acetylation regulation of G6PD is involved in the metabolic reprogramming of AML, and SIRT2 serves as a promising target for further therapeutic investigations. PMID:27586085

  15. Oxindole alkaloids from Uncaria tomentosa induce apoptosis in proliferating, G0/G1-arrested and bcl-2-expressing acute lymphoblastic leukaemia cells.

    PubMed

    Bacher, Nicole; Tiefenthaler, Martin; Sturm, Sonja; Stuppner, Hermann; Ausserlechner, Michael J; Kofler, Reinhard; Konwalinka, Günther

    2006-03-01

    Natural products are still an untapped source of promising lead compounds for the generation of antineoplastic drugs. Here, we investigated for the first time the antiproliferative and apoptotic effects of highly purified oxindole alkaloids, namely isopteropodine (A1), pteropodine (A2), isomitraphylline (A3), uncarine F (A4) and mitraphylline (A5) obtained from Uncaria tomentosa, a South American Rubiaceae, on human lymphoblastic leukaemia T cells (CCRF-CEM-C7H2). Four of the five tested alkaloids inhibited proliferation of acute lymphoblastic leukaemia cells. Furthermore, the antiproliferative effect of the most potent alkaloids pteropodine (A2) and uncarine F (A4) correlated with induction of apoptosis. After 48 h, 100 micromol/l A2 or A4 increased apoptotic cells by 57%. CEM-C7H2 sublines with tetracycline-regulated expression of bcl-2, p16ink4A or constitutively expressing the cowpox virus protein crm-A were used for further studies of the apoptosis-inducing properties of these alkaloids. Neither overexpression of bcl-2 or crm-A nor cell-cycle arrest in G0/G1 phase by tetracycline-regulated expression of p16INK4A could prevent alkaloid-induced apoptosis. Our results show the strong apoptotic effects of pteropodine and uncarine F on acute leukaemic lymphoblasts and recommend the alkaloids for further studies in xenograft models. PMID:16445836

  16. Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study.

    PubMed

    Suehiro, Youko; Hasegawa, Atsuhiko; Iino, Tadafumi; Sasada, Amane; Watanabe, Nobukazu; Matsuoka, Masao; Takamori, Ayako; Tanosaki, Ryuji; Utsunomiya, Atae; Choi, Ilseung; Fukuda, Tetsuya; Miura, Osamu; Takaishi, Shigeo; Teshima, Takanori; Akashi, Koichi; Kannagi, Mari; Uike, Naokuni; Okamura, Jun

    2015-05-01

    Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type-I (HTLV-I)-infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti-ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate- to high-risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax-specific CTL responses were observed with peaks at 16-20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide-pulsed DC vaccine is a safe and promising immunotherapy for ATL. PMID:25612920

  17. Taxonomy, biogeography and importance of Heterobasidion viruses.

    PubMed

    Vainio, Eeva J; Hantula, Jarkko

    2016-07-01

    The genus Heterobasidion consists of several species of necrotrophic and saprotrophic fungi, and includes some of the most detrimental organisms in boreal conifer forests. These fungi host a widespread and diverse mycovirus community composed of more than 16 species of Partitiviridae, a species of Narnaviridae and one taxonomically unassigned virus related to the Curvularia thermal tolerance virus. These viruses are able to cross species borders, co-infect single host strains and cause phenotypic changes in their hosts. The abundance of viruses increases over time in Heterobasidion infection centers, and they are targeted by fungal RNA interference. Long-term field studies are essential for obtaining a comprehensive view of virus effects in the nature. PMID:26477938

  18. A meta-analysis of leukaemia risk from protracted exposure to low-dose gamma radiation

    PubMed Central

    Schubauer-Berigan, M K

    2010-01-01

    Context More than 400 000 workers annually receive a measurable radiation dose and may be at increased risk of radiation-induced leukaemia. It is unclear whether leukaemia risk is elevated with protracted, low-dose exposure. Objective We conducted a meta-analysis examining the relationship between protracted low-dose ionising radiation exposure and leukaemia. Data sources Reviews by the National Academies and United Nations provided a summary of informative studies published before 2005. PubMed and Embase databases were searched for additional occupational and environmental studies published between 2005 and 2009. Study selection We selected 23 studies that: (1) examined the association between protracted exposures to ionising radiation and leukaemia excluding chronic lymphocytic subtype; (2) were a cohort or nested case–control design without major bias; (3) reported quantitative estimates of exposure; and (4) conducted exposure–response analyses using relative or excess RR per unit exposure. Methods Studies were further screened to reduce information overlap. Random effects models were developed to summarise between-study variance and obtain an aggregate estimate of the excess RR at 100 mGy. Publication bias was assessed by trim and fill and Rosenthal's file drawer methods. Results We found an ERR at 100 mGy of 0.19 (95% CI 0.07 to 0.32) by modelling results from 10 studies and adjusting for publication bias. Between-study variance was not evident (p=0.99). Conclusions Protracted exposure to low-dose gamma radiation is significantly associated with leukaemia. Our estimate agreed well with the leukaemia risk observed among exposed adults in the Life Span Study (LSS) of atomic bomb survivors, providing increased confidence in the current understanding of leukaemia risk from ionising radiation. However, unlike the estimates obtained from the LSS, our model provides a precise, quantitative summary of the direct estimates of excess risk from studies of

  19. Temporal trends in childhood leukaemia incidence following exposure to radioactive fallout from atmospheric nuclear weapons testing.

    PubMed

    Wakeford, Richard; Darby, Sarah C; Murphy, Michael F G

    2010-05-01

    Notably raised rates of childhood leukaemia incidence have been found near some nuclear installations, in particular Sellafield and Dounreay in the United Kingdom, but risk assessments have concluded that the radiation doses estimated to have been received by children or in utero as a result of operations at these installations are much too small to account for the reported increases in incidence. This has led to speculation that the risk of childhood leukaemia arising from internal exposure to radiation following the intake of radioactive material released from nuclear facilities has been substantially underestimated. The radionuclides discharged from many nuclear installations are similar to those released into the global environment by atmospheric nuclear weapons testing, which was at its height in the late-1950s and early-1960s. Measurements of anthropogenic radionuclides in members of the general public resident in the vicinity of Sellafield and Dounreay have found levels that do not differ greatly from those in persons living remote from nuclear installations that are due to ubiquitous exposure to the radioactive debris of nuclear weapons testing. Therefore, if the leukaemia risk to children resulting from deposition within the body of radioactive material discharged from nuclear facilities has been grossly underestimated, then a pronounced excess of childhood leukaemia would have been expected as a consequence of the short period of intense atmospheric weapons testing. We have examined childhood leukaemia incidence in 11 large-scale cancer registries in three continents for which data were available at least as early as 1962. We found no evidence of a wave of excess cases corresponding to the peak of radioactive fallout from atmospheric weapons testing. The absence of a discernible increase in the incidence of childhood leukaemia following the period of maximum exposure to the radioactive debris of this testing weighs heavily against the suggestion that

  20. Magic Angle Spinning NMR of Viruses

    PubMed Central

    Quinn, Caitlin; Lu, Manman; Suiter, Christopher L.; Hou, Guangjin; Zhang, Huilan; Polenova, Tatyana

    2015-01-01

    Viruses, relatively simple pathogens, are able to replicate in many living organisms and to adapt to various environments. Conventional atomic-resolution structural biology techniques, X-ray crystallography and solution NMR spectroscopy provided abundant information on the structures of individual proteins and nucleic acids comprising viruses; however, viral assemblies are not amenable to analysis by these techniques because of their large size, insolubility, and inherent lack of long-range order. In this article, we review the recent advances in magic angle spinning NMR spectroscopy that enabled atomic-resolution analysis of structure and dynamics of large viral systems and give examples of several exciting case studies. PMID:25919197

  1. Risk of childhood leukaemia in the vicinity of nuclear installations--findings and recent controversies.

    PubMed

    Laurier, Dominique; Grosche, Bernd; Hall, Per

    2002-01-01

    The identification of a local excess of cancer cases, possibly associated with ionizing radiation, always receives substantial media coverage and communication about clusters is difficult. We reviewed studies that examined the risk of leukaemia among young people near nuclear installations. An excess of leukaemia exists near some nuclear installations, at least for the reprocessing plants at Sellafield and Dounreay and the nuclear power plant Krümmel. Nonetheless, the results of multi-site studies invalidate the hypothesis of an increased risk of leukaemia related to nuclear discharge. Up until now, analytic studies have not found an explanation for the leukaemia clusters observed near certain nuclear installations. The hypothesis of an infectious aetiology associated with population mixing has been proposed, but needs to be investigated further. The review illustrates two recent examples in France (La Hague reprocessing plant) and in Germany (Krümmel power plant), where controversies developed after reports of increased leukaemia risks. These examples show the importance of recalling the current epidemiological knowledge and of using systematic recording of cases to replace the alleged excesses in a more general framework. Some elements should also be suggested from the recent French and German experiences to reinforce credibility in the results. PMID:11990512

  2. Detection of influenza C virus but not influenza D virus in Scottish respiratory samples

    PubMed Central

    Smith, Donald B.; Gaunt, Eleanor R.; Digard, Paul; Templeton, Kate; Simmonds, Peter

    2016-01-01

    Background A newly proposed genus of influenza virus (influenza D) is associated with respiratory disease in pigs and cattle. The novel virus is most closely related to human influenza C virus and can infect ferrets but infection has not been reported in humans. Objectives To ascertain if influenza D virus can be detected retrospectively in patient respiratory samples. Study design 3300 human respiratory samples from Edinburgh, Scotland, covering the period 2006–2008, were screened in pools of 10 by RT-PCR using primers capable of detecting both influenza C and D viruses. Results Influenza D was not detected in any sample. Influenza C was present in 6 samples (0.2%), compared with frequencies of 3.3% and 0.9% for influenza A and B viruses from RT-PCR testing of respiratory samples over the same period. Influenza C virus was detected in samples from individuals <2 years or >45 years old, with cases occurring throughout the year. Phylogenetic analysis of nearly complete sequences of all seven segments revealed the presence of multiple, reassortant lineages. Conclusion We were unable to detect viruses related to influenza D virus in human respiratory samples. Influenza C virus was less prevalent than influenza A and B viruses, was associated with mild disease in the young (<2 years) and old (>45 years) and comprised multiple, reassortant lineages. Inclusion of influenza C virus as part of a diagnostic testing panel for respiratory infections would be of limited additional value. PMID:26655269

  3. Living with the Diagnosis and Treatment of Leukaemia in a Child with Down's Syndrome: A Mother's Reflection

    ERIC Educational Resources Information Center

    Self, Donna

    2008-01-01

    In this article I will discuss the impact of my 2-year-old son's diagnosis and treatment of leukaemia. I will outline the background to being told he had leukaemia before describing the family dynamics that emerged during this time for me, my husband and our other child. My story will focus on managing the practicalities of a long stay in hospital…

  4. The clinical implications of gene mutations in chronic lymphocytic leukaemia.

    PubMed

    Rossi, Davide; Gaidano, Gianluca

    2016-04-12

    Chronic lymphocytic leukaemia (CLL) is a molecularly heterogeneous disease as revealed by recent genomic studies. Among genetic lesions that are recurrent in CLL, few clinically validated prognostic markers, such as TP53 mutations and 17p deletion, are available for the use in clinical practice to guide treatment decisions. Recently, several novel molecular markers have been identified in CLL. Though these mutations have not yet gained the qualification of predictive factors for treatment tailoring, they have shown to be promising to refine the prognostic stratification of patients. The introduction of targeted drugs is changing the genetics of CLL, and has disclosed the acquisition of previously unexpected drug resistant mutations in signalling pathway genes. Ultra-deep next generation sequencing has allowed to reach deep levels of resolution of the genetic portrait of CLL providing a precise definition of its subclonal genetic architecture. This approach has shown that small subclones harbouring drug resistant mutations anticipate the development of a chemorefractory phenotype. Here we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterise the clinical implications of old and new molecular lesions in the setting of both conventional chemo-immunotherapy and targeted drugs. PMID:27031852

  5. Economic evaluation of treatment for acute lymphoblastic leukaemia in childhood.

    PubMed

    Rae, C; Furlong, W; Jankovic, M; Moghrabi, Albert; Naqvi, A; Sala, A; Samson, Y; DePauw, S; Feeny, D; Barr, R

    2014-11-01

    Berlin-Frankfurt-Munster (BFM) and Dana-Farber Cancer Institute (DFCI) consortia's treatment strategies for acute lymphoblastic leukaemia (ALL) in children are widely used. We compared the health effects and monetary costs of hospital treatments for these two strategies. Parents of children treated at seven centres in Canada, Italy and the USA completed health-related quality of life (HRQL) assessments during four active treatment phases and at 2 years after treatment. Mean HRQL scores were used to calculate quality-adjusted life years (QALYs) for a period of 5 years following diagnosis. Total costs of treatment were determined from variables in administrative databases in a universally accessible and publicly funded healthcare system. Valid HRQL assessments (n = 1200) were collected for 307 BFM and 317 DFCI patients, with costs measured for 66 BFM and 28 DFCI patients. QALYs per patient were <1.0% greater for BFM than DFCI. Median HRQL scores revealed no difference in QALYs. The difference in mean total costs for BFM (US$88 480) and DFCI (US$93 026) was not significant (P = 0.600). This study provides no evidence of superiority for one treatment strategy over the other. Current BFM or DFCI strategies should represent conventional management for the next economic evaluation of treatments for ALL in childhood. PMID:24393150

  6. Present and future of molecular monitoring in chronic myeloid leukaemia.

    PubMed

    Soverini, Simona; De Benedittis, Caterina; Mancini, Manuela; Martinelli, Giovanni

    2016-05-01

    Currently, physicians treating chronic myeloid leukaemia (CML) patients can rely on a wide spectrum of therapeutic options: the best use of such options is essential to achieve excellent clinical outcomes and, possibly, treatment-free remission (TFR). To accomplish this, proper integration of expert clinical and laboratory monitoring of CML patients is fundamental. Molecular response (MR) monitoring of patients at defined time points has emerged as an important success factor for optimal disease management and BCR-ABL1 kinase domain mutation screening is useful to guide therapeutic reassessment in patients who do not achieve optimal responses to tyrosine kinase inhibitor therapy. Deeper MRs might be associated with improved long-term survival outcomes. More importantly, they are considered a gateway to TFR. In molecular biology, novel procedures and technologies are continually being developed. More sophisticated molecular tools and automated analytical solutions are emerging as CML treatment endpoints and expectations become more and more ambitious. Here we provide a critical overview of current and novel methodologies, present their strengths and pitfalls and discuss what their present and future role might be. PMID:26947577

  7. Oligoclonality and new agent evaluation in acute lymphoblastic leukaemia.

    PubMed

    Gaynon, Paul S; Sun, Weili

    2016-06-01

    New agent development rests on the fundamental assumption that candidate agents or drug combinations that induce objective responses after relapse will prevent relapse, if applied prior to relapse. However, cumulative experience now includes at least 5 examples of interventions with post-relapse objective response rates greater than 50% that failed to improve outcomes when applied prior to relapse. Emerging insights into oligoclonality provide some explanation. In acute lymphoblastic leukaemia, the predominant clones at relapse differ from the predominant clones at presentation. Arguably, the more highly proliferative clones that predominate at relapse differ in drug sensitivity from the less proliferative clones that escape primary therapy. Interventions effective against the predominant clones at relapse may have no effect on the antecedent escapee clones. Response is not sufficient in new agent development. Duration of response has attracted less attention because of variability in post-remission therapy but some patient subsets have such a uniformly dismal outcome that details of post-remission therapy may be irrelevant. Benchmarks are needed. Are recovering blasts members of the same clone or do they represent a new clone? When you eradicate the predominant clones you get a response. When you eradicate all clones, you get a cure. PMID:27221005

  8. Personalization of dexamethasone therapy in childhood acute lymphoblastic leukaemia.

    PubMed

    Jackson, Rosanna K; Irving, Julie A E; Veal, Gareth J

    2016-04-01

    Dexamethasone is a key component in the treatment of childhood acute lymphoblastic leukaemia (ALL). Despite playing a key role in the improved survival of ALL over several decades, intensification of dexamethasone therapy has also contributed to the increased toxicity associated with treatment, which is now seen to be at unacceptable levels given the favourable disease prognosis. Therefore the focus for treatment is now shifting towards reducing toxicity whilst maintaining current survival rates. As approximately 50% of patients were successfully treated on less intensive protocols of the 1980s, it has been questioned whether therapy intensification is necessary in all patients. Furthermore, there remains a subset of children who are still not cured of their disease. New strategies are therefore needed to identify patients who could benefit from dose reduction or intensification. However, adjusting a potentially life threatening therapy is a challenging task, particularly given the heterogeneous nature of ALL. This review focuses on the potential for patient stratification based on our current knowledge of dexamethasone pharmacokinetics, pharmacogenetics and the action of dexamethasone at the cellular level. A carefully designed, combined approach is needed if we are to achieve the aim of improved personalization of dexamethasone therapy for future patients. PMID:26729065

  9. The clinical implications of gene mutations in chronic lymphocytic leukaemia

    PubMed Central

    Rossi, Davide; Gaidano, Gianluca

    2016-01-01

    Chronic lymphocytic leukaemia (CLL) is a molecularly heterogeneous disease as revealed by recent genomic studies. Among genetic lesions that are recurrent in CLL, few clinically validated prognostic markers, such as TP53 mutations and 17p deletion, are available for the use in clinical practice to guide treatment decisions. Recently, several novel molecular markers have been identified in CLL. Though these mutations have not yet gained the qualification of predictive factors for treatment tailoring, they have shown to be promising to refine the prognostic stratification of patients. The introduction of targeted drugs is changing the genetics of CLL, and has disclosed the acquisition of previously unexpected drug resistant mutations in signalling pathway genes. Ultra-deep next generation sequencing has allowed to reach deep levels of resolution of the genetic portrait of CLL providing a precise definition of its subclonal genetic architecture. This approach has shown that small subclones harbouring drug resistant mutations anticipate the development of a chemorefractory phenotype. Here we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterise the clinical implications of old and new molecular lesions in the setting of both conventional chemo-immunotherapy and targeted drugs. PMID:27031852

  10. Use of natural killer cells as immunotherapy for leukaemia

    PubMed Central

    Grzywacz, Bartosz; Miller, Jeffrey S.; Verneris, Michael R.

    2008-01-01

    Natural killer (NK) cells potentially play a significant role in eradicating residual disease following allogeneic haematopoietic cell transplantation, and have been explored as tools for adoptive immunotherapy for chemotherapy-refractory patients. NK cell cytotoxicity is modulated by multiple activating and inhibitory receptors that maintain a balance between self-tolerance and providing surveillance against pathogens and malignant transformation. The functional characteristics of NK cells are dictated by the strength of inhibitory receptor signalling. Major histocompatibility complex (MHC)-specific inhibitory receptor acquisition occurs sequentially during NK cell development, and is determined by the nature of immunological reconstitution after allogeneic haematopoietic cell transplantation. Polymorphisms of inhibitory receptors [killer immunoglobulin-like receptors (KIRs)] and their ligands (MHC) contribute to interindividual variability. As a result, the functional NK cell repertoire of individual donors has variable potential for graft-vs-leukaemia reactions. Models predicting NK cell alloreactivity, including KIR ligand mismatch and missing KIR ligand strategies, are discussed as algorithms for optimal NK cell donor selection. Future modifications to improve NK cell adoptive immunotherapy by means of increasing target recognition and reducing inhibitory signalling are being explored. PMID:18790450

  11. Hairy cell leukaemia and occupational exposure to benzene.

    PubMed Central

    Clavel, J; Conso, F; Limasset, J C; Mandereau, L; Roche, P; Flandrin, G; Hémon, D

    1996-01-01

    OBJECTIVES: The role of occupational exposures in hairy cell leukaemia (HCL) was investigated through a multicentre, hospital based, case-control study. This paper analyses the role of exposure to benzene in HCL. METHODS: A population of 226 male cases of HCL and 425 matched controls were included in the study. Benzene exposure was evaluated by expert review of the detailed data on occupational exposures generated by case-control interviews. RESULTS: No association was found between HCL and employment in a job exposed to benzene (odds ratio (OR) 0.9 (95% confidence interval (95% CI) 0.6-1.3)). The sample included 125 subjects, 34 cases (15%), and 91 controls (21%) who had been exposed to benzene, as individually assessed by the experts, for at least one hour a month during one of their jobs. Benzene exposure was not associated with a risk of HCL (OR 0.8 (0.5-1.2)). No trend towards an increase in OR was detected for increasing exposures, the percentage of work time involving exposure to > 1 ppm, or the duration of exposure. No findings suggested a particular risk period, when the OR associated with the time since first or last exposure, or since the end of exposure, were examined. CONCLUSIONS: In conclusion, with the low exposures prevalent in the sample, the study did not show any association between benzene exposure and HCL. PMID:8983464

  12. Longitudinal language outcomes following intrathecal chemotherapy for acute lymphoblastic leukaemia.

    PubMed

    Lewis, Fiona M; Perry, Meghan L; Murdoch, Bruce E

    2013-04-01

    Intrathecal chemotherapy (ITC) is the treatment option for acute lymphoblastic leukaemia (ALL). Neurocognitive deficits have been described following ITC, but language status post-treatment is yet to be clarified. This study examined the language skills of nine children following ITC for ALL (mean age 7;8 years and 3;2 years post-diagnosis at baseline measurement) and nine age- and sex-matched controls, at baseline then 2 years later, using a battery of tests assessing general language skills. An assessment of cognitively-demanding high level language skills was undertaken on a sub-group of the children (n =12). Statistical analysis revealed no significant difference between children treated with ITC and controls when comparing change in performance scores from baseline measurement to 2 years post-baseline measurement. Descriptive analysis of three of the ALL participants in the Intermediate Stage survivorship at language re-assessment indicated no clinically-significant change in performance over 2 years for all measures except receptive language skills, which improved over the time for two of the children. As language skills continue to develop into late adolescence, the need for the monitoring of language abilities of children treated at a young age with ITC as they enter the Intermediate and Late Stages of survivorship is discussed. PMID:22663017

  13. Therapeutic drug monitoring of aminoglycosides in acute myeloid leukaemia patients.

    PubMed

    Mareville, Julie; Gay, Julie; Cliquennois, Emmanuel; Herbaux, Charles; Pasquier, Florence; Allorge, Delphine; Blondiaux, Nicolas; Berthon, Céline; Alfandari, Serge

    2012-05-01

    International guidelines limit the use of aminoglycosides in febrile neutropenia to severe situations. We retrospectively reviewed the use of aminoglycosides in adult acute myeloid leukaemia patients admitted in 2009. Our guidelines include precise indications (severe sepsis, shock, drug resistance), dosing regimens (once-daily 20 mg/kg/day amikacin, 5 mg/kg/day gentamicin), durations of treatment, drug monitoring timing, and target C(max) concentrations (40 mg/l amikacin, 20 mg/l gentamicin). Thirty-one patients received 46 aminoglycoside courses: 31 amikacin and 15 gentamicin. The mean prescribed dosage was 19 ± 2.8 mg/kg/day for amikacin and 4.7 ± 0.9 mg/kg/day for gentamicin. The mean duration of use was 2.9 days for both drugs. The mean C(max) for amikacin was 47 ± 13 mg/l and for gentamicin was 13.6 ± 7.5 mg/l. In compliant regimens, all amikacin patients and a third of gentamicin patients had adequate C(max). Among 23 isolated pathogens, 65.5% were susceptible to both drugs and 11.5% to amikacin only. This vindicates the 20 mg/kg/day amikacin dosage and suggests a need to increase the gentamicin dosage. PMID:22235869

  14. Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia.

    PubMed

    Scott, Lesley J

    2016-05-01

    Azacitidine (Vidaza(®)) is a pyrimidine nucleoside analogue of cytidine and is approved in the EU for use in patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients (aged ≥65 years) with AML with >30 % bone marrow blasts (BMB) who are ineligible for haematopoietic stem cell transplant. This article reviews the clinical efficacy and tolerability of azacitidine in the treatment of these patient populations, as well as summarizing its pharmacological properties. In pivotal, international, phase 3 trials, subcutaneous azacitidine was an effective and well tolerated treatment in patients with higher-risk MDS or AML, including older patients with AML with >30 % BMB, with extensive evidence from the real-world setting confirming its efficacy and safety in these patient populations. Azacitidine is the only approved hypomethylating agent that has been shown to prolong overall survival compared with conventional care regimens and thus, it is recommended as the first-line hypomethylating agent for most patients with higher-risk MDS. Hence, azacitidine remains and important agent for use in the treatment of higher-risk MDS and AML, including in older patients with AML with >30 % BMB. PMID:27193945

  15. Non-coding recurrent mutations in chronic lymphocytic leukaemia.

    PubMed

    Puente, Xose S; Beà, Silvia; Valdés-Mas, Rafael; Villamor, Neus; Gutiérrez-Abril, Jesús; Martín-Subero, José I; Munar, Marta; Rubio-Pérez, Carlota; Jares, Pedro; Aymerich, Marta; Baumann, Tycho; Beekman, Renée; Belver, Laura; Carrio, Anna; Castellano, Giancarlo; Clot, Guillem; Colado, Enrique; Colomer, Dolors; Costa, Dolors; Delgado, Julio; Enjuanes, Anna; Estivill, Xavier; Ferrando, Adolfo A; Gelpí, Josep L; González, Blanca; González, Santiago; González, Marcos; Gut, Marta; Hernández-Rivas, Jesús M; López-Guerra, Mónica; Martín-García, David; Navarro, Alba; Nicolás, Pilar; Orozco, Modesto; Payer, Ángel R; Pinyol, Magda; Pisano, David G; Puente, Diana A; Queirós, Ana C; Quesada, Víctor; Romeo-Casabona, Carlos M; Royo, Cristina; Royo, Romina; Rozman, María; Russiñol, Nuria; Salaverría, Itziar; Stamatopoulos, Kostas; Stunnenberg, Hendrik G; Tamborero, David; Terol, María J; Valencia, Alfonso; López-Bigas, Nuria; Torrents, David; Gut, Ivo; López-Guillermo, Armando; López-Otín, Carlos; Campo, Elías

    2015-10-22

    Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia. PMID:26200345

  16. [Pregnancy outcome in five women after autologous bone marrow transplantation for acute lymphoblastic leukaemia].

    PubMed

    Hołowiecka, Aleksandra; Zielińska, Monika; Rozmus, Wioletta; Krzemień, Sławomira; Hołowiecki, Jerzy

    2005-10-01

    There are reports of successful pregnancies in women with haematological malignancies after either autologous or allogeneic bone marrow transplantation (BMT). We report six cases of uncomplicated pregnancies in five women treated with high-dose chemotherapy, radiotherapy and autologous bone marrow transplantation (ABMT) for acute lymphoblastic leukaemia. One patient was diagnosed as having leukaemia during pregnancy. The pregnancy ended with medical termination. Each woman received conditioning regimens without total body irradiation (TBI). Of five women, who received AMBT, all resumed spontaneous cyclical menstruation post transplantation. All of them conceived naturally between 15-52 months following ABMT. We noted one miscarriage in our 29-year-old patient. Six pregnancies went to term and each resulted in the successful delivery of a full-term baby. We did not notice any case of relapse of leukaemia in pregnancy. PMID:16417095

  17. Chronic neutrophilic leukaemia and plasma cell-related neutrophilic leukaemoid reactions.

    PubMed

    Bain, Barbara J; Ahmad, Shahzaib

    2015-11-01

    Many cases reported as 'chronic neutrophilic leukaemia' have had an associated plasma cell neoplasm. Recent evidence suggests that the great majority of such cases represent a neutrophilic leukaemoid reaction to the underlying multiple myeloma or monoclonal gammopathy of undetermined significance. We have analysed all accessible reported cases to clarify the likely diagnosis and to ascertain whether toxic granulation, Döhle bodies and an increased neutrophil alkaline phosphatase score were useful in making a distinction between chronic neutrophilic leukaemia and a neutrophilic leukaemoid reaction. We established that all these changes occur in both conditions. Toxic granulation and Döhle bodies are more consistently present in leukaemoid reactions but also occur quite frequently in chronic neutrophilic leukaemia. The neutrophil alkaline phosphatase score is increased in both conditions and is of no value in making a distinction. PMID:26218186

  18. Mononeuritis multiplex in a patient with B-cell prolymphocytic leukaemia: a diagnostic challenge

    PubMed Central

    Le Clech, Lenaïg; Rizcallah, Marie Jeanne; Alavi, Zarrin; Hutin, Pascal

    2013-01-01

    B-cell prolymphocytic leukaemia (BPLL) is a haematological malignancy defined as lymphocytosis and splenomegaly with >55% circulating cells being clonal prolymphocytes of B-cell origin. The evolution of this disease is more aggressive than chronic lymphocytic leukaemia. We reported a case of a 62-year-old man with BPLL who, on treatment, attained cytological, immunophenotypic and complete cytogenetic remission. He subsequently developed an asymmetric sensorimotor neurological disorder, suggestive of lymphomatous infiltration (neurolymphocytosis). Repetition of the MRI and the electromyography was essential for diagnosis. Progressive mononeuritis multiplex in B-cell leukaemias/lymphomas is rare and may be the only presenting symptom of relapsed or progressive disease. Repeat imaging studies based on judicious evaluation of the clinical scenario for exclusion of other causes of neurological symptoms is necessary. This can be challenging in patients with long-standing malignancies who have received multiple courses of chemotherapy and/or radiotherapy. PMID:24000206

  19. HA14-1, a small molecule inhibitor of Bcl-2, bypasses chemoresistance in leukaemia cells.

    PubMed

    Oliver, Lisa; Mahé, Béatrice; Gréé, René; Vallette, François M; Juin, Philippe

    2007-06-01

    We analyzed the biological activity of HA14-1, a small organic compound inhibitor of Bcl-2, against established leukaemia cell lines and blasts from acute myeloid leukaemia (AML) patients. HA14-1 had a potent killing activity against the leukaemia cell line that expressed endogenous or ectopic Bcl-2. This activity was mostly caspase-independent and was not altered by the expression of a multidrug-resistant phenotype. Moreover, HA14-1 efficiently induced cell death in a broad spectrum of AML blasts but not in normal peripheral blood lymphocytes. Thus, single-agent regimens using Bcl-2 inhibitors such as HA14-1 may be advantageous in overcoming some forms of chemoresistance in AML. PMID:17224180

  20. Childhood leukaemia incidence around French nuclear installations using geographic zoning based on gaseous discharge dose estimates

    PubMed Central

    Evrard, A-S; Hémon, D; Morin, A; Laurier, D; Tirmarche, M; Backe, J-C; Chartier, M; Clavel, J

    2006-01-01

    The present study investigated for the first time the incidence of childhood leukaemia (1990–2001) around French nuclear installations using a geographic zoning based on estimated doses to the red bone marrow due to gaseous radioactive discharges. The observed number of cases of acute leukaemia (O=750) in 40 km2 centred on 23 French nuclear installations between 1990 and 2001 was lower than expected (E=795.01), although not significantly so (standardised incidence ratio SIR=0.94, 95% confidence interval=(0.88–1.01)). In none of the five zones defined on the basis of the estimated doses was the SIR significantly >1. There was no evidence of a trend in SIR with the estimated doses for all the children or for any of the three age groups studied. This study confirmed that there was no evidence of an increased incidence of childhood leukaemia around the 23 French nuclear sites. PMID:16622448

  1. Space-time clustering of childhood leukaemia in Greece: evidence supporting a viral aetiology.

    PubMed Central

    Petridou, E.; Revinthi, K.; Alexander, F. E.; Haidas, S.; Koliouskas, D.; Kosmidis, H.; Piperopoulou, F.; Tzortzatou, F.; Trichopoulos, D.

    1996-01-01

    The method introduced by Knox for evaluation of space-time clustering has been applied to 872 cases of childhood (0-14 year old) leukaemia diagnosed in Greece over the 10 year period 1980-89. Greek towns are characterised by substantial population mixing due to internal migration, whereas there is relative isolation in mountainous rural areas. Predetermined space (5 km) and time (1 year) limits were used on the basis of previous reports in order to define the clustering cell. There is highly significant evidence for clustering of childhood leukaemia in Greece as a whole, the observed number of pairs that are close in both spaces and time exceeding the expected number by 5.2% (P = 0.004). The excess is particularly evident for leukaemia cases in 0 to 4-year-old children, among whom the observed number of pairs that are close in both space and time exceeded the expected number by 9.4% (P = 0.004). There is no evidence of space-time clustering for leukaemia cases older than 5 years. The overall pattern is descriptively similar in urban and semiurban areas and is especially marked for acute lymphoblastic leukaemia at the childhood peak ages (2-4 years) with an excess of 19% (P = 0.0006). In the rural population there is evidence for clustering of cases belonging to older and broader age groups, a phenomenon compatible with a delay in the development of herd immunity against putative infectious aetiological agents. The findings of the present study provide support for the hypothesis that a substantial proportion of cases of childhood leukaemia may arise as a rare sequel to exposure to an agent or agents, most probably viral in nature. PMID:8630293

  2. Impact on learning of an e-learning module on leukaemia: a randomised controlled trial

    PubMed Central

    2012-01-01

    Background e-learning resources may be beneficial for complex or conceptually difficult topics. Leukaemia is one such topic, yet there are no reports on the efficacy of e-learning for leukaemia. This study compared the learning impact on senior medical students of a purpose-built e-learning module on leukaemia, compared with existing online resources. Methods A randomised controlled trial was performed utilising volunteer senior medical students. Participants were randomly allocated to Study and Control groups. Following a pre-test on leukaemia administered to both groups, the Study group was provided with access to the new e-learning module, while the Control group was directed to existing online resources. A post-test and an evaluation questionnaire were administered to both groups at the end of the trial period. Results Study and Control groups were equivalent in gender distribution, mean academic ability, pre-test performance and time studying leukaemia during the trial. The Study group performed significantly better than the Control group in the post-test, in which the group to which the students had been allocated was the only significant predictor of performance. The Study group’s evaluation of the module was overwhelmingly positive. Conclusions A targeted e-learning module on leukaemia had a significant effect on learning in this cohort, compared with existing online resources. We believe that the interactivity, dialogic feedback and integration with the curriculum offered by the e-learning module contributed to its impact. This has implications for e-learning design in medicine and other disciplines. PMID:22640463

  3. Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia

    PubMed Central

    Pal, D; Blair, H J; Elder, A; Dormon, K; Rennie, K J; Coleman, D J L; Weiland, J; Rankin, K S; Filby, A; Heidenreich, O; Vormoor, J

    2016-01-01

    Lack of suitable in vitro culture conditions for primary acute lymphoblastic leukaemia (ALL) cells severely impairs their experimental accessibility and the testing of new drugs on cell material reflecting clonal heterogeneity in patients. We show that Nestin-positive human mesenchymal stem cells (MSCs) support expansion of a range of biologically and clinically distinct patient-derived ALL samples. Adherent ALL cells showed an increased accumulation in the S phase of the cell cycle and diminished apoptosis when compared with cells in the suspension fraction. Moreover, surface expression of adhesion molecules CD34, CDH2 and CD10 increased several fold. Approximately 20% of the ALL cells were in G0 phase of the cell cycle, suggesting that MSCs may support quiescent ALL cells. Cellular barcoding demonstrated long-term preservation of clonal abundance. Expansion of ALL cells for >3 months compromised neither feeder dependence nor cancer initiating ability as judged by their engraftment potential in immunocompromised mice. Finally, we demonstrate the suitability of this co-culture approach for the investigation of drug combinations with luciferase-expressing primograft ALL cells. Taken together, we have developed a preclinical platform with patient-derived material that will facilitate the development of clinically effective combination therapies for ALL. PMID:27109511

  4. A four-point clinical criteria distinguishes immune thrombocytopenia from acute lymphoblastic leukaemia.

    PubMed

    Lum, S H; How, S J; Ariffin, H; Krishnan, S

    2016-02-01

    Immune thrombocytopenia is the most common diagnosis of isolated thrombocytopenia. The dilemma encountered by paediatricians is missing diagnosis of acute leukaemia in children with isolated thrombocytopenia. We demonstrated childhood ITP could be diagnosed using a four point clinical criteria without missing a diagnosis of acute leukaemia. Hence, bone marrow examination is not necessary in children with typical features compatible with ITP prior to steroid therapy. This can encourage paediatricians to choose steroid therapy, which is cheaper and non-blood product, as first line platelet elevating therapy in children with significant haemorrhage. PMID:27130741

  5. Attenuation of human influenza a viruses

    PubMed Central

    Beare, A. S.; Bynoe, M. L.

    1969-01-01

    The attenuation of two human influenza A viruses has been carried out, using the selection of inhibitor-resistant strains and multiple passages at low temperatures. A virus related to A2/Tokyo/3/67 was obtained in an inhibitor-resistant form. When this was compared with the inhibitor-sensitive strain in a volunteer trial it was relatively non-pathogenic. The second virus, A2/Hongkong/1/68, was subjected to much longer treatment, but nevertheless remained slightly sensitive to serum inhibitor. When given to volunteers it was less pathogenic than before but attenuation was incomplete. A2/Hongkong/1/68 was also modified by passage at low temperatures. Many of these passages are apparently necessary for full attenuation. All attenuated viruses were infective and antigenic. PMID:4900146

  6. Human Betacoronavirus 2c EMC/2012–related Viruses in Bats, Ghana and Europe

    PubMed Central

    Annan, Augustina; Baldwin, Heather J.; Corman, Victor Max; Klose, Stefan M.; Owusu, Michael; Nkrumah, Evans Ewald; Badu, Ebenezer Kofi; Anti, Priscilla; Agbenyega, Olivia; Meyer, Benjamin; Oppong, Samuel; Sarkodie, Yaw Adu; Kalko, Elisabeth K.V.; Lina, Peter H.C.; Godlevska, Elena V.; Reusken, Chantal; Seebens, Antje; Gloza-Rausch, Florian; Vallo, Peter; Tschapka, Marco; Drosten, Christian

    2013-01-01

    We screened fecal specimens of 4,758 bats from Ghana and 272 bats from 4 European countries for betacoronaviruses. Viruses related to the novel human betacoronavirus EMC/2012 were detected in 46 (24.9%) of 185 Nycteris bats and 40 (14.7%) of 272 Pipistrellus bats. Their genetic relatedness indicated EMC/2012 originated from bats. PMID:23622767

  7. Leukaemia, lymphoma, and multiple myeloma in seamen on tankers

    PubMed Central

    Nilsson, R. I.; Nordlinder, R.; Horte, L. G.; Jarvholm, B.

    1998-01-01

    OBJECTIVES: To investigate the risk of lymphatic and haematopoietic malignancies in deck crew on tankers exposed to cargo vapours. METHODS: The study design was as a nested case-referent study in two cohorts of male Swedish seamen 20-64 years of age at the national census 1960 (n 13,449) and 1970 (n 11,290), respectively. Cases were detected by record linkage with the Swedish Cancer Register 1961-79 and 1971-87, respectively. For each case, three to five age matched referents from the population were selected. Exposure was assessed from data in the Swedish Registry of Seamen and from a register of Swedish ships. RESULTS: Seamen in the 1970 cohort, who had been exposed to cargo vapours for at least one month on chemical or product tankers, had an increased risk of lymphatic and haematopoietic malignancies (Mantel- Haenszel odds ratio (OR) 2.6, 95% confidence interval (95% CI) 1.1 to 5.9)) with a significant exposure-response relation (conditional logistic regression analysis, p = 0.04). The ORs were increased for both lymphoma (3.2), multiple myeloma (4.0), and leukaemia (1.6), but the increase was only significant for non-Hodgkin's lymphoma (OR 3.3, 95% CI 1.1 to 10.6). There were no significantly increased risks for the 1960 cohort or for seamen exposed only on crude oil tankers, but these groups had few exposed cases and low cumulative exposure to benzene and other light petroleum products. CONCLUSIONS: Seamen exposed to cargo vapours from gasoline and other light petroleum products on chemical or product tankers had an increased incidence of lymphatic and haematopoietic malignancies. One possible cause is exposure to benzene during loading, unloading, and tank cleaning operations.   PMID:9849537

  8. Targeting survival pathways in chronic myeloid leukaemia stem cells

    PubMed Central

    Sinclair, A; Latif, A L; Holyoake, T L

    2013-01-01

    Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a fusion oncogene BCR-ABL, which encodes a protein with constitutive TK activity. The implementation of tyrosine kinase inhibitors (TKIs) marked a major advance in CML therapy; however, there are problems with current treatment. For example, relapse occurs when these drugs are discontinued in the majority of patients who have achieved a complete molecular response on TKI and these agents are less effective in patients with mutations in the BCR-ABL kinase domain. Importantly, TKI can effectively target proliferating mature cells, but do not eradicate quiescent leukaemic stem cells (LSCs), therefore allowing disease persistence despite treatment. It is essential that alternative strategies are used to target the LSC population. BCR-ABL activation is responsible for the modulation of different signalling pathways, which allows the LSC fraction to evade cell death. Several pathways have been shown to be modulated by BCR-ABL, including PI3K/AKT/mTOR, JAK-STAT and autophagy signalling pathways. Targeting components of these survival pathways, alone or in combination with TKI, therefore represents an attractive potential therapeutic approach for targeting the LSC. However, many pathways are also active in normal stem cells. Therefore, potential targets must be validated to effectively eradicate CML stem cells while sparing normal counterparts. This review summarizes the main pathways modulated in CML stem cells, the recent developments and the use of novel drugs to target components in these pathways which may be used to target the LSC population. Linked Articles This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8 PMID:23517124

  9. The Impact of Opportunistic Infections on Clinical Outcome and Healthcare Resource Uses for Adult T Cell Leukaemia

    PubMed Central

    Maeda, Toshiki; Babazono, Akira; Nishi, Takumi; Yasui, Midori; Matsuda, Shinya; Fushimi, Kiyohide; Fujimori, Kenji

    2015-01-01

    We examined the impact of opportunistic infections on in-hospital mortality, hospital length of stay (LOS), and the total cost (TC) among adult T-cell leukaemia (ATL) patients. In this retrospective cohort study, we identified 3712 patients with ATL using national hospital administrative data. Analysed opportunistic infections included Aspergillus spp., Candida spp., cytomegalovirus (CMV), herpes simplex virus (HSV), pneumocystis pneumonia (PCP), tuberculosis, varicella zoster virus (VZV), Cryptococcus spp., nontuberculous mycobacteria, and Strongyloides spp. Multilevel logistic regression analysis for in-hospital mortality and a multilevel linear regression analysis for LOS and TC were employed to determine the impact of opportunistic infections on clinical outcomes and healthcare resources. We found ATL patients infected with CMV had significantly higher in-hospital mortality (adjusted odds ratio (AOR) 2.29 [1.50–3.49] p < 0.001), longer LOS (coefficient (B): 0.13 [0.06–0.20] p < 0.001) and higher TC (B: 0.25 [0.17–0.32] p < 0.001) than those without CMV. Those with CAN and PCP were associated with a lower in-hospital mortality rate (AOR 0.72 [0.53–0.98] p = 0.035 and 0.54[0.41–0.73] p < 0.001, respectively) than their infections. VZV was associated with longer LOS (B: 0.13 [0.06–0.19] p < 0.001), while aspergillosis, HSV, or VZV infections were associated with higher TC (B: 0.16 [0.07–0.24] p < 0.001, 0.12 [0.02–0.23] p = 0.025, and 0.17 [0.10–0.24] p < 0.001, respectively). Our findings reveal that CMV infection is a major determinant of poor prognosis in patients affected by ATL. PMID:26274925

  10. Proposals for the classification of chronic (mature) B and T lymphoid leukaemias. French-American-British (FAB) Cooperative Group.

    PubMed Central

    Bennett, J M; Catovsky, D; Daniel, M T; Flandrin, G; Galton, D A; Gralnick, H R; Sultan, C

    1989-01-01

    Peripheral blood, bone marrow films, and bone marrow biopsy specimens from 110 patients, well characterised by clinical and laboratory studies, including electron microscopy, were reviewed, to determine proposals for the classification of chronic (mature) B and T cell leukaemias. On the basis of cytology and membrane phenotype the following disorders were defined: (i) B cell type: chronic lymphocytic leukaemia (CLL); CLL of mixed cell type, which includes cases with more than 10% and less than 55% prolymphocytes (CLL/PL), and a less well defined form with pleomorphic lymphocytes but less than 10% prolymphocytes; prolymphocytic leukaemia (PLL); hairy cell leukaemia (HCL); HCL variant; splenic lymphoma with circulating villous lymphocytes; leukaemic phase of non-Hodgkin's lymphoma (follicular lymphoma, intermediate, or mantle zone lymphoma and others); lymphoplasmacytic lymphoma with peripheral blood disease (mostly Waldenström's macroglobulinaemia); and plasma cell leukaemia. (ii) T cell type: T/CLL, which was differentiated from reactive T/lymphocytosis; T/PLL; adult T cell leukaemia/lymphoma; and Sézary's syndrome. The recognition of distinct entities within the B and T cell leukaemias seems to have clinical and epidemiological connotations. It is hoped that these proposals may serve as the basis for further work, discussion, and improved management of patients. Images Fig 1 Fig 1 Fig 1 Fig 2 Fig 3 Fig 3 Fig 4 Fig 5 Fig 6 PMID:2738163

  11. Friend strain of spleen focus-forming virus: a recombinant between mouse type C ecotropic viral sequences and sequences related to xenotropic virus.

    PubMed Central

    Troxler, D H; Boyars, J K; Parks, W P; Scolnick, E M

    1977-01-01

    The genome of the Friend strain of the spleen focus-forming virus (SFFV) has been analyzed by molecular hybridization. SFFV is composed of genetic sequences homologous to Friend type C helper virus (F-MuLV) and SFFV-specific sequences not present in F-MuLV. These SFFV-specific sequences are present in both the Friend and Rauscher strains of murine erythroleukemia virus. The SFFV-specific sequences are partially homologous to three separate strains of mouse xenotropic virus but not to several cloned mouse ecotropic viruses. Thus, the Friend strain of SFFV appears to be a recombinant between a portion of the F-MuLV genome and RNA sequences that are highly related to murine xenotropic viruses. The implications of the acquisition of the xenotropic virus-related sequences are discussed in relation to the leukemogenicity of SFFV, and a model for the pathogenicity of other murine leukemia-inducing viruses is proposed. PMID:194058

  12. HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias.

    PubMed

    Calero-Nieto, F J; Joshi, A; Bonadies, N; Kinston, S; Chan, W-I; Gudgin, E; Pridans, C; Landry, J-R; Kikuchi, J; Huntly, B J; Gottgens, B

    2013-11-28

    The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2. PMID:23708655

  13. Feedback mechanisms control coexistence in a stem cell model of acute myeloid leukaemia.

    PubMed

    Crowell, Helena L; MacLean, Adam L; Stumpf, Michael P H

    2016-07-21

    Haematopoietic stem cell dynamics regulate healthy blood cell production and are disrupted during leukaemia. Competition models of cellular species help to elucidate stem cell dynamics in the bone marrow microenvironment (or niche), and to determine how these dynamics impact leukaemia progression. Here we develop two models that target acute myeloid leukaemia with particular focus on the mechanisms that control proliferation via feedback signalling. It is within regions of parameter space permissive of coexistence that the effects of competition are most subtle and the clinical outcome least certain. Steady state and linear stability analyses identify parameter regions that allow for coexistence to occur, and allow us to characterise behaviour near critical points. Where analytical expressions are no longer informative, we proceed statistically and sample parameter space over a coexistence region. We find that the rates of proliferation and differentiation of healthy progenitors exert key control over coexistence. We also show that inclusion of a regulatory feedback onto progenitor cells promotes healthy haematopoiesis at the expense of leukaemia, and that - somewhat paradoxically - within the coexistence region feedback increases the sensitivity of the system to dominance by one lineage over another. PMID:27130539

  14. Massive retroperitoneal lymphadenopathy as a terminal event in hairy cell leukaemia.

    PubMed

    Mehta, A B; Catovsky, D; O'Brien, C J; Lott, M; Bowley, N; Hemmingway, A

    1983-01-01

    A case of hairy cell leukaemia complicated as a terminal event by massive retroperitoneal lymphadenopathy is described. The patient had recently been treated with lithium carbonate and had previously been demonstrated to suffer from a systemic vasculitis, either or both of which may have contributed to the development of this rare complication. PMID:6360496

  15. Dendritic cell-based immunotherapy in myeloid leukaemia: translating fundamental mechanisms into clinical applications.

    PubMed

    van de Loosdrecht, A A; van den Ancker, W; Houtenbos, I; Ossenkoppele, G J; Westers, T M

    2009-01-01

    Immunotherapy for leukaemia patients, aiming at the generation of anti-leukaemic T cell responses, could provide a new therapeutic approach to eliminate minimal residual disease (MRD) cells in acute myeloid leukaemia (AML). Leukaemic blasts harbour several ways to escape the immune system including deficient MHC class II expression, low levels of co-stimulatory molecules and suppressive cytokines. Therapeutic vaccination with dendritic cells (DC) is now recognized as an important investigational therapy. Due to their unique antigen presenting capacity, immunosuppressive features of the leukaemic blasts can be circumvented. DC can be successfully cultured from leukaemic blasts in 60-70% of patients and show functional potential in vivo. Alternatively, monocyte derived DC obtained at time of complete remission loaded with leukaemia-specific antigens can be used as vaccine. Several sources of leukaemia-associated antigen and different methods of loading antigen onto DC have been used in an attempt to optimize antitumour responses including apoptotic cells, necrotic cell lysates and tumour-associated pep-tides. Currently, the AML-derived cell line MUTZ-3, an immortalized equivalent of CD34(+) DC precursor cells, is under investigation for vaccination purposes. For effective DC vaccination the intrinsic tolerant state of the patient must be overcome. Therefore, the development of efficient and safe adjuvants in antigen specific immunotherapeutic programs should be encouraged. PMID:19031033

  16. Childhood leukaemia in North West England 1954-1977: epidemiology, incidence and survival.

    PubMed Central

    Birch, J. M.; Swindell, R.; Marsden, H. B.; Morris Jones, P. H.

    1981-01-01

    The annual incidence of leukaemia among children aged up to 14 years as estimated by the Manchester Children's Tumour Registry has been analysed for the 24 years 1954-1977. A significant increase in acute lymphoid leukaemia (ALL) was found, while the incidence of acute myeloid leukaemia (AML) remained constant. Other types of leukaemia were too rare to be analysed separately. The increase in ALL was concentrated among boys in the 1--5-year age group. Analysis with respect to initial white-cell count showed the increase to be more pronounced in children with initial white cell counts of 1-5 x 10(4)/microliters. The proportion of cases presenting in Lancashire compared with Greater Manchester did not change during the study period. The distribution of cases with respect to social class and socio-economic group of the parents also remained constant. Due to advances in the treatment of childhood ALL survival improved considerably during the study period and no increase in mortality was seen. PMID:6939448

  17. Synergistic targeted therapy for acute promyelocytic leukaemia: a model of translational research in human cancer.

    PubMed

    Mi, J-Q; Chen, S-J; Zhou, G-B; Yan, X-J; Chen, Z

    2015-12-01

    Acute promyelocytic leukaemia (APL), the M3 subtype of acute myeloid leukaemia, was once a lethal disease, yet nowadays the majority of patients with APL can be successfully cured by molecularly targeted therapy. This dramatic improvement in the survival rate is an example of the advantage of modern medicine. APL is characterized by a balanced reciprocal chromosomal translocation fusing the promyelocytic leukaemia (PML) gene on chromosome 15 with the retinoic acid receptor α (RARα) gene on chromosome 17. It has been found that all-trans-retinoic acid (ATRA) or arsenic trioxide (ATO) alone exerts therapeutic effect on APL patients with the PML-RARα fusion gene, and the combination of both drugs can act synergistically to further enhance the cure rate of the patients. Here, we provide an insight into the pathogenesis of APL and the mechanisms underlying the respective roles of ATRA and ATO. In addition, treatments that lead to more effective differentiation and apoptosis of APL cells, including leukaemia-initiating cells, and more thorough eradication of the disease will be discussed. Moreover, as a model of translational research, the development of a cure for APL has followed a bidirectional approach of 'bench to bedside' and 'bedside to bench', which can serve as a valuable example for the diagnosis and treatment of other malignancies. PMID:26058416

  18. Levels of expression of CD19 and CD20 in chronic B cell leukaemias.

    PubMed Central

    Ginaldi, L; De Martinis, M; Matutes, E; Farahat, N; Morilla, R; Catovsky, D

    1998-01-01

    AIMS: To investigate whether the antigen levels of the B cell lineage markers CD19 and CD20 can distinguish between normal and neoplastic B cells or characterise distinct expression patterns among the chronic B cell leukaemias. METHODS: Peripheral blood cells from 70 patients with B cell disorders and 17 healthy donors were analysed by quantitative flow cytometry. Direct immunofluorescence staining was performed with phycoerythrin conjugated CD19 and CD20 monoclonal antibodies. Standard microbeads with different capacities to bind mouse immunoglobulins were used to convert the mean fluorescence intensity (MFI) values into number of antigen molecules/cell, expressed as antibody binding capacity (ABC). RESULTS: CD19 and CD20 ABC values in leukaemic B cells differed from those of normal blood B lymphocytes. The results identified distinct profiles of CD19 and CD20 expression in the various types of B cell leukaemias. In all leukaemias studied except hairy cell leukaemia (HCL), CD19 expression was significantly lower than the mean (SD) value in normal B cells (22 (7) x 10(3) molecules/cell), as follows: chronic lymphocytic leukaemia (CLL), 13 (7) x 10(3); B prolymphocytic leukaemia (B-PLL), 16 (9) x 10(3); splenic lymphoma with villous lymphocytes (SLVL), 15 (11) x 10(3); mantle cell lymphoma (MCL), 10 (7) x 10(3). In HCL there was strong CD19 expression (38 (16) x 10(3)). In contrast, the level of expression of membrane CD20 was higher than the mean (SD) value in normal B cells (94 (16) x 10(3) molecules/cell) in MCL (123 (51) x 10(3)); B-PLL (129 (47) x 10(3)); SLVL (167 (72) x 10(3)); and HCL (312 (110) x 10(3)); while it was significantly lower (65 (11) x 10(3)) in CLL compared with normal B cells and the other B cell leukaemias. CONCLUSIONS: Quantitative determination of CD19 and CD20 may provide useful diagnostic information for the study of B lymphoproliferative disorders. PMID:9708202

  19. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus.

    PubMed

    Schmiegelow, Kjeld; Attarbaschi, Andishe; Barzilai, Shlomit; Escherich, Gabriele; Frandsen, Thomas Leth; Halsey, Christina; Hough, Rachael; Jeha, Sima; Kato, Motohiro; Liang, Der-Cherng; Mikkelsen, Torben Stamm; Möricke, Anja; Niinimäki, Riitta; Piette, Caroline; Putti, Maria Caterina; Raetz, Elizabeth; Silverman, Lewis B; Skinner, Roderick; Tuckuviene, Ruta; van der Sluis, Inge; Zapotocka, Ester

    2016-06-01

    Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment. PMID:27299279

  20. Splenic B cell lymphoma with circulating villous lymphocytes: differential diagnosis of B cell leukaemias with large spleens.

    PubMed Central

    Melo, J V; Hegde, U; Parreira, A; Thompson, I; Lampert, I A; Catovsky, D

    1987-01-01

    The clinical, haematological, morphological and histological features of a series of 22 patients presenting with splenic lymphoma with circulating villous lymphocytes were assessed and compared with those of patients with other forms of chronic B cell leukaemia in an attempt to differentiate this condition from hairy cell leukaemia, prolymphocytic leukaemia, and chronic lymphocytic leukaemia, with which this condition has many features in common. The disease was twice as common in men than in women, with a mean (SD) age at diagnosis of 72 (9) years, and the most consistent presenting feature was massive enlargement of the spleen, which showed white and red pulp disease with a plasmacytic component. Small monoclonal bands were found in 60% of cases. Images Fig 1 Fig 2 Fig 3 Fig 4 PMID:3497180

  1. Trends in childhood leukaemia in the Nordic countries in relation to fallout from atmospheric nuclear weapons testing.

    PubMed Central

    Darby, S. C.; Olsen, J. H.; Doll, R.; Thakrar, B.; Brown, P. D.; Storm, H. H.; Barlow, L.; Langmark, F.; Teppo, L.; Tulinius, H.

    1992-01-01

    OBJECTIVE--To obtain further information about the risks of childhood leukaemia after exposure to ionising radiation at low doses and low dose rates before or after birth or to the father's testes shortly before conception. DESIGN--Observational study of trends in incidence of childhood leukaemia in relation to estimated radiation exposures due to fallout from atmospheric nuclear weapons testing during the 1950s and 1960s. SETTING--Nordic countries. SUBJECTS--Children aged under 15 years. MAIN OUTCOME MEASURES--Incidence rates of leukaemia by age at diagnosis, sex, country, and calendar year of diagnosis or year of birth; exposure category; relation between leukaemia and exposure for children aged 0-14 and 0-4 separately. RESULTS--During the high fallout period the average estimated dose equivalent to the fetal red bone marrow was around 140 mu Sv and the average annual testicular dose 140 mu Sv. There was little evidence of increased incidence of leukaemia among children born in these years. Doses to the red bone marrow of a child after birth were higher, and during the high exposure period children would have been subjected to an additional dose equivalent of around 1500 mu Sv, similar to doses received by children in several parts of central and eastern Europe owing to the Chernobyl accident and about 50% greater than the annual dose equivalent to the red bone marrow of a child from natural radiation. leukaemia incidence and red marrow dose was not related overall, but rates of leukaemia in the high exposure period were slightly higher than in the surrounding medium exposure period (relative risk for ages 0-14: 1.07, 95% confidence interval 1.00 to 1.14; for ages 0-4: 1.11, 1.00 to 1.24). CONCLUSIONS--Current predicted risks of childhood leukaemia after exposure to radiation are not greatly underestimated for low dose rate exposures. PMID:1586779

  2. Ionising radiation and risk of death from leukaemia and lymphoma in radiation-monitored workers (INWORKS): an international cohort study

    PubMed Central

    Leuraud, Klervi; Richardson, David B; Cardis, Elisabeth; Daniels, Robert D; Gillies, Michael; O'Hagan, Jacqueline A; Hamra, Ghassan B; Haylock, Richard; Laurier, Dominique; Moissonnier, Monika; Schubauer-Berigan, Mary K; Thierry-Chef, Isabelle; Kesminiene, Ausrele

    2015-01-01

    Summary Background There is much uncertainty about the risks of leukaemia and lymphoma after repeated or protracted low-dose radiation exposure typical of occupational, environmental, and diagnostic medical settings. We quantified associations between protracted low-dose radiation exposures and leukaemia, lymphoma, and multiple myeloma mortality among radiation-monitored adults employed in France, the UK, and the USA. Methods We assembled a cohort of 308 297 radiation-monitored workers employed for at least 1 year by the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France, the Departments of Energy and Defence in the USA, and nuclear industry employers included in the National Registry for Radiation Workers in the UK. The cohort was followed up for a total of 8·22 million person-years. We ascertained deaths caused by leukaemia, lymphoma, and multiple myeloma. We used Poisson regression to quantify associations between estimated red bone marrow absorbed dose and leukaemia and lymphoma mortality. Findings Doses were accrued at very low rates (mean 1·1 mGy per year, SD 2·6). The excess relative risk of leukaemia mortality (excluding chronic lymphocytic leukaemia) was 2·96 per Gy (90% CI 1·17–5·21; lagged 2 years), most notably because of an association between radiation dose and mortality from chronic myeloid leukaemia (excess relative risk per Gy 10·45, 90% CI 4·48–19·65). Interpretation This study provides strong evidence of positive associations between protracted low-dose radiation exposure and leukaemia. Funding Centers for Disease Control and Prevention, Ministry of Health, Labour and Welfare of Japan, Institut de Radioprotection et de Sûreté Nucléaire, AREVA, Electricité de France, National Institute for Occupational Safety and Health, US Department of Energy, US Department of Health and Human Services, University of North Carolina, Public Health England. PMID:26436129

  3. Leukaemia, brain tumours and exposure to extremely low frequency magnetic fields: cohort study of Swiss railway employees

    PubMed Central

    Röösli, Martin; Lörtscher, Manfred; Egger, Matthias; Pfluger, Dominik; Schreier, Nadja; Lörtscher, Emanuel; Locher, Peter; Spoerri, Adrian; Minder, Christoph

    2007-01-01

    Aims To investigate the relationship between extremely low frequency magnetic field (ELF‐MF) exposure and mortality from leukaemia and brain tumour in a cohort of Swiss railway workers. Methods 20 141 Swiss railway employees with 464 129 person‐years of follow‐up between 1972 and 2002 were studied. Mortality rates for leukaemia and brain tumour of highly exposed train drivers (21 μT average annual exposure) were compared with medium and low exposed occupational groups (i.e. station masters with an average exposure of 1 μT). In addition, individual cumulative exposure was calculated from on‐site measurements and modelling of past exposures. Results The hazard ratio (HR) for leukaemia mortality of train drivers was 1.43 (95% CI 0.74 to 2.77) compared with station masters. For myeloid leukaemia the HR of train drivers was 4.74 (95% CI 1.04 to 21.60) and for Hodgkin's disease 3.29 (95% CI 0.69 to 15.63). Lymphoid leukaemia, non‐Hodgkin's disease and brain tumour mortality were not associated with magnetic field exposure. Concordant results were obtained from analyses based on individual cumulative exposure. Conclusions Some evidence of an exposure–response association was found for myeloid leukaemia and Hodgkin's disease, but not for other haematopoietic and lymphatic malignancies and brain tumours. PMID:17525094

  4. Biochemical characterization of endogenous type C virus information in differentiated and undifferentiated murine teratocarcinoma-derived cell lines.

    PubMed Central

    Emanoil-Ravicovitch, R; Hojman-Montes-de-Oca, F; Robert, J; Garcette, M; Callahan, R; Peries, J; Boiron, M

    1980-01-01

    Undifferentiated teratocarcinoma cells express sixfold-higher levels of endogenous xenotropic type C virus-related RNA than differentiated cells. Three species of polyadenylated viral RNA (35S, 24S, and 14S) have been identified in the undifferentiated teratocarcinoma cells. Paradoxically, neither viral particles nor viral proteins have been detected in these cells. PMID:6246284

  5. Fallout from Chernobyl and incidence of childhood leukaemia in Finland, 1976-92.

    PubMed Central

    Auvinen, A.; Hakama, M.; Arvela, H.; Hakulinen, T.; Rahola, T.; Suomela, M.; Söderman, B.; Rytömaa, T.

    1994-01-01

    OBJECTIVE--To assess effects of fallout from Chernobyl on incidence of childhood leukaemia in Finland. DESIGN--Nationwide cohort study. External exposure measured for 455 Finnish municipalities with instruments driven 19,000 km throughout the country. Values specific to municipalities corrected for shielding due to houses and fallout from A bomb testing. Internal exposure estimated from whole body measurements on a random sample of 81 children. Mean effective dose for two years after incident calculated from these measurements. Data on childhood leukaemia obtained from Finnish cancer registry and verified through hospitals treating childhood cancers. SETTING--Finland, one of the countries most heavily contaminated by the Chernobyl accident; the population was divided into fifths by exposure. SUBJECTS--Children aged 0-14 years in 1976-92. MAIN OUTCOME MEASURES--Standardised incidence ratio of childhood leukaemia and relative excess risk of childhood leukaemia per mSv. From incidence data of Finnish cancer registry for 1976-85, expected numbers specific to sex and age group (0-4, 5-9, and 10-14 years) were calculated for each municipality for three periods (1976-85, 1986-8, and 1989-92) and pooled as exposure fifths. Dose response was estimated as regression slope of standardised incidence ratios on mean doses for fifths for each period. RESULTS--Population weighted mean effective doses for first two years after the accident were 410 microSv for the whole country and 970 microSv for the population fifth with the highest dose. In all Finland the incidence of childhood leukaemia did not increase 1976-92. The relative excess risk 1989-92 was not significantly different from zero (7% per mSv; 95% confidence interval -27% to 41%). CONCLUSIONS--An important increase in childhood leukaemia can be excluded. Any effect is smaller than eight extra cases per million children per year in Finland. The results are consistent with the magnitude of effect expected. PMID:8044092

  6. Ceramide and glutathione define two independently regulated pathways of cell death initiated by p53 in Molt-4 leukaemia cells.

    PubMed Central

    El-Assaad, Wissal; Kozhaya, Lina; Araysi, Sawsan; Panjarian, Shoghag; Bitar, Fadi F; Baz, Elizabeth; El-Sabban, Marwan E; Dbaibo, Ghassan S

    2003-01-01

    The tumour suppressor p53 induces cell death by launching several pathways that are either dependent on or independent of gene transcription. Accumulation of the sphingolipid ceramide and reactive oxygen species are among these pathways. Crossregulation of these two pathways is possible owing to the demonstrated inhibition of neutral sphingomyelinase by glutathione, the predominant cellular antioxidant, and has been observed in some cytokine-dependent cell-death models. In a model of irradiation-induced cell death of Molt-4 leukaemia cells, it was found that ceramide accumulation and glutathione depletion were dependent on p53 up-regulation. The loss of p53 owing to expression of the papilloma virus E6 protein inhibited both pathways after irradiation. However, in this model, these two pathways appeared to be independently regulated on the basis of the following observations: (1) glutathione supplementation or depletion did not alter irradiation-induced ceramide accumulation, (2) exogenous ceramide treatment did not induce glutathione depletion, (3) glutathione depletion was dependent on new protein synthesis, whereas ceramide accumulation was independent of it and (4) caspase activation was required for ceramide accumulation but not for glutathione depletion. Furthermore, caspase 9 activation, which is dependent on the release of mitochondrial cytochrome c, was not required for ceramide accumulation. This suggested that a caspase, other than caspase 9, was necessary for ceramide accumulation. Interestingly, Bcl-2 expression inhibited these pathways, indicating a possible role for mitochondria in regulating both pathways. These findings indicate that these two pathways exhibit cross-regulation in cytokine-dependent, but not in p53-dependent, cell-death models. PMID:12967322

  7. The solution structure of the RING finger domain from the acute promyelocytic leukaemia proto-oncoprotein PML.

    PubMed Central

    Borden, K L; Boddy, M N; Lally, J; O'Reilly, N J; Martin, S; Howe, K; Solomon, E; Freemont, P S

    1995-01-01

    Acute promyelocytic leukaemia (APL) has been ascribed to a chromosomal translocation event which results in a fusion protein comprising the PML protein and the retinoic acid receptor alpha. PML is normally a component of a nuclear multiprotein complex (termed ND10, Kr bodies, nuclear bodies, PML oncogenic domains or PODs) which is disrupted in the APL disease state. PML contains a number of characterized motifs including a Zn2+ binding domain called the RING or C3HC4 finger. Here we describe the solution structure of the PML RING finger as solved by 1H NMR methods at physiological pH with r.m.s. deviations for backbone atoms of 0.88 and 1.39 A for all atoms. Additional biophysical studies including CD and optical spectroscopy, show that the PML RING finger requires Zn2+ for autonomous folding and that cysteines are used in metal ligation. A comparison of the structure with the previously solved equine herpes virus IE110 RING finger, shows significant differences suggesting that the RING motif is structurally diverse. The role of the RING domain in PML nuclear body formation was tested in vivo, by using site-directed mutagenesis and immunofluorescence on transiently transfected NIH 3T3 cells. Independently mutating two pairs of cysteines in each of the Zn2+ binding sites prevents PML nuclear body formation, suggesting that a fully folded RING domain is necessary for this process. These results suggest that the PML RING domain is probably involved in protein-protein interactions, a feature which may be common to other RING finger domains. Images PMID:7729428

  8. A specialist leukaemia/lymphoma registry in the UK. Part 1: Incidence and geographical distribution of Hodgkin's disease. Leukaemia Research Fund Data Collection Study Group.

    PubMed Central

    McKinney, P. A.; Alexander, F. E.; Ricketts, T. J.; Williams, J.; Cartwright, R. A.

    1989-01-01

    This paper describes the epidemiology of Hodgkin's disease occurring in parts of the United Kingdom between 1984 and 1986. The cases were carefully diagnosed and the data rigorously cross-checked as part of the larger Leukaemia Research Fund Data Collection Survey of all lymphoid and haematogenous malignancies. The age-specific rates show the lack of an older adult second peak. Spatial variation is examined in some detail. At county and district levels there is little heterogeneity in the distribution of cases. However, at the electoral ward level there were real differences for the younger age group (0-34). PMID:2605103

  9. Neonatal acute lymphocytic leukaemia: an unusual presentation of a rare disease.

    PubMed

    Palman, Jason; Karam, Maria; Chee, Ying; Kandala, Vijay

    2015-01-01

    Infantile acute lymphocytic leukaemia (ALL) seldom presents within the first month of life. Most are diagnosed before birth. Postnatal diagnoses are easily recognisable when characteristic features are present, namely hepatosplenomegaly, leukaemia cutis or infiltrative disease of the extramedullar and central nervous system. However, some children present with vague and non-specific symptoms masquerading as other diseases. We report an unusual presentation of infantile ALL in a 19-day-old infant, who struggled with feeding after a diagnosis of gastro-oesophageal reflux disease since birth. To the best of our knowledge, this is the youngest case report of neonatal ALL, presenting with vomiting, lethargy and dehydration. The neonate presented to our paediatric assessment unit acutely due to progression of her symptoms. General physical examination was unremarkable apart from signs of lethargy and dehydration. Blood investigation revealed an incidental finding of high white cells, including 90% blast cells. Early diagnosis in this case meant early treatment and a good prognosis. PMID:26178003

  10. Mild axonal neuropathy of children during treatment for acute lymphoblastic leukaemia.

    PubMed

    Reinders-Messelink, H A; Van Weerden, T W; Fock, J M; Gidding, C E; Vingerhoets, H M; Schoemaker, M M; Göeken, L N; Bökkerink, J P; Kamps, W A

    2000-01-01

    Neurophysiological functioning was studied prospectively in children treated for acute lymphoblastic leukaemia with a low dose vincristine regime (8 x 1.5 mg/m2/dose), to obtain more insight into vincristine neuropathy. A WHO neurotoxicity score was estimated and vibration sense and electrophysiological measurements were taken at standardized times during vincristine treatment. The WHO neurotoxicity score showed decreased or disappearance of Achilles tendon reflexes, and mild sensory disturbances, but a grade 3-4 neurotoxicity was not demonstrated by any of the children. Vibration perception thresholds increased progressively during treatment and amplitudes of action potentials of peroneal and sensory ulnar and median nerves decreased, whereas nerve conduction velocities stayed unchanged. Both vibration perception thresholds and the electrophysiological findings hardly exceeded the limits of normality. We conclude that children treated for acute lymphoblastic leukaemia with a low dose vincristine regimen have mild axonal neuropathy which may be responsible for the motor problems in these children. PMID:11030069

  11. Femoral diaphyseal stress fracture as the initial presentation of acute leukaemia in an adolescent.

    PubMed

    Chase, Helen Emily; Pang, Joe Hwong; Sanghrajka, Anish Pradip

    2016-01-01

    A 14-year-old boy was referred to the orthopaedic clinic by his general practitioner, reporting of a 6-week history of left thigh pain. Clinical examination was unremarkable. Radiographs demonstrated a periosteal reaction at the proximal femur. MRI scans demonstrated a stress fracture of the femur, with no associated sinister features and no evidence of a pathological lesion. As the fracture healed and symptoms improved, the patient became unwell with weight loss, lethargy, chest and jaw pain and fevers. After multiple blood tests over a 25-day period, including five full blood counts and two normal blood films, a third blood film finally demonstrated blasts in keeping with acute leukaemia. We discuss a literature review of musculoskeletal manifestations of leukaemia and the often atypical presentations found. PMID:27353177

  12. Stage IV sporadic Burkitt's leukaemia with osteolysis in the maxillary sinuses

    PubMed Central

    Yoshioka, Yohsuke; Yamachika, Eiki; Matsubara, Masakazu; Iida, Seiji

    2016-01-01

    We present a case of paediatric Stage IV sporadic Burkitt's leukaemia presenting as cheek enlargement with osteolysis of the maxilla. An 8-year-old boy was referred to our department with diffuse swelling of both cheeks. Head and neck examination revealed bilateral diffuse nontender swelling, non-fluctuant but slightly compressible. Computed tomography imaging showed enhancing bilateral bulky lesions expanding the maxillary sinuses, with associated osteolysis in the posterior walls of both sinuses. Laboratory results included blast cells in the peripheral blood, suggesting a haematopoietic tumour. We referred the patient to the Department of Paediatric Haematology and Oncology. Additional examinations eventually led to the diagnosis of Stage IV sporadic Burkitt's leukaemia. PMID:26872961

  13. Angiogenic factors in chronic lymphocytic leukaemia (CLL): Where do we stand?

    PubMed

    Aguirre Palma, Luis Mario; Gehrke, Iris; Kreuzer, Karl-Anton

    2015-03-01

    The role of angiogenesis in haematological malignancies such as chronic lymphocytic leukaemia (CLL) is difficult to envision, because leukaemia cells are not dependent on a network of blood vessels to support basic physiological requirements. Regardless, CLL cells secrete high levels of major angiogenic factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF). Nonetheless, it remains unclear how most angiogenic factors regulate accumulation and delayed apoptosis of CLL cells. Angiogenic factors such as leptin, granulocyte colony-stimulating factor (G-CSF), follistatin, angiopoietin-1 (Ang1), angiogenin (ANG), midkine (MK), pleiotrophin (PTN), progranulin (PGRN), proliferin (PLF), placental growth factor (PIGF), and endothelial locus-1 (Del-1), represent novel therapeutic targets of future CLL research but have remained widely overlooked. This review aims to outline our current understanding of angiogenic growth factors and their relationship with CLL, a still uncured haematopoietic malignancy. PMID:25459668

  14. Chronic myelogenous leukaemia with persistent neutrophilia, eosinophilia and basophilia in a cat.

    PubMed

    Mochizuki, Hiroyuki; Seki, Takahiro; Nakahara, Yoshitaka; Tomita, Akitada; Takahashi, Masashi; Fujino, Yasuhito; Ohno, Koichi; Tsujimoto, Hajime

    2014-06-01

    Chronic myelogenous leukaemia was diagnosed in a 7-year-old male neutered domestic shorthair cat. Leukocytosis (74,900/µl)--mature neutrophilia, eosinophilia and basophilia--was observed. Bone marrow aspiration revealed hypercellularity with proliferation of cells of myeloid lineage. An underlying condition leading to leukocytosis was not identified. The severe leukocytosis did not respond to antibiotic therapy. Based on these findings, chronic myelogenous leukaemia was diagnosed. Because of the absence of clinical signs, the cat was monitored without treatment until 7 months after diagnosis, when it developed pruritic skin lesions. Pruritus was controlled with oral prednisolone. Forty-two months after diagnosis, the cat developed nasal lymphoma, which was treated with radiation therapy, resulting in complete remission. The cat was still in good physical condition 63 months after diagnosis, despite the persistence of marked neutrophilia, eosinophilia and basophilia. PMID:24108200

  15. Belinostat, a potent HDACi, exerts antileukaemic effect in human acute promyelocytic leukaemia cells via chromatin remodelling

    PubMed Central

    Valiuliene, Giedre; Stirblyte, Ieva; Cicenaite, Dovile; Kaupinis, Algirdas; Valius, Mindaugas; Navakauskiene, Ruta

    2015-01-01

    Epigenetic changes play a significant role in leukaemia pathogenesis, therefore histone deacetylases (HDACis) are widely accepted as an attractive strategy for acute promyelocytic leukaemia (APL) treatment. Belinostat (Bel, PXD101), a hydroxamate-type HDACi, has proved to be a promising cure in clinical trials for solid tumours and haematological malignancies. However, insight into molecular effects of Bel on APL, is still lacking. In this study, we investigated the effect of Bel alone and in combination with differentiation inducer retinoic acid (RA) on human promyelocytic leukaemia NB4 and HL-60 cells. We found that treatment with Bel, depending on the dosage used, inhibits cell proliferation, whereas in combination with RA enhances and accelerates granulocytic leukaemia cell differentiation. We also evaluated the effect of used treatments with Bel and RA on certain epigenetic modifiers (HDAC1, HDAC2, PCAF) as well as cell cycle regulators (p27) gene expression and protein level modulation. We showed that Bel in combination with RA up-regulates basal histone H4 hyperacetylation level more strongly compared to Bel or RA alone. Furthermore, chromatin immunoprecipitation assay indicated that Bel induces the accumulation of hyperacetylated histone H4 at the p27 promoter region. Mass spectrometry analysis revealed that in control NB4 cells, hyperacetylated histone H4 is mainly found in association with proteins involved in DNA replication and transcription, whereas after Bel treatment it is found with proteins implicated in pro-apoptotic processes, in defence against oxidative stress and tumour suppression. Summarizing, our study provides some novel insights into the molecular mechanisms of HDACi Bel action on APL cells. PMID:25864732

  16. Difficult diagnosis of invasive fungal infection predominantly involving the lower gastrointestinal tract in acute lymphoblastic leukaemia

    PubMed Central

    Avcu, Gulhadiye; Karapinar, Deniz Yilmaz; Yazici, Pinar; Duyu, Muhterem; Polat, Suleyha Hilmioglu; Atabay, Berna; Doganavsargil, Basak; Karapinar, Bulent

    2016-01-01

    Invasive fungal infections are most commonly seen in immunocompromised patients and usually affect the respiratory system. Gastrointestinal system involvement of mucormycosis and invasive aspergillosis is rarely reported in childhood. Here we describe a 5 year old boy with acute lymphoblastic leukaemia who developed invasive fungal infection particularly affecting the lower gastrointestinal system to emphasise the difficulties in diagnosis and management of invasive fungal infections in immunocompromised patients. PMID:26937339

  17. Difficult diagnosis of invasive fungal infection predominantly involving the lower gastrointestinal tract in acute lymphoblastic leukaemia.

    PubMed

    Avcu, Gulhadiye; Karapinar, Deniz Yilmaz; Yazici, Pinar; Duyu, Muhterem; Polat, Suleyha Hilmioglu; Atabay, Berna; Doganavsargil, Basak; Karapinar, Bulent

    2016-03-01

    Invasive fungal infections are most commonly seen in immunocompromised patients and usually affect the respiratory system. Gastrointestinal system involvement of mucormycosis and invasive aspergillosis is rarely reported in childhood. Here we describe a 5 year old boy with acute lymphoblastic leukaemia who developed invasive fungal infection particularly affecting the lower gastrointestinal system to emphasise the difficulties in diagnosis and management of invasive fungal infections in immunocompromised patients. PMID:26937339

  18. Demonstration of cytoplasmic and nuclear antigens in acute leukaemia using flow cytometry.

    PubMed Central

    Farahat, N; van der Plas, D; Praxedes, M; Morilla, R; Matutes, E; Catovsky, D

    1994-01-01

    AIMS--To detect cytoplasmic and nuclear antigens using flow cytometry in acute leukaemia and to use this technique for double marker combinations. METHODS--Cytoplasmic staining was carried out in samples from 40 cases of acute leukaemia with monoclonal antibodies against the myeloid antigen CD13, the lymphoid antigens CD3, CD22, mu chain and the enzymes terminal deoxynucleotidyl transferase (TdT) and myeloperoxidase (MPO). The cells were fixed with paraformaldehyde and permeabilised with Tween 20 and Becton Dickinson's FACS lysing solution. Flow cytometry results were compared in the same cases with immunocytochemistry results using the alkaline phosphatase anti-alkaline phosphatase method. RESULTS--The gentle permeabilisation induced by this method permitted preservation of the membrane antigens and the size and morphology of the cells. The results using flow cytometry were comparable with those obtained using immunocytochemistry, with nearly complete concordance in most cases. CONCLUSIONS--This technique is simple, rapid, sensitive and reproducible and it is suitable for double staining procedures, such as nuclear and cytoplasmic, nuclear and membrane, or cytoplasmic and membrane. It therefore provides a powerful tool for extending the use of immunophenotyping for the diagnosis and follow up of acute leukaemia. It could also be used for the investigation of minimal residual disease. PMID:7962655

  19. Inhibitors of cyclooxygenase-2 (COX-2) suppressed the proliferation and differentiation of human leukaemia cell lines.

    PubMed

    Nakanishi, Y; Kamijo, R; Takizawa, K; Hatori, M; Nagumo, M

    2001-08-01

    Prostaglandins (PG) are known to play important roles in the proliferation and differentiation of leukaemia cells. The effect of the inhibitors of cyclooxygenase-2 (COX-2), a rate-limiting enzyme for the synthesis of PG, on the proliferation and differentiation of leukaemia cell lines was investigated. COX-2 inhibitors, NS-398 and nabumetone, suppressed the proliferation of U-937 and ML-1 cells by inducing a G0/G1 cell-cycle arrest. Cell-cycle arrest induced by these COX-2 inhibitors was not associated with an upregulation of the cyclin-dependent kinase inhibitors. COX-2 inhibitors also inhibited the differentiation of these cells induced by interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and retinoic acid (RA). Treatment with NS-398 did not suppress the levels of PGs produced by these cells. Although COX-2 antisense oligonucleotide showed a similar inhibitory effect on these cells, its inhibitory effect was smaller than that of NS-398. These results suggest that COX-2 inhibitors may suppress the proliferation and differentiation of leukaemia cells both via COX-2-dependent and -independent pathways. PMID:11506967

  20. BRAF mutation detection in hairy cell leukaemia from archival haematolymphoid specimens.

    PubMed

    Thomas, Carla; Amanuel, Benhur; Finlayson, Jill; Grieu-Iacopetta, Fabienne; Spagnolo, Dominic V; Erber, Wendy N

    2015-06-01

    Hairy cell leukaemia (HCL) is a rare, indolent chronic B-cell leukaemia accounting for approximately 2% of all adult leukaemias. The recent association of the BRAF p.Val600Glu (V600E) mutation in HCL makes it a valuable molecular diagnostic marker. We compared the ability of Sanger sequencing, fluorescent single-strand conformational polymorphism (F-SSCP) and high resolution melting (HRM) analysis to detect BRAF mutations in 20 cases of HCL consisting of four archival Romanowsky stained air-dried peripheral blood and bone marrow aspirate smears, 12 mercury fixed decalcified bone marrow trephine biopsies, three formalin fixed, paraffin embedded (FFPE) splenectomy samples and one fresh peripheral blood sample. DNA was amplified and BRAF mutation status determined by the three methods above. V600E mutation was identified in 94%, 89% and 72% of HCL cases by F-SSCP, HRM and Sanger sequencing, respectively. In one case, in addition to the p.Val600Glu mutation, a p.Lys601Thr (K601T) mutation was identified. DNA from archival slide scrapings, mercury-fixed and FFPE tissue can be used to identify BRAF mutations with high sensitivity, especially using HRM/F-SSCP. The V600E mutation can be used as a supplementary molecular marker to aid in the diagnosis of HCL and the presence of the mutation may provide a target for therapy. PMID:25938346

  1. Value of monoclonal anti-myeloperoxidase (MPO7) for diagnosing acute leukaemia.

    PubMed Central

    Storr, J; Dolan, G; Coustan-Smith, E; Barnett, D; Reilly, J T

    1990-01-01

    The expression of myeloperoxidase (MPO) was studied in 100 cases of acute leukaemia (83 with acute myeloid leukaemia (AML) and 17 acute lymphoblastic leukaemia (ALL) by both a conventional cytochemical method and the immunocytochemical antiperoxidase (APAAP) technique using the monoclonal antibody MPO7. In each case the staining was evaluated by light microscopical examination (percentage of positive cells). Of the 83 cases of AML, 78 (93.9%) were positive for MPO7 compared with 70 (84.3%) by cytochemistry. Antibodies against the myeloid markers CD13 and CD33 were positive in 71 (85.5%) and 70 (84.3%) cases, respectively. Importantly, all cases of ALL were negative for both MPO7 and cytochemical MPO staining even when they were positive for CD13 and CD33. These results indicate that the anti-myeloperoxidase antibody MPO7 is the most sensitive and specific reagent for the diagnosis of AML and should therefore be included in routine immunophenotyping panels. Images PMID:1977771

  2. Multi-loci diagnosis of acute lymphoblastic leukaemia with high-throughput sequencing and bioinformatics analysis.

    PubMed

    Ferret, Yann; Caillault, Aurélie; Sebda, Shéhérazade; Duez, Marc; Grardel, Nathalie; Duployez, Nicolas; Villenet, Céline; Figeac, Martin; Preudhomme, Claude; Salson, Mikaël; Giraud, Mathieu

    2016-05-01

    High-throughput sequencing (HTS) is considered a technical revolution that has improved our knowledge of lymphoid and autoimmune diseases, changing our approach to leukaemia both at diagnosis and during follow-up. As part of an immunoglobulin/T cell receptor-based minimal residual disease (MRD) assessment of acute lymphoblastic leukaemia patients, we assessed the performance and feasibility of the replacement of the first steps of the approach based on DNA isolation and Sanger sequencing, using a HTS protocol combined with bioinformatics analysis and visualization using the Vidjil software. We prospectively analysed the diagnostic and relapse samples of 34 paediatric patients, thus identifying 125 leukaemic clones with recombinations on multiple loci (TRG, TRD, IGH and IGK), including Dd2/Dd3 and Intron/KDE rearrangements. Sequencing failures were halved (14% vs. 34%, P = 0.0007), enabling more patients to be monitored. Furthermore, more markers per patient could be monitored, reducing the probability of false negative MRD results. The whole analysis, from sample receipt to clinical validation, was shorter than our current diagnostic protocol, with equal resources. V(D)J recombination was successfully assigned by the software, even for unusual recombinations. This study emphasizes the progress that HTS with adapted bioinformatics tools can bring to the diagnosis of leukaemia patients. PMID:26898266

  3. Dendritic cells and myeloid leukaemias: plasticity and commitment in cell differentiation.

    PubMed

    Rasaiyaah, Jane; Yong, Kwee; Katz, David R; Kellam, Paul; Chain, Benjamin M

    2007-08-01

    Dendritic cells (DCs) are key antigen-presenting cells (APCs), which link innate and adaptive immunity, ultimately activating antigen-specific T cells. This review examines the relationship between the acute and chronic myeloid leukaemias and cells with DC properties. DCs are non-dividing terminally differentiated cells, and ex vivo leukaemic cells or cell lines show little similarity to DCs. However, many leukaemias differentiate further in response to defined stimuli, and retain a degree of lineage plasticity. Therefore, several studies have explored the response of leukaemic cells to the in vitro regimens used to differentiate ex vivo primary DCs. Recent data suggest that the most 'dendritic-like' cells can be derived from more undifferentiated myeloid leukaemias, such as the myelomonocytic Mutz-3 cell line. These findings have important implications for understanding the developmental origins of DCs, for harnessing the APC properties of this class of tumour to stimulate the therapeutic anti-tumour immunity, and for developing useful models for the study of human DC physiology and pathology. There is a strong rationale for further exploration of this class of tumour and its relationship to the normal DC. PMID:17614817

  4. Ibrutinib (Imbruvica). Relapsed chronic lymphocytic leukaemia and mantle cell lymphoma: uncertain impact on survival.

    PubMed

    January

    2016-04-01

    codynamic interactions are also likely in view of its adverse effect profile. There is no consensus on the treatment of patients with refractory or relapsed mantle cell lymphoma, or for patients with relapsed or possibly refractory chronic lymphocytic leukaemia. Ibrutinib inhibits an enzyme involved in regulating B lymphocyte activity. It has been authorised in the European Union for these conditions. Clinical evaluation of ibrutinib in mantle cell lymphoma is based on a single non-comparative trial in 111 patients, in which the median overall survival time was 22.5 months. Clinical evaluation of ibrutinib in chronic lymphocytic leukaemia is based on two randomised trials. One unblinded trial compared ibrutinib versus ofatumumab and involved 391 patients, most of whom were sufficiently fit to receive anticancer combination therapy. Ibrutinib was more effective than ofatumumab, but the choice of this comparator might not have been appropriate for most of the patients who received it. The other double-blind, placebo-controlled trial involved 578 patients with relapsed or refractory chronic lymphocytic leukaemia. Ibrutinib was added to the bendamustine + rituximab combination. No significant difference in mortality was observed between the two groups. The main adverse effects of ibrutinib were: gastrointestinal disorders such as diarrhoea; life-threatening infections and bleeding disorders; and cardiac disorders, including atrial fibrillation. Ibrutinib carries a risk of multiple pharmacokinetic interactions. Pharmacodynamic interactions are also likely in view of its adverse effect profile. PMID:27183765

  5. Active Immunotherapy Used Alone for Maintenance of Patients with Acute Myeloid Leukaemia

    PubMed Central

    Freeman, Charles B.; Harris, Rodney; Geary, Colin G.; Leyland, Michael J.; MaCiver, John E.; Delamore, Irvine W.

    1973-01-01

    A total of 32 patients suffering from acute myeloid leukaemia were initially treated with daunorubicin and cytosine arabinoside, and eight who achieved full remission were given a brief cytoreduction course of cyclophosphamide and thioguanine. Of these eight patients seven were then actively immunized with 10 irradiated allogeneic acute myeloid leukaemia cells and B.C.G. at weekly intervals. Six of these patients have survived in apparent good health for more than one year. Bone marrow changes suggestive of relapse were used as an indication for further short courses of chemotherapy, and except on single occasions in two different patients clinical relapse has been prevented. The average duration of first (bone marrow) remission appears to be comparable with the best achieved in trials using regular chemotherapy for maintenance, though criteria for determining relapse may be different. The rate of reinduction of remissions (bone marrow) in this series was high, with a subsequent increase in overall survival time. Possible explanations for the high rate of reinduction include, firstly, the effects of active immunization with specific leukaemia antigen; secondly, non-specific adjuvant effect; thirdly, avoidance of drug resistance; and, fourthly, early diagnosis of relapse by frequent bone marrow examinations. PMID:4519012

  6. Zika virus-associated neurological disorders: a review.

    PubMed

    Araujo, Abelardo Q C; Silva, Marcus Tulius T; Araujo, Alexandra P Q C

    2016-08-01

    Zika virus, an arbovirus transmitted by mosquitoes of the Aedes species, is now rapidly disseminating throughout the Americas and the ongoing Brazilian outbreak is the largest Zika virus epidemic so far described. In addition to being associated with a non-specific acute febrile illness, a number of neurological manifestations, mainly microcephaly and Guillain-Barré syndrome, have been associated with infection. These with other rarer neurological conditions suggest that Zika virus, similar to other flaviviruses, is neuropathogenic. The surge of Zika virus-related microcephaly cases in Brazil has received much attention and the role of the virus in this and in other neurological manifestations is growing. Zika virus has been shown to be transmitted perinatally and the virus can be detected in amniotic fluid, placenta and foetus brain tissue. A significant increase in Guillain-Barré syndrome incidence has also been reported during this, as well as in previous outbreaks. More recently, meningoencephalitis and myelitis have also been reported following Zika virus infection. In summary, while preliminary studies have suggested a clear relationship between Zika virus infection and certain neurological conditions, only longitudinal studies in this epidemic, as well as experimental studies either in animal models or in vitro, will help to better understand the role of the virus and the pathogenesis of these disorders. PMID:27357348

  7. Bat guano virome: predominance of dietary viruses from insects and plants plus novel mammalian viruses.

    PubMed

    Li, Linlin; Victoria, Joseph G; Wang, Chunlin; Jones, Morris; Fellers, Gary M; Kunz, Thomas H; Delwart, Eric

    2010-07-01

    Bats are hosts to a variety of viruses capable of zoonotic transmissions. Because of increased contact between bats, humans, and other animal species, the possibility exists for further cross-species transmissions and ensuing disease outbreaks. We describe here full and partial viral genomes identified using metagenomics in the guano of bats from California and Texas. A total of 34% and 58% of 390,000 sequence reads from bat guano in California and Texas, respectively, were related to eukaryotic viruses, and the largest proportion of those infect insects, reflecting the diet of these insectivorous bats, including members of the viral families Dicistroviridae, Iflaviridae, Tetraviridae, and Nodaviridae and the subfamily Densovirinae. The second largest proportion of virus-related sequences infects plants and fungi, likely reflecting the diet of ingested insects, including members of the viral families Luteoviridae, Secoviridae, Tymoviridae, and Partitiviridae and the genus Sobemovirus. Bat guano viruses related to those infecting mammals comprised the third largest group, including members of the viral families Parvoviridae, Circoviridae, Picornaviridae, Adenoviridae, Poxviridae, Astroviridae, and Coronaviridae. No close relative of known human viral pathogens was identified in these bat populations. Phylogenetic analysis was used to clarify the relationship to known viral taxa of novel sequences detected in bat guano samples, showing that some guano viral sequences fall outside existing taxonomic groups. This initial characterization of the bat guano virome, the first metagenomic analysis of viruses in wild mammals using second-generation sequencing, therefore showed the presence of previously unidentified viral species, genera, and possibly families. Viral metagenomics is a useful tool for genetically characterizing viruses present in animals with the known capability of direct or indirect viral zoonosis to humans. PMID:20463061

  8. Bat guano virome: predominance of dietary viruses from insects and plants plus novel mammalian viruses

    USGS Publications Warehouse

    Li, Linlin; Joseph, G. Victoria; Wang, Chunlin; Jones, Morris; Fellers, Gary M.; Kunz, Thomas H.; Delwart, Eric

    2010-01-01

    Bats are hosts to a variety of viruses capable of zoonotic transmissions. Because of increased contact between bats, humans, and other animal species, the possibility exists for further cross-species transmissions and ensuing disease outbreaks. We describe here full and partial viral genomes identified using metagenomics in the guano of bats from California and Texas. A total of 34% and 58% of 390,000 sequence reads from bat guano in California and Texas, respectively, were related to eukaryotic viruses, and the largest proportion of those infect insects, reflecting the diet of these insectivorous bats, including members of the viral families Dicistroviridae, Iflaviridae, Tetraviridae, and Nodaviridae and the subfamily Densovirinae. The second largest proportion of virus-related sequences infects plants and fungi, likely reflecting the diet of ingested insects, including members of the viral families Luteoviridae, Secoviridae, Tymoviridae, and Partitiviridae and the genus Sobemovirus. Bat guano viruses related to those infecting mammals comprised the third largest group, including members of the viral families Parvoviridae, Circoviridae, Picornaviridae, Adenoviridae, Poxviridae, Astroviridae, and Coronaviridae. No close relative of known human viral pathogens was identified in these bat populations. Phylogenetic analysis was used to clarify the relationship to known viral taxa of novel sequences detected in bat guano samples, showing that some guano viral sequences fall outside existing taxonomic groups. This initial characterization of the bat guano virome, the first metagenomic analysis of viruses in wild mammals using second-generation sequencing, therefore showed the presence of previously unidentified viral species, genera, and possibly families. Viral metagenomics is a useful tool for genetically characterizing viruses present in animals with the known capability of direct or indirect viral zoonosis to humans.

  9. Natural reservoirs for homologs of hepatitis C virus.

    PubMed

    Pfaender, Stephanie; Brown, Richard Jp; Pietschmann, Thomas; Steinmann, Eike

    2014-03-01

    Hepatitis C virus is considered a major public health problem, infecting 2%-3% of the human population. Hepatitis C virus infection causes acute and chronic liver disease, including chronic hepatitis, cirrhosis and hepatocellular carcinoma. In fact, hepatitis C virus infection is the most frequent indication for liver transplantation and a vaccine is not available. Hepatitis C virus displays a narrow host species tropism, naturally infecting only humans, although chimpanzees are also susceptible to experimental infection. To date, there is no evidence for an animal reservoir of viruses closely related to hepatitis C virus which may have crossed the species barrier to cause disease in humans and resulted in the current pandemic. In fact, due to this restricted host range, a robust immunocompetent small animal model is still lacking, hampering mechanistic analysis of virus pathogenesis, immune control and prophylactic vaccine development. Recently, several studies discovered new viruses related to hepatitis C virus, belonging to the hepaci- and pegivirus genera, in small wild mammals (rodents and bats) and domesticated animals which live in close contact with humans (dogs and horses). Genetic and biological characterization of these newly discovered hepatitis C virus-like viruses infecting different mammals will contribute to our understanding of the origins of hepatitis C virus in humans and enhance our ability to study pathogenesis and immune responses using tractable animal models. In this review article, we start with an introduction on the genetic diversity of hepatitis C virus and then focus on the newly discovered viruses closely related to hepatitis C virus. Finally, we discuss possible theories about the origin of this important viral human pathogen. PMID:26038514

  10. ECHO virus

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/001340.htm ECHO virus To use the sharing features on this page, please enable JavaScript. Enteric cytopathic human orphan (ECHO) viruses are a group of viruses that lead to ...

  11. Differences in the lymphoproliferative response of cattle and sheep to bovine leucosis virus infection.

    PubMed

    Dimmock, C K; Rogers, R J; Chung, Y S; McKenzie, A R; Waugh, P D

    1986-04-01

    Lymphoblastic leukaemia, preceded by a significantly increasing percentage of prolymphocytes in peripheral blood smears for from 12 to 68 weeks before death was a feature of sheep which developed lymphosarcoma following inoculation with the Australian strain of bovine leucosis virus (BLV). Lymphocytosis and/or the appearance of immature cells were a reliable predictor of tumour formation in sheep, but not in cattle. There was a terminal lymphoblastic leukaemia in only 43 of 84 cattle with lymphosarcoma. Differences in the morphological appearance and glycogen content of the leukaemic lymphoblasts of sheep and cattle were observed. In spite of these differences the high frequency of lymphocytosis and lymphosarcoma in experimentally infected sheep suggests that they could be a useful model for studying the pathological and immunological responses to BLV infection. PMID:3012856

  12. Rapidly progressing, fatal and acute promyelocytic leukaemia that initially manifested as a painful third molar: a case report

    PubMed Central

    2009-01-01

    Introduction Acute promyelocytic leukaemia, an uncommon and devastating subtype of leukaemia, is highly prevalent in Latin American populations. The disease may be detected by a dentist since oral signs are often the initial manifestation. However, despite several cases describing oral manifestations of acute promyelocytic leukaemia and genetic analysis, reports of acute promyelocytic leukaemia in Hispanic populations are scarce. The identification of third molar pain as an initial clinical manifestation is also uncommon. This is the first known case involving these particular features. Case presentation A 24-year-old Latin American man without relevant antecedents consulted a dentist for pain in his third molar. After two dental extractions, the patient experienced increased pain, poor healing, jaw enlargement and bleeding. A physical examination later revealed that the patient had pallor, jaw enlargement, ecchymoses and gingival haemorrhage. Laboratory findings showed pancytopaenia, delayed coagulation times, hypoalbuminaemia and elevated lactate dehydrogenase. Splenomegaly was detected on ultrasonography. Peripheral blood and bone marrow analyses revealed a hypercellular infiltrate of atypical promyelocytic cells. Cytogenetic analysis showing genetic translocation t(15;17) further confirmed acute promyelocytic leukaemia. Despite early chemotherapy, the patient died within one week due to intracranial bleeding secondary to disseminated intravascular coagulation. Conclusion The description of this unusual presentation of acute promyelocytic leukaemia, the diagnostic difficulties and the fatal outcome are particularly directed toward dental surgery practitioners to emphasise the importance of clinical assessment and preoperative evaluation as a minimal clinically-oriented routine. This case may also be of particular interest to haematologists, since the patient's cytogenetic analysis, clinical course and therapeutic response are well documented. PMID:19946580

  13. Hepatitis B Reactivation in a HBsAg-Negative, HBcAb-Positive Patient Receiving Fludarabine for the Treatment of Chronic Lymphocytic Leukaemia

    PubMed Central

    Toscanini, Federica; De Leo, Pasqualina; Calcagno, Giuseppe; Malfatti, Federica; Grasso, Alessandro; Anselmo, Marco

    2011-01-01

    Hepatitis B virus (HBV) reactivation is an increasingly recognized cause of morbidity and mortality in patients undergoing chemotherapy. In haematology, the risk of reactivation of B hepatitis among HBsAg-positive patients has been documented; therefore, use of lamivudine prophylaxis is recommended before starting chemotherapy. Differently, for HBsAg-negative patients with markers of previous HBV infection (i.e., presence of isolated anti-HBc positivity) (anticore patients) management strategies are not univocal. We describe a rare case of HBV reactivation in an anticore patient after fludarabine therapy for chronic lymphocytic leukaemia. The patient fully recovered after a 6-month course of lamivudine with persistent HBV-DNA clearance and loss of HBsAg. The most important feature of this case is that fludarabine alone infrequently determines HBV reactivation, especially in anticore patients. Therefore, we suggest that patients candidates to receive fludarabine therapy should be considered for lamivudine prophylaxis, not only if HBsAg-positive, but even if anticore-positive only. PMID:25954538

  14. Survival of twenty-two months in a patient with primary plasma cell leukaemia treated with melphalan and prednisolone.

    PubMed Central

    Walker, J. D.; Kaczmarski, R. S.

    1988-01-01

    In the majority of cases plasma cell leukaemia is a rapidly fatal disease with a mean survival time of five months. There have been reports of increased survival using various regimens of chemotherapy although most cases eventually relapse. We describe a patient with primary plasma cell leukaemia who responded to a combination of oral melphalan and prednisolone with control of the disease in the bone marrow but relapsed with extramedullary disease in the central nervous system and testes, and died 22 months after diagnosis. Melphalan poorly penetrates the central nervous system and its testicular penetration is unknown. Images Figure 1 PMID:3174543

  15. T cell acute lymphoblastic leukaemia presenting with sudden onset right oculomotor nerve palsy with normal neuroradiography and cerebrospinal fluid studies

    PubMed Central

    Bhatt, Vijaya Raj; Naqi, Muniba; Bartaula, Rajiv; Murukutla, Srujitha; Misra, Sulagna; Popalzai, Muhammad; Paramanathan, Kavitha; Dai, Qun

    2012-01-01

    Leptomeningeal disease presenting with neurological dysfunction is not uncommon in leukaemia. However, it is often accompanied by abnormalities in cerebrospinal fluid (CSF) studies and/or neuroradiography. Here, the authors describe a case of a young patient presenting with sudden onset right oculomotor nerve palsy with normal neuroradiography and CSF studies, who was subsequently diagnosed to have T cell acute lymphoblastic leukaemia (T-ALL). This case highlights that neurological manifestations can be the initial presenting feature of T-ALL and can occur suddenly despite normal neuroradiography and initial CSF studies. PMID:22605802

  16. Report of the second international symposium on molecular epidemiology in childhood leukaemia and embryonal tumours, Rio de Janeiro, Brazil.

    PubMed

    Pombo de Oliveira, M S; Ferman, S; de Camargo, B

    2008-01-01

    The recent International Symposium on Molecular epidemiology in Embryonal Tumours and Paediatric Leukaemia was held on 4-6 March 2008 in Rio de Janeiro, Brazil. It proved a very productive meeting in which studies relating to genetics, therapeutical trials, identification of risk factors in acute leukaemia neuroblastoma and Wilms' tumours were presented. Over 120 participants gathered for three days of fruitful discussions, including representatives of paediatrics, haematology, laboratory, epidemiology and pathology. Debates were held about strategies of applications of important biomarkers for clinical trials. Highlights of each of the scientific presentations are summarized below. PMID:22275972

  17. Geranylated flavanone tomentodiplacone B inhibits proliferation of human monocytic leukaemia (THP-1) cells

    PubMed Central

    Kollár, Peter; Bárta, Tomáš; Závalová, Veronika; Šmejkal, Karel; Hampl, Aleš

    2011-01-01

    BACKGROUND AND PURPOSE Paulownia tomentosa is a rich source of geranylated flavanones, some of which we have previously shown to have cytotoxic activity. To identify members of this class of compounds with cytostatic effects, we assessed the effects of the geranylated flavanone tomentodiplacone B (TOM B) on cell cycle progression and cell cycle regulatory pathways of THP-1 human monocytic leukaemia cells. EXPERIMENTAL APPROACH Cell viability was measured by dye exclusion and proliferation by WST-1 assays; cell cycle was monitored by flow cytometry. Regulatory proteins were assessed by immunoprecipitation and kinase assays, and Western blotting. KEY RESULTS Tomentodiplacone B had no effect during the first 24 h of cell growth at concentrations between 1 and 2.5 µM, but inhibited cell growth in a dose-dependent manner at concentrations of 5 µM or higher. Growth inhibition during the first 24 h of exposure to TOM B was not accompanied by cytotoxicity as cells were accumulated in G1 phase dose-dependently. This G1 phase accumulation was associated with down-regulation of cyclin-dependent kinase 2 activity and also protein levels of cyclins E1 and A2. However, key stress-related molecules (γ-H2AX, p53 and p21) were not induced, suggesting that TOM B acts by directly inhibiting the cyclin-dependent kinase 2 signalling pathway rather than initiating DNA damage or cellular stress. CONCLUSIONS AND IMPLICATIONS Our study provides the first evidence that TOM B directly inhibits proliferation of human monocytic leukaemia cells, and thus is a potential anticancer agent, preventing leukaemia cells from progressing from G1 phase into DNA synthesis. PMID:21175584

  18. Mixed lineage leukaemia histone methylases 1 collaborate with ERα to regulate HOXA10 expression in AML

    PubMed Central

    Yao, Jie; Fang, Li-Chao; Yang, Zai-Lin; Huang, Hui; Li, Yan; Deng, Jun; Zheng, Junsong

    2014-01-01

    HOXA10, a homeobox-containing gene involved in definitive haematopoiesis, which implicated in the pathogenesis of AML (acute myeloid leukaemia), has been studied extensively. But the regulatory mechanism that drives HOXA10 expression is still unclear. In the present paper, HOXA10 regulated by MLL1 (mixed lineage leukaemia histone methylase 1) with an epigenetic way has been demonstrated. The HOXA10 promoter contains several EREs (oestrogen response elements), including ERE1 and ERE2, which are close to the transcription start site, and are associated with E2-mediated activation of HOXA10. It has been shown that knockdown of the ERα (oestrogen receptor α) suppresses E2-mediated activation of HOXA10. Similarly, knockdown of MLL1 suppresses activation of HOXA10 and is bound to the ERE of HOXA10 promoter in an E2-dependent manner by forming complex with ERα. Knockdown of ERα affects the E2-dependent binding of MLL1 into HOXA10 EREs, suggesting critical roles of ERα in recruiting MLL on the HOXA10 promoter. More interestingly, the methylation status of histone protein H3K4 (H3 at lysine 4) with E2 is much higher than without E2 treatment in leukaemia cell. On the contrary, the methylation status of HOXA10 promoter with E2 treatment is much lower, which elevate the HOXA10 expression. Moreover, with ERα knockdown, the H3K4 methylation level is also decrease in myeloid cell. Overall, it has been clearly demonstrated that HOXA10 is transcriptionally regulated by MLL1, which, in coordination with ERα, plays a critical role in this process with epigenetic way and suggests a potential anti-E2 treatment of AML. PMID:25307539

  19. Residential exposure to electromagnetic fields and childhood leukaemia: a meta-analysis.

    PubMed Central

    Angelillo, I. F.; Villari, P.

    1999-01-01

    Although individual epidemiological investigations have suggested associations between residential exposure to electromagnetic fields (EMFs) and childhood leukaemia, overall the findings have been inconclusive. Several of these studies do, however, lend themselves to application of the meta-analysis technique. For this purpose we carried out searches using MEDLINE and other sources, and 14 case-control studies and one cohort study were identified and evaluated for epidemiological quality and included in the meta-analysis. Relative risk estimates were extracted from each of the studies and pooled. Separate meta-analyses were performed on the basis of the assessed EMF exposure (wiring configuration codes, distance to power distribution equipment, spot and 24-h measures of magnetic field strength (magnetic flux density) and calculated magnetic field). The meta-analysis based on wiring configuration codes yielded a pooled relative risk estimate of 1.46 (95% confidence interval (CI) = 1.05-2.04, P = 0.024) and for that for exposure to 24-h measurements of magnetic fields, 1.59 (95% CI = 1.14-2.22, P = 0.006), indicating a potential effect of residential EMF exposure on childhood leukaemia. In most cases, lower risk estimates were obtained by pooling high-quality studies than pooling low-quality studies. There appears to be a clear trend for more recent studies to be of higher quality. Enough evidence exists to conclude that dismissing concerns about residential EMFs and childhood leukaemia is unwarranted. Additional high-quality epidemiological studies incorporating comparable measures for both exposure and outcomes are, however, needed to confirm these findings and, should they prove to be true, the case options for minimizing exposure should be thoroughly investigated to provide definitive answers for policy-makers. PMID:10612886

  20. Distribution of childhood leukaemias and non-Hodgkin's lymphomas near nuclear installations in England and Wales.

    PubMed Central

    Bithell, J. F.; Dutton, S. J.; Draper, G. J.; Neary, N. M.

    1994-01-01

    OBJECTIVE--To examine the relation between the risk of childhood leukaemia and non-Hodgkin's lymphoma and proximity of residence to nuclear installations in England and Wales. DESIGN--Observed and expected numbers of cases were calculated and analysed by standard methods based on ratios of observed to expected counts and by a new statistical test, the linear risk score test, based on ranks and designed to be sensitive to excess incidence in close proximity to a putative source of risk. SETTING--Electoral wards within 25 km of 23 nuclear installations and six control sites that had been investigated for suitability for generating stations but never used. SUBJECTS--Children below age 15 in England and Wales, 1966-87. MAIN OUTCOME MEASURE--Registration of any leukaemia or non-Hodgkin's lymphoma. RESULTS--In none of the 25 km circles around the installations was the incidence ratio significantly greater than 1.0. The only significant results for the linear risk score test were for Sellafield (P = 0.00002) and Burghfield (P = 0.031). The circles for Aldermaston and Burghfield overlap; the incidence ratio was 1.10 in each. One of the control sites gave a significant linear risk score test result (P = 0.020). All the tests carried out were one sided with P values estimated by simulation. CONCLUSION--There is no evidence of a general increase of childhood leukaemia or non-Hodgkin's lymphoma around nuclear installations. Apart from Sellafield, the evidence for distance related risk is very weak. PMID:8086902

  1. Foodborne viruses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Testing for human pathogenic viruses in foods represents a formidable task requiring the extraction, concentration, and assay of a host of viruses from a wide range of food matrices. The enteric viruses, particularly genogroup I and II (GI and GII) noroviruses and hepatitis A virus, are the princip...

  2. Treatment-related deaths in second complete remission in childhood acute myeloid leukaemia.

    PubMed

    Molgaard-Hansen, Lene; Möttönen, Merja; Glosli, Heidi; Jónmundsson, Guðmundur K; Abrahamsson, Jonas; Hasle, Henrik

    2011-03-01

    The frequency and causes of treatment-related deaths (TRD) in second complete remission (CR2) in acute myeloid leukaemia (AML) were investigated in a historical, prospective cohort study of 429 children included in the Nordic Society of Paediatric Haematology and Oncology (NOPHO)-AML-88 and -93 trials. Relapse occurred in 158 children (39%). Seventeen (18%) of the 96 patients entering CR2 suffered TRD. The main causes were infection (59%) and complications from graft-versus-host disease (22%). Fourteen (82%) of 17 TRDs occurred in children undergoing haematopoietic stem cell transplantations (HSCT). Optimal supportive care after HSCT is essential, and studies on risk factors for TRD are needed. PMID:21241281

  3. The biology behind PI3K inhibition in chronic lymphocytic leukaemia

    PubMed Central

    Ortiz-Maldonado, Valentín; García-Morillo, Marcial

    2015-01-01

    Phosphoinositide 3′-kinase (PI3K) is a key component of both chronic active and tonic B-cell receptor-signalling pathways. As such, PI3K inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukaemia. Multiple in vitro experiments and clinical trials have shown efficacy of these agents across all prognostic subgroups with a favourable toxicity profile. Moreover, in vitro studies suggest that combinations with monoclonal antibodies and/or other immune strategies could enhance the effect of PI3K inhibition. PMID:25642313

  4. Richter's transformation presenting as splenic rupture after 6 years of complete remission of chronic lymphocytic leukaemia.

    PubMed

    Thyagarajan, Braghadheeswar; Alagusundaramoorthy, Sayee Sundar; Shah, Lopa; Agrawal, Abhinav

    2016-01-01

    Richter's transformation is a rare clinical condition occurring in about 5-10% of patients with chronic lymphocytic leukaemia (CLL). Patients usually present with lymphadenopathy, hepatosplenomegaly and elevated serum lactate dehydrogenase levels. These patients have a very poor prognosis with a median survival of about 10 months. We present a patient, with a history of CLL in complete remission, who presented with splenic rupture requiring splenectomy. She was eventually diagnosed with diffuse large B-cell lymphoma with Richter's transformation. PMID:27288204

  5. Cancer coverage: the public face of childhood leukaemia in 1960s Britain

    PubMed Central

    Barnes, Emm

    2008-01-01

    In the 1960s, stories of children fighting cancer, previously absent from the British news, started to feature ever more prominently in the national press. Conventional treatments could not keep children alive for many months, so the promise of a cure through the use of an alternative anti-cancer ‘serum’ was not easily dismissed as quackery. The Ministry of Health and cancer research organisations struggled to find a fair and honest way to inform the public and affected families about childhood leukaemia without raising or crushing hope. PMID:18316127

  6. The challenge of obesity in paediatric leukaemia treatment: it is not just size that matters.

    PubMed

    Tolbert, Jaszianne; Kearns, Gregory L

    2015-01-01

    In the last two decades, tremendous advances have been made in the treatment of acute lymphocytic leukaemia (ALL) in children with 5 year 'cure' rates in excess of 90%. The maintenance of remission is due, in part, to individualisation of therapy which must consider age, body size, genetic constitution and the impact of disease on drug disposition and action. This review, focused on treatment of ALL and one of the therapeutic mainstays, 6-mercaptopurine, illustrates the importance of obesity as a modulating factor in dose individualisation. PMID:25336436

  7. Isolation, Genetic Characterization, and Seroprevalence of Adana Virus, a Novel Phlebovirus Belonging to the Salehabad Virus Complex, in Turkey

    PubMed Central

    Alkan, Cigdem; Alwassouf, Sulaf; Piorkowski, Géraldine; Bichaud, Laurence; Tezcan, Seda; Dincer, Ender; Ergunay, Koray; Ozbel, Yusuf; Alten, Bulent; de Lamballerie, Xavier

    2015-01-01

    ABSTRACT A new phlebovirus, Adana virus, was isolated from a pool of Phlebotomus spp. (Diptera; Psychodidae) in the province of Adana, in the Mediterranean region of Turkey. Genetic analysis based on complete coding of genomic sequences indicated that Adana virus belongs to the Salehabad virus species of the genus Phlebovirus in the family Bunyaviridae. Adana virus is the third virus of the Salehabad virus species for which the complete sequence has been determined. To understand the epidemiology of Adana virus, a seroprevalence study using microneutralization assay was performed to detect the presence of specific antibodies in human and domestic animal sera collected in Adana as well as Mersin province, located 147 km west of Adana. The results demonstrate that the virus is present in both provinces. High seroprevalence rates in goats, sheep, and dogs support intensive exposure to Adana virus in the region, which has not been previously reported for any virus included in the Salehabad serocomplex; however, low seroprevalence rates in humans suggest that Adana virus is not likely to constitute an important public health problem in exposed human populations, but this deserves further studies. IMPORTANCE Until recently, in the genus Phlebovirus, the Salehabad virus species consisted of two viruses: Salehabad virus, isolated from sand flies in Iran, and Arbia virus, isolated from sand flies in Italy. Here we present the isolation and complete genome characterization of the Adana virus, which we propose to be included in the Salehabad virus species. To our knowledge, this is the first report of the isolation and complete genome characterization, from sand flies in Turkey, of a Salehabad virus-related phlebovirus with supporting seropositivity in the Mediterranean, Aegean, and Central Anatolia regions, where phleboviruses have been circulating and causing outbreaks. Salehabad species viruses have generally been considered to be a group of viruses with little medical or

  8. Inventing Viruses.

    PubMed

    Summers, William C

    2014-11-01

    In the nineteenth century, "virus" commonly meant an agent (usually unknown) that caused disease in inoculation experiments. By the 1890s, however, some disease-causing agents were found to pass through filters that retained the common bacteria. Such an agent was called "filterable virus," the best known being the virus that caused tobacco mosaic disease. By the 1920s there were many examples of filterable viruses, but no clear understanding of their nature. However, by the 1930s, the term "filterable virus" was being abandoned in favor of simply "virus," meaning an agent other than bacteria. Visualization of viruses by the electron microscope in the late 1930s finally settled their particulate nature. This article describes the ever-changing concept of "virus" and how virologists talked about viruses. These changes reflected their invention and reinvention of the concept of a virus as it was revised in light of new knowledge, new scientific values and interests, and new hegemonic technologies. PMID:26958713

  9. Feline immunodeficiency virus in South America.

    PubMed

    Teixeira, Bruno M; Hagiwara, Mitika K; Cruz, Juliano C M; Hosie, Margaret J

    2012-03-01

    The rapid emergence of AIDS in humans during the period between 1980 and 2000 has led to extensive efforts to understand more fully similar etiologic agents of chronic and progressive acquired immunodeficiency disease in several mammalian species. Lentiviruses that have gene sequence homology with human immunodeficiency virus (HIV) have been found in different species (including sheep, goats, horses, cattle, cats, and several Old World monkey species). Lentiviruses, comprising a genus of the Retroviridae family, cause persistent infection that can lead to varying degrees of morbidity and mortality depending on the virus and the host species involved. Feline immunodeficiency virus (FIV) causes an immune system disease in domestic cats (Felis catus) involving depletion of the CD4+ population of T lymphocytes, increased susceptibility to opportunistic infections, and sometimes death. Viruses related to domestic cat FIV occur also in a variety of nondomestic felids. This is a brief overview of the current state of knowledge of this large and ancient group of viruses (FIVs) in South America. PMID:22590677

  10. Feline Immunodeficiency Virus in South America

    PubMed Central

    Teixeira, Bruno M.; Hagiwara, Mitika K.; Cruz, Juliano C. M.; Hosie, Margaret J.

    2012-01-01

    The rapid emergence of AIDS in humans during the period between 1980 and 2000 has led to extensive efforts to understand more fully similar etiologic agents of chronic and progressive acquired immunodeficiency disease in several mammalian species. Lentiviruses that have gene sequence homology with human immunodeficiency virus (HIV) have been found in different species (including sheep, goats, horses, cattle, cats, and several Old World monkey species). Lentiviruses, comprising a genus of the Retroviridae family, cause persistent infection that can lead to varying degrees of morbidity and mortality depending on the virus and the host species involved. Feline immunodeficiency virus (FIV) causes an immune system disease in domestic cats (Felis catus) involving depletion of the CD4+ population of T lymphocytes, increased susceptibility to opportunistic infections, and sometimes death. Viruses related to domestic cat FIV occur also in a variety of nondomestic felids. This is a brief overview of the current state of knowledge of this large and ancient group of viruses (FIVs) in South America. PMID:22590677

  11. A case–control study of occupational contact levels in the childhood leukaemia cluster at Seascale, Cumbria, UK

    PubMed Central

    Kinlen, Leo J

    2015-01-01

    Objectives To investigate adult occupational contact levels and risk of childhood leukaemia and non-Hodgkin's lymphoma (LNHL) in Seascale, an association found in other situations of rural population mixing (PM). Design Matched case–control study. Setting Seascale, Cumbria, UK. Participants For each case of LNHL recorded in patients under age 25 years during 1950–2006, up to 20 matched controls were chosen and parental occupational details obtained; an exception was a single working young adult, whose own occupation (and that of controls) was used. Primary outcome measures Contact levels of occupations were categorised as: low/medium (reference group), high or very high contact levels, as in previous studies, with provision for certain unusual occupations. In particular, specialist policemen responsible for security and access at the nearby Sellafield nuclear complex were allocated to the highest contact category, and those Sellafield employees who worked in controlled areas to the middle (high) category. Since of possible bias, unusual contact aspects noted in the main research and development (R&D) building were reserved for a supplementary analysis. ORs were calculated for the occupational contact levels. Results Compared to the reference group, the social class adjusted ORs for the high and very high contact categories were 8.18 (95% CI 0.95 to 70.33) and 14.90 (1.20 to 184.90), respectively, with a significant trend across the categories (p value=0.024). In the supplementary analysis with R&D workers moved to the very high contact category, the OR for the latter became 29.68 (2.12 to 415.79), and the p value for trend, 0.011. Conclusions The Seascale LNHL excess was most marked among those young people linked with high occupational contact levels; it is therefore not an exception to the pattern of family infection shown by other PM-related excesses. The findings have implications for the choice of controls in certain types of virus study. PMID:26243554

  12. Pre-clinical antitumour evaluation of Biphosphinic Palladacycle Complex in human leukaemia cells.

    PubMed

    Oliveira, Carlos R; Barbosa, Christiano M V; Nascimento, Fábio D; Lanetzki, Camilla S; Meneghin, Marília B; Pereira, Flávia E G; Paredes-Gamero, Edgar J; Ferreira, Alice T; Rodrigues, Tiago; Queiroz, Mary L S; Caires, Antonio C F; Tersariol, Ivarne L S; Bincoletto, Claudia

    2009-02-12

    Previous studies reported by our group have introduced a new antitumoural drug called Biphosphinic Palladacycle Complex (BPC). In this paper we show that BPC causes apoptosis in leukaemia cells (HL60 and Jurkat), but not in normal human lymphocytes. IC(50) values obtained for both cell lines using the MTT and trypan blue exclusion assays 5h after BPC treatment were lower than 8.0 microM. Using metachromatic fluorophore, acridine orange, we observed that BPC elicited lysosomal rupture of leukaemic cells. Furthermore, BPC triggered caspase-3 and caspase-6 activation and apoptosis in cell lines, inducing chromatin condensation, apoptotic bodies, and DNA fragmentation. Interestingly, the lysosomal cathepsin B inhibitor CA074 markedly decreased BPC-induced caspase-3 and caspase-6 activation as well as cell death. Lysosomal BPC-induced membrane destabilisation was not dependent on reactive oxygen species generation, which was consistent with the absence of cellular HL60 and Jurkat membrane lipid peroxidation. We conclude that, following BPC treatment, lysosomal membrane rupture precedes cell death and the apoptotic signalling pathway is initiated by the release of cathepsin B in the cytoplasm of leukaemia cells. As no toxic effects for human lymphocytes were observed, we suggest that BPC is more selective for transformed cells, mainly due to their exacerbated lysosome expression. PMID:19026616

  13. Efficacy of multi-functional liposomes containing daunorubicin and emetine for treatment of acute myeloid leukaemia.

    PubMed

    Myhren, Lene; Nilssen, Ida Mostrøm; Nicolas, Valérie; Døskeland, Stein Ove; Barratt, Gillian; Herfindal, Lars

    2014-09-01

    Despite recent advances in chemotherapy against acute myeloid leukaemia (AML), the disease still has high mortality, particularly for patients who tolerate extensive chemotherapy poorly. Nano-formulations have potential to minimise the adverse effects of chemotherapy. We present here a liposomal formulation encapsulating both the anthracycline daunorubicin (DNR) and emetine (Eme) for enhanced cytotoxic effect against AML cells. Eme could be loaded into the PEGylated liposomes together with DNR by the acid precipitation principle, with a loading efficiency of Eme at about 50% of that of DNR. The liposome surface was modified with folate to enhance drug loading into cells, giving higher cytotoxic activity. Both intracellular drug loading and cytotoxic activity could be further increased by anti-folate treatment of AML cells with methotrexate (MTX). The combination of DNR and Eme also increased drug loading in MTX-treated cells compared to DNR alone. Liposomes with both DNR and Eme were particularly efficient against AMLs with deficient p53. In conclusion, we have produced a multi-functional liposomal anti-leukaemic drug formulation designed to overcome some of the problems in anthracycline chemotherapy: (1) Combination of DNR and Eme to diminish drug resistance. (2) Using PEGylated stealth liposomes to minimise adverse side-effects. (3) Molecules on the liposomal surface target proteins on AML-cells ensure selectivity, which was enhanced by priming the leukaemia cells with MTX. PMID:24747809

  14. Versatility and nuances of the architecture of haematopoiesis - Implications for the nature of leukaemia.

    PubMed

    Brown, Geoffrey; Hughes, Philip J; Ceredig, Rhodri; Michell, Robert H

    2012-01-01

    For many years there was a widely accepted picture of how a haematopoietic stem cell (HSC) gives rise to the multiple types of blood and immune cells. This described the general nature of stem and progenitor cells and the pathways of cell development. Recent years have seen many attempts to re-draw the map of haematopoiesis. These have become increasingly complex, and they often envisage multiples routes to some cell types. The 'established' view that self-renewal in haematopoiesis only occurs in HSCs has been challenged by the recognition of self-renewing HSC-derived progenitor cells that display at least some fate restriction. This evolution of how normal haematopoiesis is viewed has inevitable implications for understanding the origins, disease progression and classification of the leukaemias. In essence, some progenitor cells are now seen as possessing a larger repertoire of routes to end-fates than was previously thought. This leads one to ask whether leukaemia stem cells are equally or less versatile than their normal counterparts? PMID:22071138

  15. Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia.

    PubMed

    Hirsch, Pierre; Zhang, Yanyan; Tang, Ruoping; Joulin, Virginie; Boutroux, Hélène; Pronier, Elodie; Moatti, Hannah; Flandrin, Pascale; Marzac, Christophe; Bories, Dominique; Fava, Fanny; Mokrani, Hayat; Betems, Aline; Lorre, Florence; Favier, Rémi; Féger, Frédéric; Mohty, Mohamad; Douay, Luc; Legrand, Ollivier; Bilhou-Nabera, Chrystèle; Louache, Fawzia; Delhommeau, François

    2016-01-01

    In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner. PMID:27534895

  16. Tracer‐Based Metabolic NMR‐Based Flux Analysis in a Leukaemia Cell Line

    PubMed Central

    Carrigan, John B.; Reed, Michelle A. C.; Ludwig, Christian; Khanim, Farhat L.; Bunce, Christopher M.

    2016-01-01

    Abstract High levels of reactive oxygen species (ROS) have a profound impact on acute myeloid leukaemia cells and can be used to specifically target these cells with novel therapies. We have previously shown how the combination of two redeployed drugs, the contraceptive steroid medroxyprogesterone and the lipid‐regulating drug bezafibrate exert anti‐leukaemic effects by producing ROS. Here we report a 13C‐tracer‐based NMR metabolic study to understand how these drugs work in K562 leukaemia cells. Our study shows that [1,2‐13C]glucose is incorporated into ribose sugars, indicating activity in oxidative and non‐oxidative pentose phosphate pathways alongside lactate production. There is little label incorporation into the tricarboxylic acid cycle from glucose, but much greater incorporation arises from the use of [3‐13C]glutamine. The combined medroxyprogesterone and bezafibrate treatment decreases label incorporation from both glucose and glutamine into α‐ketoglutarate and increased that for succinate, which is consistent with ROS‐mediated conversion of α‐ketoglutarate to succinate. Most interestingly, this combined treatment drastically reduced the production of several pyrimidine synthesis intermediates. PMID:27347458

  17. Plastic embedded core biopsy: a complementary approach to bone marrow aspiration for diagnosing acute myeloid leukaemia.

    PubMed Central

    Islam, A; Frisch, B; Henderson, E S

    1989-01-01

    Bone marrow aspirates and biopsy specimens were taken at diagnosis from 51 patients with acute myeloid leukaemia (AML). The diagnosis was based on morphological and cytochemical analyses, and the leukaemias were classified by FAB criteria. A considerable difference was observed between the results of bone marrow aspirates and the findings of plastic-embedded bone marrow biopsy specimens, particularly in marrow cellularity, extent of blast cell infiltration, and cell type involved in the leukaemic process. The myelomonocytic cell type seemed to predominate in the sections. In four cases there was considerable marrow infiltration with maturing, but dysplastic, granulocytic cells in the sections, but not in the aspirate smears. Features of potential prognostic importance, such as bone marrow infiltration with inflammatory cells, were easily recognised and quantified in the sections. These results indicate that plastic embedded bone marrow biopsy sections complement the findings of bone marrow aspiration in the diagnosis of AML and may also provide information of independent prognostic importance that cannot be obtained by other means. Images Fig 2 Fig 5 Fig 6 Fig 7 Fig 8 PMID:2649520

  18. ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation.

    PubMed

    Hartmann, Luise; Dutta, Sayantanee; Opatz, Sabrina; Vosberg, Sebastian; Reiter, Katrin; Leubolt, Georg; Metzeler, Klaus H; Herold, Tobias; Bamopoulos, Stefanos A; Bräundl, Kathrin; Zellmeier, Evelyn; Ksienzyk, Bianka; Konstandin, Nikola P; Schneider, Stephanie; Hopfner, Karl-Peter; Graf, Alexander; Krebs, Stefan; Blum, Helmut; Middeke, Jan Moritz; Stölzel, Friedrich; Thiede, Christian; Wolf, Stephan; Bohlander, Stefan K; Preiss, Caroline; Chen-Wichmann, Linping; Wichmann, Christian; Sauerland, Maria Cristina; Büchner, Thomas; Berdel, Wolfgang E; Wörmann, Bernhard J; Braess, Jan; Hiddemann, Wolfgang; Spiekermann, Karsten; Greif, Philipp A

    2016-01-01

    The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion. PMID:27252013

  19. Subcellular localization of EEN/endophilin A2, a fusion partner gene in leukaemia

    PubMed Central

    2004-01-01

    EEN (extra eleven nineteen), also known as EA2 (endophilin A2), a fusion partner of the MLL (mixed-lineage leukaemia) gene in human acute leukaemia, is a member of the endophilin A family, involved in the formation of endocytic vesicles. We present evidence to show that EEN/EA2 is localized predominantly in nuclei of various cell lines of haemopoietic, fibroblast and epithelial origin, in contrast with its reported cytoplasmic localization in neurons and osteoclasts, and that EEN/EA2 exhibits nucleocytoplasmic shuttling. During the cell cycle, EEN/EA2 shows dynamic localization: it is perichromosomal in prometaphase, co-localizes with the bipolar spindle in metaphase and anaphase and redistributes to the midzone and midbody in telophase. This pattern of distribution coincides with changes in protein levels of EEN/EA2, with the highest levels being observed in G2/M-phase. Our results suggest that distinct subcellular localization of the endophilin A family members probably underpins their diverse cellular functions and indicates a role for EEN/EA2 in the cell cycle. PMID:15214844

  20. ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation

    PubMed Central

    Hartmann, Luise; Dutta, Sayantanee; Opatz, Sabrina; Vosberg, Sebastian; Reiter, Katrin; Leubolt, Georg; Metzeler, Klaus H.; Herold, Tobias; Bamopoulos, Stefanos A.; Bräundl, Kathrin; Zellmeier, Evelyn; Ksienzyk, Bianka; Konstandin, Nikola P.; Schneider, Stephanie; Hopfner, Karl-Peter; Graf, Alexander; Krebs, Stefan; Blum, Helmut; Middeke, Jan Moritz; Stölzel, Friedrich; Thiede, Christian; Wolf, Stephan; Bohlander, Stefan K.; Preiss, Caroline; Chen-Wichmann, Linping; Wichmann, Christian; Sauerland, Maria Cristina; Büchner, Thomas; Berdel, Wolfgang E.; Wörmann, Bernhard J.; Braess, Jan; Hiddemann, Wolfgang; Spiekermann, Karsten; Greif, Philipp A.

    2016-01-01

    The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion. PMID:27252013

  1. Hydroxyurea synergizes with valproic acid in wild-type p53 acute myeloid leukaemia

    PubMed Central

    Leitch, Calum; Osdal, Tereza; Andresen, Vibeke; Molland, Maren; Kristiansen, Silje; Nguyen, Xuan Nhi; Bruserud, Øystein; Gjertsen, Bjørn Tore; McCormack, Emmet

    2016-01-01

    Palliative care in acute myeloid leukaemia (AML) is inadequate. For elderly patients, unfit for intensive chemotherapy, median survival is 2–3 months. As such, there is urgent demand for low-toxic palliative alternatives. We have repositioned two commonly administered anti-leukaemia drugs, valproic acid (VPA) and hydroxyurea (HU), as a combination therapy in AML. The anti-leukemic effect of VPA and HU was assessed in multiple AML cell lines confirming the superior anti-leukemic effect of combination therapy. Mechanistic studies revealed that VPA amplified the ability of HU to slow S-phase progression and this correlated with significantly increased DNA damage. VPA was also shown to reduce expression of the DNA repair protein, Rad51. Interestingly, the tumour suppressor protein p53 was revealed to mitigate cell cycle recovery following combination induced arrest. The efficacy of combination therapy was validated in vivo. Combination treatment increased survival in OCI-AML3 and patient-derived xenograft mouse models of AML. Therapy response was confirmed by optical imaging with multiplexed near-infrared labelled antibodies. The combination of HU and VPA indicates significant potential in preclinical models of AML. Both compounds are widely available and well tolerated. We believe that repositioning this combination could significantly enhance the palliative care of patients unsuited to intensive chemotherapy. PMID:26812881

  2. Cohort Profile: The French Childhood Cancer Survivor Study For Leukaemia (LEA Cohort)

    PubMed Central

    Berbis, Julie; Michel, Gérard; Baruchel, André; Bertrand, Yves; Chastagner, Pascal; Demeocq, François; Kanold, Justyna; Leverger, Guy; Plantaz, Dominique; Poirée, Marilyne; Stephan, Jean-Louis; Auquier, Pascal; Contet, Audrey; Dalle, Jean-Hugues; Ducassou, Stéphane; Gandemer, Virginie; Lutz, Patrick; Sirvent, Nicolas; Tabone, Marie-Dominique; Thouvenin-Doulet, Sandrine

    2015-01-01

    The main aim of the Leucémies de l’Enfant et l’Adolescent (LEA) project (Childhood and Adolescent Leukaemia) is to study the determinants (medical, socioeconomic, behavioural and environmental) of medium- and long-term outcomes of patients treated for childhood acute leukaemia (AL). The LEA study began in 2004 and is based on a French multicentric prospective cohort. Included are children treated for AL since January 1980 (incident and prevalent cases), surviving at month 24 for myeloblastic AL and lymphoblastic AL grafted in first complete remission or at month 48 for lymphoblastic AL not grafted in first complete remission. Information is collected during specific medical visits and notably includes the following data: socioeconomic data, AL history, physical late effects (such as fertility, cardiac function and metabolic syndrome) and quality of life. Data are collected every 2 years until the patient is 20 years old and has had a 10-year follow-up duration from diagnosis or last relapse. Thereafter, assessments are planned every 4 years. In active centres in 2013, eligible patients number more than 3000. The cohort has already included 2385 survivors, with rate of exhaustiveness of almost 80%. Data access can be requested from principal coordinators and must be approved by the steering committee. PMID:24639445

  3. Some immunological properties of lymphoid cells from patients with acute lymphatic leukaemia (ALL)

    PubMed Central

    Melief, C. J. M.; Schweitzer, Marjan; Zeylemaker, W. P.; Verhagen, E. H.; Eijsvoogel, V. P.

    1973-01-01

    The in vitro responses of lymphoid cells from the blood of children with acute lymphatic leukaemia to stimulation with phytohaemagglutinin, pokeweed mitogen, allogeneic lymphocytes and a cocktail of five different antigens were studied. In addition the stimulatory capacity in mixed lymphocyte culture was investigated as well as the formation of rosettes with sheep erythrocytes which were either uncoated or coated with antibody and complement. Whereas lymphocytes from acute lymphatic leukaemia patients in remission responded well to all stimuli tested, lymphoid cells from all seven patients in leukaemic stages with at least 80% lymphatic cells in the differential leucocyte count uniformly displayed strongly reduced or even absent responses. The phytohaemagglutinin response of cells from leukaemic stages was not only reduced but also delayed and the stimulatory capacity in mixed lymphocyte culture was always stronger than the responding capacity. These data indicate that the responses of cells from leukaemic stages are due to the presence of a small proportion of residual normal lymphocytes whereas the leukaemic cells themselves are unable to respond. The stimulatory capacity in mixed lymphocyte culture was reduced in four cases. The cells from two patients, however, displayed increased stimulatory capacity. The cells from different patients varied strongly with respect to the presence of surface markers as tested by rosette formation with sheep erythrocytes either uncoated or coated with antibody and complement. PMID:4520119

  4. Medical neglect death due to acute lymphoblastic leukaemia: an autopsy case report.

    PubMed

    Usumoto, Yosuke; Sameshima, Naomi; Tsuji, Akiko; Kudo, Keiko; Nishida, Naoki; Ikeda, Noriaki

    2014-12-01

    We report the case of 2-year-old girl who died of precursor B-cell acute lymphoblastic leukaemia (ALL), the most common cancer in children. She had no remarkable medical history. She was transferred to a hospital because of respiratory distress and died 4 hours after arrival. Two weeks before death, she had a fever of 39 degrees C, which subsided after the administration of a naturopathic herbal remedy. She developed jaundice 1 week before death, and her condition worsened on the day of death. Laboratory test results on admission showed a markedly elevated white blood cell count. Accordingly, the cause of death was suspected to be acute leukaemia. Forensic autopsy revealed the cause of death to be precursor B-cell ALL. With advancements in medical technology, the 5-year survival rate of children with ALL is nearly 90%. However, in this case, the deceased's parents preferred complementary and alternative medicine (i.e., naturopathy) to evidence-based medicine and had not taken her to a hospital for a medical check-up or immunisation since she was an infant. Thus, if she had received routine medical care, she would have a more than 60% chance of being alive 5 years after diagnosis. Therefore, we conclude that the parents should be accused of medical neglect regardless of their motives. PMID:25895240

  5. Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia

    PubMed Central

    Hirsch, Pierre; Zhang, Yanyan; Tang, Ruoping; Joulin, Virginie; Boutroux, Hélène; Pronier, Elodie; Moatti, Hannah; Flandrin, Pascale; Marzac, Christophe; Bories, Dominique; Fava, Fanny; Mokrani, Hayat; Betems, Aline; Lorre, Florence; Favier, Rémi; Féger, Frédéric; Mohty, Mohamad; Douay, Luc; Legrand, Ollivier; Bilhou-Nabera, Chrystèle; Louache, Fawzia; Delhommeau, François

    2016-01-01

    In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner. PMID:27534895

  6. Central nervous system haemorrhage causing early death in acute promyelocytic leukaemia

    PubMed Central

    Borowska, Anna; Stelmaszczyk-Emmel, Anna

    2016-01-01

    Acute promyelocytic leukaemia (APL) is a rare type of paediatric leukaemia characterised by a specific genetic mutation and life-threatening coagulopathy. The discovery of all-trans retinoic acid (ATRA), which acts directly on promyelocytic locus-retinoic acid receptor α (PML-RARα) gene product, brought a revolution to the therapy of this disorder. Unfortunately, despite an improvement in the complete remission rate, the early death (ED) rate has not changed significantly, and the haemorrhages remain a major problem. The most common bleeding site, which accounts for about 65-80% of haemorrhages, is the central nervous system. Second in line are pulmonary haemorrhages (32%), while gastrointestinal bleedings are relatively rare. Haemorrhages result from thrombocytopaenia, disseminated intravascular coagulopathy (DIC), and systemic fibrinolysis. Herein we present a boy aged one year and nine months with APL. The patient was not eligible for ATRA administration due to poor clinical condition. He developed bleeding diathesis that presented as disseminated intravascular coagulation (DIC) and led to intracranial haemorrhage, which resulted in the patient's death. PMID:26862315

  7. Breastfeeding and early infection in the aetiology of childhood leukaemia in Down syndrome

    PubMed Central

    Flores-Lujano, J; Perez-Saldivar, M L; Fuentes-Pananá, E M; Gorodezky, C; Bernaldez-Rios, R; Del Campo-Martinez, M A; Martinez-Avalos, A; Medina-Sanson, A; Paredes-Aguilera, R; De Diego-Flores Chapa, J; Bolea-Murga, V; Rodriguez-Zepeda, M C; Rivera-Luna, R; Palomo-Colli, M A; Romero-Guzman, L; Perez-Vera, P; Alvarado-Ibarra, M; Salamanca-Gómez, F; Fajardo-Gutierrez, A; Mejía-Aranguré, J M

    2009-01-01

    Background: For a child to develop acute leukaemia (AL), environmental exposure may not be sufficient: interaction with a susceptibility factor to the disease, such as Down syndrome (DS), may also be necessary. We assessed whether breastfeeding and early infection were associated with the risk of developing AL in children with DS. Methods: Children with DS in Mexico City, and either with or without AL, were the cases (N=57) and controls (N=218), respectively. Population was divided in children with AL and with acute lymphoblastic leukaemia (ALL) and also in children ⩽6 and >6 years old. Results: Breastfeeding and early infections showed moderate (but not significant) association for AL, whereas hospitalisation by infection during the first year of life increased the risk: odds ratios (confidence interval 95%) were 0.84 (0.43–1.61), 1.70 (0.82–3.52); and 3.57 (1.59–8.05), respectively. A similar result was obtained when only ALL was analysed. Conclusion: We found that breastfeeding was a protective factor for developing AL and ALL, and during the first year of life, infections requiring hospitalisation were related to a risk for developing the disease in those children with DS >6 years of age. These data do not support the Greaves's hypothesis of early infection being protective for developing ALL. PMID:19707206

  8. Transplantation of CD3/CD19 depleted allografts from haploidentical family donors in paediatric leukaemia.

    PubMed

    Lang, Peter; Teltschik, Heiko-Manuel; Feuchtinger, Tobias; Müller, Ingo; Pfeiffer, Matthias; Schumm, Michael; Ebinger, Martin; Schwarze, Carl P; Gruhn, Bernd; Schrauder, Andre; Albert, Michael H; Greil, Johann; Urban, Christian; Handgretinger, Rupert

    2014-06-01

    Transplantation of T- and B-cell depleted allografts from haploidentical family donors was evaluated within a prospective phase II trial in children with acute lymphoblastic leukaemia, acute myeloid leukaemia and advanced myelodysplastic syndrome (n = 46). 20 patients had active disease; 19 patients received a second or third stem cell transplantation (SCT). Toxicity-reduced conditioning regimens consisted of fludarabine or clofarabine (in active disease only), thiotepa, melphalan and serotherapy. Graft manipulation was carried out with immunomagnetic microbeads. Primary engraftment occurred in 88%, with a median time to reach >1·0 × 10⁹/l leucocytes, >20 × 10⁹/l platelets and >0·1 × 10⁹/l T-cells of 10, 11 and 50 days, respectively. After retransplantation, engraftment occurred in 100%. Acute graft-versus-host disease (GvHD) grade II and III-IV occurred in 20% and 7%, chronic GvHD occurred in 21%. Both conditioning regimens had comparable toxicity. Transplant-related mortality (TRM) was 8% at one year and 20% at 5 years. Event-free survival at 3 years was: 25% (whole group), 46% (first, second or third complete remission [CR], first SCT) vs. 8% (active disease, first SCT) and 20% (second or third SCT, any disease status). This approach allows first or subsequent haploidentical SCTs to be performed with low TRM. Patients in CR may benefit from SCT, whereas the results in patients with active disease were poor. PMID:24588540

  9. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

    PubMed Central

    Puente, Xose S.; Pinyol, Magda; Quesada, Víctor; Conde, Laura; Ordóñez, Gonzalo R.; Villamor, Neus; Escaramis, Georgia; Jares, Pedro; Beà, Sílvia; González-Díaz, Marcos; Bassaganyas, Laia; Baumann, Tycho; Juan, Manel; López-Guerra, Mónica; Colomer, Dolors; Tubío, José M. C.; López, Cristina; Navarro, Alba; Tornador, Cristian; Aymerich, Marta; Rozman, María; Hernández, Jesús M.; Puente, Diana A.; Freije, José M. P.; Velasco, Gloria; Gutiérrez-Fernández, Ana; Costa, Dolors; Carrió, Anna; Guijarro, Sara; Enjuanes, Anna; Hernández, Lluís; Yagüe, Jordi; Nicolás, Pilar; Romeo-Casabona, Carlos M.; Himmelbauer, Heinz; Castillo, Ester; Dohm, Juliane C.; de Sanjosé, Silvia; Piris, Miguel A.; de Alava, Enrique; Miguel, Jesús San; Royo, Romina; Gelpí, Josep L.; Torrents, David; Orozco, Modesto; Pisano, David G.; Valencia, Alfonso; Guigó, Roderic; Bayés, Mónica; Heath, Simon; Gut, Marta; Klatt, Peter; Marshall, John; Raine, Keiran; Stebbings, Lucy A.; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.; Gut, Ivo; López-Guillermo, Armando; Estivill, Xavier; Montserrat, Emili; López-Otín, Carlos; Campo, Elías

    2012-01-01

    Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution1,2. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes3,4. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer. PMID:21642962

  10. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia

    SciTech Connect

    Cowan-Jacob, Sandra W. Fendrich, Gabriele; Floersheimer, Andreas; Furet, Pascal; Liebetanz, Janis; Rummel, Gabriele; Rheinberger, Paul; Centeleghe, Mario; Fabbro, Doriano; Manley, Paul W.

    2007-01-01

    A case study showing how the determination of multiple cocrystal structures of the protein tyrosine kinase c-Abl was used to support drug discovery, resulting in a compound effective in the treatment of chronic myelogenous leukaemia. Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery.

  11. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia | Office of Cancer Genomics

    Cancer.gov

    There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden.

  12. SWI/SNF Subunits SMARCA4, SMARCD2 and DPF2 Collaborate in MLL-Rearranged Leukaemia Maintenance

    PubMed Central

    Sankar, Aditya; Miyagi, Satoru; Rundsten, Carsten Friis; Johansen, Jens Vilstrup; Helin, Kristian

    2015-01-01

    Alterations in chromatin structure caused by deregulated epigenetic mechanisms collaborate with underlying genetic lesions to promote cancer. SMARCA4/BRG1, a core component of the SWI/SNF ATP-dependent chromatin-remodelling complex, has been implicated by its mutational spectrum as exerting a tumour-suppressor function in many solid tumours; recently however, it has been reported to sustain leukaemogenic transformation in MLL-rearranged leukaemia in mice. Here we further explore the role of SMARCA4 and the two SWI/SNF subunits SMARCD2/BAF60B and DPF2/BAF45D in leukaemia. We observed the selective requirement for these proteins for leukaemic cell expansion and self-renewal in-vitro as well as in leukaemia. Gene expression profiling in human cells of each of these three factors suggests that they have overlapping functions in leukaemia. The gene expression changes induced by loss of the three proteins demonstrate that they are required for the expression of haematopoietic stem cell associated genes but in contrast to previous results obtained in mouse cells, the three proteins are not required for the expression of c-MYC regulated genes. PMID:26571505

  13. The proportion of childhood leukaemia incidence in Great Britain that may be caused by natural background ionizing radiation.

    PubMed

    Wakeford, R; Kendall, G M; Little, M P

    2009-04-01

    The aetiology of childhood leukaemia remains generally unknown, although exposure to moderate and high levels of ionizing radiation, such as those experienced during the atomic bombings of Japan or from radiotherapy, is an established cause. Risk models based primarily on studies of the Japanese atomic bomb survivors imply that low-level exposure to ionizing radiation, including ubiquitous natural background radiation, also raises the risk of childhood leukaemia. Using two sets of recently published leukaemia risk models and estimates of natural background radiation red-bone-marrow doses received by children, about 20% of the cases of childhood leukaemia in Great Britain are predicted to be attributable to this source. However, for one of these sets of risk models this attributable fraction is materially dependent on how the radiation-induced risk is assumed to be transferred between the Japanese atomic bomb survivors and Western children. Over a range of annual doses representing the range (0.5-2.5 mSv/year) experienced by most populations, the attributable proportion for the preferred risk-transfer model varies between 8 and 30%, with small deviations from a linear relationship that are largely due to the saturation of the model, although again this range of attributable fractions depends on the assumed transfer of risk between populations. PMID:19151785

  14. Adult myeloid leukaemia, geology, and domestic exposure to radon and gamma radiation: a case control study in central Italy

    PubMed Central

    Forastiere, F.; Sperati, A.; Cherubini, G.; Miceli, M.; Biggeri, A.; Axelson, O.

    1998-01-01

    OBJECTIVES: To investigate whether indoor randon or gamma radiation might play a part in myeloid leukaemia as suggested by studies based on crude geographical or geological data for exposure assessment. METHODS: For six months randon and gamma radiation was measured with solid state nuclear track detectors and thermoluminescent dosimeters in dwellings of 44 adult male cases of acute myeloid leukaemia and 211 controls (all subjects deceased). Conditional logistic regression ORs (ORs) and 95% confidence intervals (95% CIs) were estimated for quartiles of radon and gamma radiation and for municipality and dwelling characteristics. RESULTS: The risk of leukaemia was associated with an increasing urbanisation index (p value for trend = 0.008). An increased OR was found among those living in more modern houses (OR 3.0, 95% CI 1.4 to 6.6). Confirming the findings of a previous study in the same area, geological features bore a positive association with myeloid leukemia, even by adjusting for level of urbanisation. Contrary to expectations from the previous study, however, no association appeared between myeloid leukaemia and radon and gamma radiation; for the highest quartiles of exposure, ORs were 0.56 (95% CI 0.2 to 1.4) and 0.52 (95% CI 0.2 to 1.4), respectively. Considering only subjects who had lived > or = 20 years in the monitored home and adjusting for urbanisation, there was still no effect of exposure to radiation. CONCLUSIONS: In view of the limited numbers, the results do not in general refute a possible risk of myeloid leukaemia from exposure to indoor radon or gamma radiation, but decrease the credibility of such a relation in the area studied and also of other studies suggesting an effect without monitoring indoor radiation. Some other fairly strong determinants have appeared--that is, level of urbanisation and living in modern houses-- that might need further consideration.   PMID:9614394

  15. Risk analysis of leukaemia incidence among people living along the Techa River: a nested case-control study.

    PubMed

    Ostroumova, E; Gagnière, B; Laurier, D; Gudkova, N; Krestinina, L; Verger, P; Hubert, P; Bard, D; Akleyev, A; Tirmarche, M; Kossenko, M

    2006-03-01

    Large quantities of radioactive materials released over time from the Mayak nuclear weapons facility caused significant internal and external exposure for people living along the banks of the Techa River (Southern Urals, Russia). We conducted a nested case-control study in the Extended Techa River Cohort to determine whether the risk of leukaemia incidence increased with protracted exposure to ionising radiation or with other non-radiation risk factors. The study included 83 cases identified over 47 years of follow-up and 415 controls matched for sex, age at diagnosis, age (within a 5 year age group), and date of initial residence in the riverside area. External and internal doses have been calculated using the Techa River Dosimetry System 1996 (TRDS96). Conditional logistic regression was used to calculate odds ratios per Gray (OR/Gy) and 95% confidence intervals (95% CI). After excluding cases of chronic lymphoid leukaemia, the OR/Gy of total, external, and internal doses were 4.6 (95% CI: 1.7-12.3), 7.2 (95%CI: 1.7-30.0) and 5.4 (95%CI: 1.1-27.2), respectively. A history of solid tumour, either malignant or benign, before the leukaemia diagnosis was associated with a 2.5-fold increase in the leukaemia risk (95% CI: 1.1-5.9). Even though the analysis of confounders was less useful than expected because of missing data, multivariate analyses that took the exposure dose into account confirmed the association between leukaemia incidence and tumour history. PMID:16522942

  16. Zika Virus

    MedlinePlus

    ... Search The CDC Cancel Submit Search The CDC Zika Virus Note: Javascript is disabled or is not supported ... Areas with Zika Countries and territories with active Zika virus transmission... Mosquito Control Prevent mosquito bites, integrated mosquito ...

  17. Zika Virus

    MedlinePlus

    Zika is a virus that is spread by mosquitoes. A pregnant mother can pass it to her ... through blood transfusions. There have been outbreaks of Zika virus in Africa, Southeast Asia, the Pacific Islands, ...

  18. Zika Virus

    MedlinePlus

    Zika is a virus that is spread mostly by mosquitoes. A pregnant mother can pass it to ... through blood transfusions. There have been outbreaks of Zika virus in the United States, Africa, Southeast Asia, ...

  19. Chikungunya Virus

    MedlinePlus

    ... traveling to countries with chikungunya virus, use insect repellent, wear long sleeves and pants, and stay in ... Chikungunya Prevention is key! Prevent Infection. Use mosquito repellent. Chikungunya Virus Distribution Chikungunya in the U.S. What's ...

  20. Hepadna viruses

    SciTech Connect

    Robinson, W.; Koike, K.; Will, H.

    1987-01-01

    This book examines the molecular biology, disease pathogenesis, epidemiology, and clinical features of hepadna and other viruses with hepatic tropism and outlines future directions and approaches for their management. The volume's six sections provide a review of the various features, mechanisms, and functions of these viruses, ranging from hepadna virus replication and regulation of gene expression to the structure and function of hepadna-virus gene products.

  1. ECHO virus

    MedlinePlus

    Enteric cytopathic human orphan (ECHO) viruses are a group of viruses that lead to gastrointestinal infection and skin rashes. ... Echovirus is one of several families of viruses that affect the ... are common. In the United States, they are most common in ...

  2. Successful pregnancy after total body irradiation and bone marrow transplantation for acute leukaemia.

    PubMed

    Giri, N; Vowels, M R; Barr, A L; Mameghan, H

    1992-07-01

    We report successful pregnancies in two young women (aged 24 and 20 years) following allogeneic bone marrow transplantation (BMT) for acute non-lymphoblastic leukaemia. Conditioning therapy consisted of cyclophosphamide (120 mg/kg) and total body irradiation (TBI, 12 Gy) in 2 Gy fractions once daily for 6 days or twice daily for 3 days. Graft-versus-host disease prophylaxis was with methotrexate alone. Both women were amenorrhoeic after BMT and gonadal testing indicated hypergonadotrophic hypogonadism. Both women had normal pregnancies (2 years and 5 years after BMT) resulting in normal healthy infants. Previously successful pregnancy has been reported after TBI in three women in whom the TBI dose was less than 8 Gy. Our cases illustrate that normal outcome of pregnancy is possible at even higher doses of TBI. PMID:1515886

  3. MicroRNA control of myelopoiesis and the differentiation block in acute myeloid leukaemia

    PubMed Central

    Palma, Catalina A; Tonna, Elise J; Ma, David F; Lutherborrow, Mark A

    2012-01-01

    Abstract In the relatively short period of time since their discovery, microRNAs have been shown to control many important cellular functions such as cell differentiation, growth, proliferation and apoptosis. In addition, microRNAs have been demonstrated as key drivers of many malignancies and can function as either tumour suppressors or oncogenes. The haematopoietic system is not outside the realm of microRNA control with microRNAs controlling aspects of stem cell and progenitor self-renewal and differentiation, with many, if not all, haematological disorders associated with aberrant microRNA expression and function. In this review, we focus on the current understanding of microRNA control of haematopoiesis and detail the evidence for the contribution and clinical relevance of aberrant microRNA function to the characteristic block of differentiation in acute myeloid leukaemia. PMID:22225649

  4. Mycobacterium genavense infection in a patient with long-standing chronic lymphocytic leukaemia.

    PubMed

    Krebs, T; Zimmerli, S; Bodmer, T; Lämmle, B

    2000-10-01

    We describe the first case of disseminated infection with Mycobacterium genavense in an HIV-seronegative patient with a chronic haematological disorder. Our patient, an 80-year-old woman, had been under long-term treatment with chlorambucil (partially in combination with prednisone) for B-cell chronic lymphocytic leukaemia (B-CLL). When she developed general fatigue and progressive anaemia, as well as progressive lymphadenopathy and splenomegaly, bone marrow biopsy revealed granulomas with acid-fast bacilli, and cultures of both bone marrow and blood grew M. genavense. The patient's CD4+ cell count was approximately 100 microL(-1). Treatment with clarithromycin, ethambutol and rifabutin resulted in improvement of anaemia and general health as well as in regression of lymphadenopathy and splenomegaly. PMID:11086646

  5. Childhood-onset eosinophilic granulomatosis with polyangiitis: a rare childhood vasculitis mimicking anthrax and eosinophilic leukaemia.

    PubMed

    Sahin, Sezgin; Adrovic, Amra; Barut, Kenan; Kasapcopur, Ozgur

    2016-01-01

    A 14-year-old boy previously misdiagnosed as having cutaneous anthrax was referred with a 2-month history of multiple wide and deep ulceronecrotic lesions in the lower extremities, which occurred after contact with animals. Skin biopsy was compatible with vasculitis. Further examination at our hospital elicited eosinophilia and a history of asthma. On the second day of hospitalisation, he developed deep vein thrombosis. A diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) was established and intravenous methylprednisolone was administered. The patient showed remarkable improvement of the cutaneous lesions. Diagnosis of EGPA is challenging in the vasculitic phase and necessitates a detailed history that specifically questions the patient for an asthma background. This case illustrates a severe cutaneous presentation of EGPA and emphasises the difficulty of diagnosis as a result of overlapped signs and symptoms with cutaneous anthrax and leukaemia. EGPA should be kept in mind in the differential diagnosis of cutaneous lesions associated with eosinophilia. PMID:26887883

  6. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

    PubMed Central

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; Meldi, Kristen; Yoshida, Kenichi; Morabito, Margot; Chautard, Emilie; Auboeuf, Didier; Fenaux, Pierre; Braun, Thorsten; Itzykson, Raphael; de Botton, Stéphane; Quesnel, Bruno; Commes, Thérèse; Jourdan, Eric; Vainchenker, William; Bernard, Olivier; Pata-Merci, Noemie; Solier, Stéphanie; Gayevskiy, Velimir; Dinger, Marcel E.; Cowley, Mark J.; Selimoglu-Buet, Dorothée; Meyer, Vincent; Artiguenave, François; Deleuze, Jean-François; Preudhomme, Claude; Stratton, Michael R.; Alexandrov, Ludmil B.; Padron, Eric; Ogawa, Seishi; Koscielny, Serge; Figueroa, Maria; Solary, Eric

    2016-01-01

    The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect. PMID:26908133

  7. Chronic Myeloid Leukaemia Presenting as Bilateral Retinal Haemorrhages with Multiple Retinal Infiltrates

    PubMed Central

    Barot, Rakesh K.; Gohel, Devadatta Jayantilal; Bhagat, Nupur

    2016-01-01

    Chronic Myeloid Leukaemia (CML) causes retinopathy manifesting as venous dilation and tortuosity, perivascular sheathing, retinal haemorrhages, microaneurysms, cotton-wool spots and optic nerve infiltration. Retina is the most commonly involved intraocular structure in CML. However, retinal involvement is a rare form of presentation of CML and few cases have been reported. We report a case of CML presenting as unilateral sudden visual loss. Fundus showed multiple white centered retinal haemorrhages in both eyes with unilateral macular oedema. Blood work-up showed raised WBC count, high platelet count and low Haemoglobin. Cytological analysis of bone marrow biopsy confirmed Philadelphia chromosome. After a course of Imatinib, visual acuity improved and haemorrhages resolved with normalization of macular thickness. In our case, patient presented early, leading to early detection producing better visual prognosis. This highlights the importance of detailed hematological work up in patients with retinal involvement to rule out leukaemic retinopathy.

  8. Mutations affecting both the rearranged and the unrearranged PML alleles in refractory acute promyelocytic leukaemia.

    PubMed

    Iaccarino, Licia; Ottone, Tiziana; Divona, Mariadomenica; Cicconi, Laura; Cairoli, Roberto; Voso, Maria Teresa; Lo-Coco, Francesco

    2016-03-01

    Acute promyelocytic leukaemia (APL) is characterized by the PML/RARA fusion transcript. PML and RARA mutations have been shown to directly respond to arsenic trioxide (ATO) and all-trans retinoic (ATRA). We analysed the prevalence of PML mutations in 32 patients with de novo or therapy-related APL (t-APL; n = 5), treated with ATO. We identified one ATO-resistant t-APL patient, who presented a PML A216T mutation in both the rearranged and unrearranged PML alleles, and two mutations in the rearranged RARA gene. In this patient, subclones with different PML and RARA mutations acquired clonal dominance during the disease course, probably leading to treatment resistance. PMID:26728337

  9. Initial presentation of CNS-restricted acute lymphoblastic B cell leukaemia as peripheral polyneuropathy.

    PubMed

    Piovezani Ramos, Guilherme; Villasboas Bisneto, Jose C; Chen, Dong; Pardanani, Animesh

    2016-01-01

    We report a case of a 58-year-old woman who presented with a 1-month course of progressive lower and upper extremity weakness in addition to binocular diplopia. Diagnostic lumbar puncture revealed atypical lymphoid cells with 28% blasts. Immunophenotype was consistent with B cell acute lymphoblastic leukaemia (B-ALL). Further work up showed no systemic involvement but extensive thoracolumbar-sacral leptomeningeal disease. The patient was treated with several courses of intrathecal and systemic chemotherapy followed by craniospinal irradiation for consolidation. There was initial steady improvement in neurological symptoms and leptomeningeal disease, the latter being ascertained through radiological studies and cerebrospinal fluid examination. After 10 months of response, the patient relapsed with central nervous system (CNS) and systemic disease. B-ALL is a rare precursor lymphoid neoplasm that generally presents with systemic disease. While CNS involvement is not uncommon, isolated involvement of this compartment without systemic disease is exceedingly rare. PMID:27095809

  10. Notch signalling in T cell lymphoblastic leukaemia/lymphoma and other haematological malignancies

    PubMed Central

    Aster, Jon C.; Blacklow, Stephen C.; Pear, Warren S.

    2010-01-01

    Notch receptors participate in a highly conserved signalling pathway that regulates normal development and tissue homeostasis in a context- and dose-dependent manner. Deregulated Notch signalling has been implicated in many diseases, but the clearest example of a pathogenic role is found in T cell lymphoblastic leukaemia/lymphoma (T-LL), in which the majority of human and murine tumours have acquired mutations that lead to aberrant increases in Notch1 signalling. Remarkably, it appears that the selective pressure for Notch mutations is virtually unique among cancers to T-LL, presumably reflecting a special context-dependent role for Notch in normal T cell progenitors. Nevertheless, there are some recent reports suggesting that Notch signalling has subtle yet important roles in other forms of hematologic malignancy as well. Here, we review the role of Notch signalling in various blood cancers, focusing on T-LL with an eye toward targeted therapeutics. PMID:20967796

  11. Monitoring minimal residual disease in acute myeloid leukaemia: a review of the current evolving strategies

    PubMed Central

    Ommen, Hans Beier

    2016-01-01

    Several disease-monitoring techniques are available for the physician treating acute myeloid leukaemia (AML). Besides immunohistochemistry assisted light microscopy, the past 20 years have seen the development and preclinical perfection of a number of techniques, most notably quantitative polymerase chain reaction (PCR) and multicolor flow cytometry. Late additions to the group of applicable assays include next generation sequencing and digital PCR. In this review the principles of use of these modalities at three different time points during the AML disease course are discussed, namely at the time of treatment evaluation, pretransplantation and postconsolidation. The drawbacks and pitfalls of each different technique are delineated. The evidence or lack of evidence for minimal residual disease guided treatment decisions is discussed. Lastly, future strategies in the MRD field are suggested and commented upon. PMID:26834951

  12. Non-tumour bone marrow lymphocytes correlate with improved overall survival in childhood acute lymphoblastic leukaemia.

    PubMed

    Edwin, Claire; Dean, Joanne; Bonnett, Laura; Phillips, Kate; Keenan, Russell

    2016-10-01

    Composition of tumour immune cell infiltrates correlates with response to treatment and overall survival (OS) in several cancer settings. We retrospectively examined immune cells present in diagnostic bone marrow aspirates from paediatric patients with B-cell acute lymphoblastic leukaemia. Our analysis identified a sub-group (∼30% of patients) with >2.37% CD20 and >6.05% CD7 expression, which had 100% OS, and a sub-group (∼30% of patients) with ≤2.37% CD20 and ≤6.05% CD7 expression at increased risk of treatment failure (66.7% OS, P < 0.05). Immune cell infiltrate at diagnosis may predict treatment response and could provide a means to enhance immediate treatment risk stratification. PMID:27348401

  13. Second-generation tyrosine kinase inhibitors in first-line treatment of chronic myeloid leukaemia (CML).

    PubMed

    Abruzzese, Elisabetta; Breccia, Massimo; Latagliata, Roberto

    2014-02-01

    Tyrosine kinase inhibitors (TKIs) have contributed to marked improvements in survival in patients with chronic myeloid leukaemia (CML). This article discusses the place of the second-generation TKIs dasatinib and nilotinib in the first-line treatment of CML and is based on published literature. The new agents are more potent and effective than imatinib. Data from pivotal clinical trials indicate that response to dasatinib and nilotinib is greater and more rapid than that to imatinib, resulting in a higher probability of patients achieving an optimal response to treatment. Differences between the newer agents with respect to patient groups for whom caution is advised, drug interaction potential, haematological toxicity, pulmonary toxicity, changes in the immune system and effects on laboratory parameters are discussed. With similar levels of efficacy, the choice of second-generation agents should be guided by the characteristics of the individual patient and the most suitable dosing regimen. PMID:24043361

  14. First reported association of chronic lymphocytic leukaemia and interstitial granulomatous dermatitis.

    PubMed

    Riaz, Irbaz Bin; Kamal, Muhammad Umar; Segal, Robert J; Anwer, Faiz

    2016-01-01

    Interstitial granulomatous dermatitis (IGD), a rare disease, is well known to be associated with connective tissue disorders, malignancies and several drugs. We describe this first case of IGD in association with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). A 66-year-old woman with a 6-year history of untreated CLL/SLL, presented with a 2-month history of progressively worsening eruption of the left thigh, along with fatigue, lymphadenopathy and night sweats. Skin biopsy showed findings consistent with IGD and infiltration of CLL. The eruption was non-responsive to treatment with antibiotics and local steroids. There was a significant improvement in the rash after an initial cycle of chemotherapy (combination therapy with bendamustine and rituximab) and complete resolution by the third cycle, for the treatment of her CLL. We suggest that the possibility of an underlying haematological malignancy should be investigated in patients with a skin rash non-responsive to conventional therapy. PMID:27194675

  15. Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia

    PubMed Central

    Blunt, Matthew D.; Steele, Andrew J.

    2015-01-01

    PI3Kδ inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL). However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms. PMID:26500849

  16. Pharmacotherapeutic Management of Chronic Lymphocytic Leukaemia in Patients with Comorbidities: New Agents, New Hope.

    PubMed

    Goede, Valentin; Hallek, Michael

    2015-11-01

    Chronic lymphocytic leukaemia (CLL) is mostly considered a disease of the elderly. As such, many patients present with comorbidities. Several scores allow for a qualitative and quantitative assessment of comorbidity in patients with CLL. Although our knowledge about the impact of comorbidity on outcomes in patients with CLL is still incomplete, it is becoming increasingly apparent that comorbidities could negatively interfere with CLL treatment. Recently, a number of new agents have been approved for use in patients with previously untreated CLL and comorbidities (i.e. obinutuzumab, ofatumumab), as well as in patients with previously treated or high-risk CLL (i.e. idelalisib, ibrutinib). This review discusses the role of comorbidity in patients with CLL, together with the changing treatment landscape for CLL in this patient population. PMID:26446155

  17. Successful treatment of disseminated mucormycosis in a neutropenic patient with T-cell acute lymphoblastic leukaemia

    PubMed Central

    Guymer, Chelsea; Khurana, Sanjeev; Suppiah, Ram; Hennessey, Iain; Cooper, Celia

    2013-01-01

    Mucormycosis is a rare angioinvasive fungal infection, more commonly seen in immunosuppressed patients, with reported mortality rates of 95% in disseminated disease. We present a case report of a patient with T-cell acute lymphoblastic leukaemia who developed disseminated infection with mucormycosis (involving the pancreas, left occipital lobe, right lower lobe of lung, appendix and right kidney) after having completed induction and consolidation chemotherapy. Growth of Lichtheimia corymbifera was initially isolated following a right pleural tap with fungal elements identified repeatedly on subsequent pathology specimens. Following radical surgical debridement and concurrent treatment with combination antifungal therapy, the patient survived. This case demonstrates that aggressive multisite surgical de-bulking of disseminated fungal foci, in conjunction with combination antifungal therapy and reversal of immunosuppression, can result in survival despite the grave prognosis associated with disseminated mucormycosis. PMID:23904418

  18. A case of mandibular osteomyelitis in a patient with chronic myelomonocytic leukaemia.

    PubMed

    Kojima, Yuki; Ishigami, Takashi; Akiba, Masakazu

    2016-01-01

    We report a case of chronic myelomonocytic leukaemia (CMMoL) in a 68-year-old man who developed osteomyelitis of the mandible. At the initial visit, he reported uncontrolled gingival bleeding, despite self-administered haemostasis. He complained of severe pain in the socket, despite potent opioid analgesia. After consultation with the internal medicine specialists, we undertook a surgical anti-inflammatory approach that included sequestrectomy with massive blood transfusion. His physical condition was ameliorated after the surgical procedure, and he was discharged from the hospital. However, 3 months later, he died because of cardiac arrest after haemorrhagic shock and cardiovascular failure because his CMMoL had developed to an acute blastic crisis. This experience demonstrates that the most important goal in such cases is to alleviate a patient's discomfort by applying minimally invasive actions to eliminate infection and improve the quality of life without causing deterioration in the CMMoL status. PMID:27572681

  19. A case of mandibular osteomyelitis in a patient with chronic myelomonocytic leukaemia

    PubMed Central

    Kojima, Yuki; Ishigami, Takashi; Akiba, Masakazu

    2016-01-01

    We report a case of chronic myelomonocytic leukaemia (CMMoL) in a 68-year-old man who developed osteomyelitis of the mandible. At the initial visit, he reported uncontrolled gingival bleeding, despite self-administered haemostasis. He complained of severe pain in the socket, despite potent opioid analgesia. After consultation with the internal medicine specialists, we undertook a surgical anti-inflammatory approach that included sequestrectomy with massive blood transfusion. His physical condition was ameliorated after the surgical procedure, and he was discharged from the hospital. However, 3 months later, he died because of cardiac arrest after haemorrhagic shock and cardiovascular failure because his CMMoL had developed to an acute blastic crisis. This experience demonstrates that the most important goal in such cases is to alleviate a patient's discomfort by applying minimally invasive actions to eliminate infection and improve the quality of life without causing deterioration in the CMMoL status. PMID:27572681

  20. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents.

    PubMed

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; Meldi, Kristen; Yoshida, Kenichi; Morabito, Margot; Chautard, Emilie; Auboeuf, Didier; Fenaux, Pierre; Braun, Thorsten; Itzykson, Raphael; de Botton, Stéphane; Quesnel, Bruno; Commes, Thérèse; Jourdan, Eric; Vainchenker, William; Bernard, Olivier; Pata-Merci, Noemie; Solier, Stéphanie; Gayevskiy, Velimir; Dinger, Marcel E; Cowley, Mark J; Selimoglu-Buet, Dorothée; Meyer, Vincent; Artiguenave, François; Deleuze, Jean-François; Preudhomme, Claude; Stratton, Michael R; Alexandrov, Ludmil B; Padron, Eric; Ogawa, Seishi; Koscielny, Serge; Figueroa, Maria; Solary, Eric

    2016-01-01

    The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect. PMID:26908133

  1. Anti-leukaemia activity as a bystander effect of graft-versus-host reactions.

    PubMed Central

    Johnson, P. R.; Hersey, P.

    1976-01-01

    The production of graft-versus-host (GVH) reactions in (PVGc X Wistar) F1 hybrids by the transfer of PVGc spleen cells resulted in significant resistance of these recipients to a subsequent challenge with the PVGc leukaemia. Protection was markedly dependent on dose and timing of allogeneic cell transfer and was abrogated by irradiation of the cells prior to transfer. GVH activity was shown to be a prerequisite for induction of the protective effect but was equally effective when produced by the transfer of Wistar spleen cells in place of PVGc cells. These points, plus the fact that invitro investigations of possible immune mechanisms failed to demonstrate cytotoxic immunity in treated rats, suggested a nonspecific "bystander" effect as the mechanism of protection. The implications of such a mechanism are discussed. PMID:5100

  2. Infectious proxies and childhood leukaemia: findings from the United Kingdom Childhood Cancer Study (UKCCS).

    PubMed

    Roman, Eve; Simpson, Jill; Ansell, Pat; Lightfoot, Tracy; Smith, Alex

    2009-01-01

    The United Kingdom Childhood Cancer Study (UKCCS) was specifically designed to investigate the potential etiological role of infections as one of its objectives and information on a number of markers of infectious exposure from multiple sources was collected (www.ukccs.org). This study found that a mother's recollections of past minor illness episodes in her children were unreliable, producing systematic case-control differences. From birth onwards children diagnosed with ALL between 2-5 years were found to have had more clinically diagnosed infectious illness episodes (not fewer) than unaffected children, with those with two or more neonatal infections being diagnosed with leukaemia around 7 months earlier than those with only one or none. The findings from these analyses and their implications for future research are reviewed and discussed in this paper. PMID:19091606

  3. Leukaemia cell of origin identified by chromatin landscape of bulk tumour cells.

    PubMed

    George, Joshy; Uyar, Asli; Young, Kira; Kuffler, Lauren; Waldron-Francis, Kaiden; Marquez, Eladio; Ucar, Duygu; Trowbridge, Jennifer J

    2016-01-01

    The precise identity of a tumour's cell of origin can influence disease prognosis and outcome. Methods to reliably define tumour cell of origin from primary, bulk tumour cell samples has been a challenge. Here we use a well-defined model of MLL-rearranged acute myeloid leukaemia (AML) to demonstrate that transforming haematopoietic stem cells (HSCs) and multipotent progenitors results in more aggressive AML than transforming committed progenitor cells. Transcriptome profiling reveals a gene expression signature broadly distinguishing stem cell-derived versus progenitor cell-derived AML, including genes involved in immune escape, extravasation and small GTPase signal transduction. However, whole-genome profiling of open chromatin reveals precise and robust biomarkers reflecting each cell of origin tested, from bulk AML tumour cell sampling. We find that bulk AML tumour cells exhibit distinct open chromatin loci that reflect the transformed cell of origin and suggest that open chromatin patterns may be leveraged as prognostic signatures in human AML. PMID:27397025

  4. Genetic Aberrations in Childhood Acute Lymphoblastic Leukaemia: Application of High-Density Single Nucleotide Polymorphism Array

    PubMed Central

    Sulong, Sarina

    2010-01-01

    Screening of the entire human genome using high-density single nucleotide polymorphism array (SNPA) has become a powerful technique used in cancer genetics and population genetics studies. The GeneChip® Mapping Array, introduced by Affymetrix, is one SNPA platform utilised for genotyping studies. This GeneChip system allows researchers to gain a comprehensive view of cancer biology on a single platform for the quantification of chromosomal amplifications, deletions, and loss of heterozygosity or for allelic imbalance studies. Importantly, this array analysis has the potential to reveal novel genetic findings involved in the multistep development of cancer. Given the importance of genetic factors in leukaemogenesis and the usefulness of screening the whole genome, SNPA analysis has been utilised in many studies to characterise genetic aberrations in childhood acute lymphoblastic leukaemia. PMID:22135543

  5. Fatal disseminated fusarium infection in acute lymphoblastic leukaemia in complete remission

    PubMed Central

    Austen, B; McCarthy, H; Wilkins, B; Smith, A; Duncombe, A

    2001-01-01

    Fusarium species are increasingly recognised as serious pathogens in the immunocompromised. The outcome in the context of persistent severe neutropenia has been almost universally fatal. However, there have been several case reports of successful treatment if neutrophil recovery can be achieved. This report presents the case of a fatality that occurred despite neutrophil recovery. A 67 year old man developed disseminated fusariosis during the neutropenic phase of induction chemotherapy for acute lymphoblastic leukaemia. Fusarium dimerum was isolated from blood cultures. This species is highly unusual and very few case reports exist in the literature. An initial response to amphotericin treatment coincided with neutrophil recovery but a subsequent relapse occurred, despite adequate neutrophil counts, which proved fatal. It is postulated that reseeding of the blood from an occult site, namely the right vitreum in this case, led to this secondary relapse despite achieving complete leukaemic remission. Key Words: fusarium • disseminated • neutropenia • remission PMID:11376027

  6. Septic shock during platelet transfusion in a patient with acute myeloid leukaemia.

    PubMed

    Haesebaert, Julie; Bénet, Thomas; Michallet, Mauricette; Vanhems, Philippe

    2013-01-01

    Although rare, transfusion-associated bacterial contamination (TABC) is nowadays the main risk associated with platelet concentrate (PC) transfusion. Consequences vary from spontaneously resolving symptoms to severe sepsis and death. In this report we have summarised a case of bacterial contamination and sepsis during PC transfusion in a patient with acute myeloid leukaemia. Fifteen minutes after the PC transfusion began, she developed chills and rapidly worsened to septic shock. The episode was managed appropriately. The patient's blood cultures and PC unit cultures grew Escherichia coli. The microbiological susceptibilities of isolates from the patient and platelet bag were identical. No other source of E coli was found. Donor and blood products issued from the same donation investigations were negative. The causality between sepsis and PC transfusion might be difficult to confirm. As no method is available in daily practice to eliminate TABC risk, physicians should always consider TABC by immediately stopping the transfusion and conducting appropriate investigations. PMID:24172770

  7. Management of viral hepatitis in patients with haematological malignancy and in patients undergoing haemopoietic stem cell transplantation: recommendations of the 5th European Conference on Infections in Leukaemia (ECIL-5).

    PubMed

    Mallet, Vincent; van Bömmel, Florian; Doerig, Christopher; Pischke, Sven; Hermine, Olivier; Locasciulli, Anna; Cordonnier, Catherine; Berg, Thomas; Moradpour, Darius; Wedemeyer, Heiner; Ljungman, Per

    2016-05-01

    Viral hepatitis affects millions of people worldwide, and host immunity is the key determinant of patient outcome. Viral hepatitis can be life threatening in patients with haematological malignancy, including haemopoietic stem cell transplant recipients, because of the virus itself, or through a need to decrease the dose of chemotherapy. A past or currently infected haemopoietic stem cell donor could also transmit viral hepatitis. The burden of viral hepatitis in patients with haematological malignancies and the weak evidence on which previous guidelines are based has prompted the European Conference on Infection in Leukaemia (ECIL-5) to convene a group of experts in the fields of viral hepatitis and of haematological malignancy to specifically address previously unconsidered issues and grade the available quality of evidence according to the Infectious Diseases Society of America grading system. The group recommends that all patients should be screened for hepatotropic viruses before haematological treatment and that patients or haemopoietic stem cell donors with markers of past or current viral hepatitis should be assessed by an expert. Screening, vaccination, and treatment rules are reported in this Review. PMID:27599653

  8. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

    PubMed Central

    Zuber, Johannes; Shi, Junwei; Wang, Eric; Rappaport, Amy R.; Herrmann, Harald; Sison, Edward A.; Magoon, Daniel; Qi, Jun; Blatt, Katharina; Wunderlich, Mark; Taylor, Meredith J.; Johns, Christopher; Chicas, Agustin; Mulloy, James C.; Kogan, Scott C.; Brown, Patrick; Valent, Peter; Bradner, James E.; Lowe, Scott W.; Vakoc, Christopher R.

    2012-01-01

    Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs1. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states2. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. PMID:21814200

  9. TESTIN Induces Rapid Death and Suppresses Proliferation in Childhood B Acute Lymphoblastic Leukaemia Cells

    PubMed Central

    Weeks, Robert J.; Ludgate, Jackie L.; LeMée, Gwenn; Morison, Ian M.

    2016-01-01

    Background Childhood acute lymphoblastic leukaemia (ALL) is the most common malignancy in children. Despite high cure rates, side effects and late consequences of the intensive treatments are common. Unquestionably, the identification of new therapeutic targets will lead to safer, more effective treatments. We identified TES promoter methylation and transcriptional silencing as a very common molecular abnormality in childhood ALL, irrespective of molecular subtype. The aims of the present study were to demonstrate that TES promoter methylation is aberrant, to determine the effects of TES re-expression in ALL, and to determine if those effects are mediated via TP53 activity. Methods Normal fetal and adult tissue DNA was isolated and TES promoter methylation determined by Sequenom MassARRAY. Quantitative RT-PCR and immunoblot were used to confirm re-expression of TES in ALL cell lines after 5’-aza-2’-deoxycytidine (decitabine) exposure or transfection with TES expression plasmids. The effects of TES re-expression on ALL cells were investigated using standard cell proliferation, cell death and cell cycle assays. Results In this study, we confirm that the TES promoter is unmethylated in normal adult and fetal tissues. We report that decitabine treatment of ALL cell lines results in demethylation of the TES promoter and attendant expression of TES mRNA. Re-expression of TESTIN protein in ALL cells using expression plasmid transfection results in rapid cell death or cell cycle arrest independent of TP53 activity. Conclusions These results suggest that TES is aberrantly methylated in ALL and that re-expression of TESTIN has anti-leukaemia effects which point to novel therapeutic opportunities for childhood ALL. PMID:26985820

  10. The risk profile of childhood leukaemia in Greece: a nationwide case-control study.

    PubMed

    Petridou, E; Trichopoulos, D; Kalapothaki, V; Pourtsidis, A; Kogevinas, M; Kalmanti, M; Koliouskas, D; Kosmidis, H; Panagiotou, J P; Piperopoulou, F; Tzortzatou, F

    1997-01-01

    The risk profile of childhood leukaemia in Greece was studied through a case-control investigation that included all 153 incident cases of the disease, ascertained throughout the country during 1993 and 1994, and two hospital controls for every case matched for gender, age and place of residence. The data were analysed using conditional logistic regression and the associations are expressed in terms of adjusted odds ratios (OR) and their 95% confidence intervals. Cases were born to mothers of a higher standard education, the OR for an increment of four schooling years being 1.48 (1.17-1.87) and had higher birth weight, the OR for an increment of 500g being 1.36 (1.04-1.77). Pet ownership and birth after a pregnancy with anaemia were associated with increased risk, the ORs being 2.18 (1.14-4.16) and 2.60 (1.39-4.86) respectively. From the frequency analyses, indicative inverse associations were found with birth order, household crowding and previous hospitalization with allergic diseases, whereas indicative positive associations were found with diabetes mellitus during pregnancy and with neonatal jaundice. Substantial or significant elevations were not found with respect to maternal smoking and coffee drinking during pregnancy, diagnostic radiography and ultrasonographic examinations or blood transfusions. A significant inverse association with maternal consumption of alcohol could be due to multiple comparisons, but a detrimental effect can probably be excluded. A non-significant positive association with total shots of viral vaccinations and a weak non-significant inverse association with breast feeding were also found. We interpret the findings of this study as being compatible with acute childhood leukaemia being linked with delayed development of herd immunity to fairly common infectious agents, in conjunction with accelerated perinatal and early post-natal growth. PMID:9365177

  11. Cerebrospinal fluid asparagine depletion during pegylated asparaginase therapy in children with acute lymphoblastic leukaemia.

    PubMed

    Henriksen, Louise T; Nersting, Jacob; Raja, Raheel A; Frandsen, Thomas L; Rosthøj, Steen; Schrøder, Henrik; Albertsen, Birgitte K

    2014-07-01

    L-asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Cerebrospinal fluid (CSF) asparagine depletion is considered a marker of asparaginase effect in the central nervous system (CNS) and may play a role in CNS-directed anti-leukaemia therapy. The objective of this study was to describe CSF asparagine depletion during 30 weeks of pegylated asparaginase therapy, 1000 iu/m(2) i.m. every second week, and to correlate CSF asparagine concentration with serum L-asparaginase enzyme activity. Danish children (1-17 years) with ALL, treated according to the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol, standard and intermediate risk, were included. CSF samples were obtained throughout L-asparaginase treatment at every scheduled lumbar puncture. A total of 128 samples from 31 patients were available for analysis. Median CSF asparagine concentration decreased from a pre-treatment level of 5·3 μmol/l to median levels ≤1·5 μmol/l. However, only 4/31 patients (five samples) had CSF asparagine concentrations below the limit of detection (0·1 μmol/l). In 11 patients, 24 paired same day serum and CSF samples were obtained. A decrease in CSF asparagine corresponded to serum enzyme activities above 50 iu/l. Higher serum enzyme activities were not followed by more extensive depletion. In conclusion, pegylated asparaginase 1000 iu/m(2) i.m. every second week effectively reduced CSF asparagine levels. PMID:24702187

  12. Allergy and acute leukaemia in children with Down syndrome: a population study. Report from the Mexican inter-institutional group for the identification of the causes of childhood leukaemia

    PubMed Central

    Núñez-Enríquez, J C; Fajardo-Gutiérrez, A; Buchán-Durán, E P; Bernáldez-Ríos, R; Medina-Sansón, A; Jiménez-Hernández, E; Amador-Sanchez, R; Peñaloza-Gonzalez, J G; Paredes-Aguilera, R; Alvarez-Rodriguez, F J; Bolea-Murga, V; de Diego Flores-Chapa, J; Flores-Lujano, J; Bekker-Mendez, V C; Rivera-Luna, R; del Carmen Rodriguez-Zepeda, M; Rangel-López, A; Dorantes-Acosta, E M; Núñez-Villegas, N; Velazquez-Aviña, M M; Torres-Nava, J R; Reyes-Zepeda, N C; Cárdenas-Cardos, R; Flores-Villegas, L V; Martinez-Avalos, A; Salamanca-Gómez, F; Gorodezky, C; Arellano-Galindo, J; Mejía-Aranguré, J M

    2013-01-01

    Background: Allergies have been described as protective factors against the development of childhood acute leukaemia (AL). Our objective was to investigate the associations between allergy history and the development of AL and acute lymphoblastic leukaemia (ALL) in children with Down syndrome (DS). Methods: A case–control study was performed in Mexico City. The cases (n=97) were diagnosed at nine public hospitals, and the controls (n=222) were recruited at institutions for children with DS. Odds ratios (OR) were calculated. Results: Asthma was positively associated with AL development (OR=4.18; 95% confidence interval (CI): 1.47–11.87), whereas skin allergies were negatively associated (OR=0.42; 95% CI: 0.20–0.91). Conclusion: Our findings suggest that allergies and AL in children with DS share biological and immune mechanisms. To our knowledge, this is the first study reporting associations between allergies and AL in children with DS. PMID:23695017

  13. Divergent Viruses Discovered in Arthropods and Vertebrates Revise the Evolutionary History of the Flaviviridae and Related Viruses

    PubMed Central

    Shi, Mang; Lin, Xian-Dan; Vasilakis, Nikos; Tian, Jun-Hua; Li, Ci-Xiu; Chen, Liang-Jun; Eastwood, Gillian; Diao, Xiu-Nian; Chen, Ming-Hui; Chen, Xiao; Qin, Xin-Cheng; Widen, Steven G.; Wood, Thomas G.; Tesh, Robert B.; Xu, Jianguo; Holmes, Edward C.

    2015-01-01

    ABSTRACT Viruses of the family Flaviviridae are important pathogens of humans and other animals and are currently classified into four genera. To better understand their diversity, evolutionary history, and genomic flexibility, we used transcriptome sequencing (RNA-seq) to search for the viruses related to the Flaviviridae in a range of potential invertebrate and vertebrate hosts. Accordingly, we recovered the full genomes of five segmented jingmenviruses and 12 distant relatives of the known Flaviviridae (“flavi-like” viruses) from a range of arthropod species. Although these viruses are highly divergent, they share a similar genomic plan and common ancestry with the Flaviviridae in the NS3 and NS5 regions. Remarkably, although these viruses fill in major gaps in the phylogenetic diversity of the Flaviviridae, genomic comparisons reveal important changes in genome structure, genome size, and replication/gene regulation strategy during evolutionary history. In addition, the wide diversity of flavi-like viruses found in invertebrates, as well as their deep phylogenetic positions, suggests that they may represent the ancestral forms from which the vertebrate-infecting viruses evolved. For the vertebrate viruses, we expanded the previously mammal-only pegivirus-hepacivirus group to include a virus from the graceful catshark (Proscyllium habereri), which in turn implies that these viruses possess a larger host range than is currently known. In sum, our data show that the Flaviviridae infect a far wider range of hosts and exhibit greater diversity in genome structure than previously anticipated. IMPORTANCE The family Flaviviridae of RNA viruses contains several notorious human pathogens, including dengue virus, West Nile virus, and hepatitis C virus. To date, however, our understanding of the biodiversity and evolution of the Flaviviridae has largely been directed toward vertebrate hosts and their blood-feeding arthropod vectors. Therefore, we investigated an

  14. Immunohistochemical distinction of haematogones from B lymphoblastic leukaemia/lymphoma or B-cell acute lymphoblastic leukaemia (B-ALL) on bone marrow trephine biopsies: a study on 62 patients.

    PubMed

    Al-Shieban, Saeed; Byrne, Elizabeth; Trivedi, Pritesh; Morilla, Ricardo; Matutes, Estella; Naresh, Kikkeri N

    2011-08-01

    Haematogones are normal, maturing B-cell precursors. They can be confused with neoplastic immature lymphoid cells of B lymphoblastic leukaemia/lymphoma or B-cell acute lymphoblastic leukaemia (B-ALL). Though multi-colour flow-cytometry strategies for distinguishing haematogones from cells of B-ALL are well-described, similar strategies have not been determined for bone marrow trephine biopsies (BMTB). We revisited the morphological and immunohistochemical features (CD20, CD34, TdT and PAX5 expression) in 69 BMTB from 62 patients - 27 with excess haematogones; seven with residual B-ALL after therapy; 18 with no reported excess of haematogones or residual acute leukaemia on BMTB; and 17 diagnostic samples of B-ALL. The distinctive immunophenotypic pattern of BMTB with excess haematogones was of CD34, TdT, CD20 and PAX5 accounting for increasing proportions of cells in the order mentioned, whereas among B-ALL, the immunohistochemical pattern was of CD20, PAX5 and TdT accounting for an equal proportion of cells. Furthermore, among haematogones, the intensity of CD20 expression was extremely heterogeneous as compared to the neoplastic cells in CD20-positive B-ALL. The TdT-positive haematogones were generally small and uniform, while a certain degree of heterogeneity was noticed among neoplastic B-ALL cells. This study provides a practical strategy to distinguish haematogones from B-ALL cells in BMTB. PMID:21722099

  15. A Fatal Case of Acute Myeloid Leukaemia-Methotrexate Related or Primary Autoimmune Disease Related: A Rare Case Report.

    PubMed

    Agarwal, Saurabh; Kaeley, Nidhi; Gupta, Priyanka; Gupta, Vibha; Bhatia, Rohan

    2016-03-01

    Methotrexate is being used for many years in the treatment of chronic medical disorders e.g. rheumatoid arthritis since 1951. It has been associated with various systemic toxicities and complications including bone marrow suppression and lymphomas. The development of leukaemia in a patient of chronic rheumatoid arthritis is either related with the primary disease or due to the drugs which are used in the treatment like cyclophosphamide. In our present case, a 70-year-old female who was a known case of Rheumatoid Arthritis (RA) and was on methotrexate once a week orally for the past 20 years presented with complaints of loss of appetite, loss of weight and anaemia since 2 months. After thorough examination and investigation, she was diagnosed with acute myeloid leukaemia (AML-M4) with bilateral chest consolidation. PMID:27134915

  16. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study

    PubMed Central

    Pearce, Mark S; Salotti, Jane A; Little, Mark P; McHugh, Kieran; Lee, Choonsik; Kim, Kwang Pyo; Howe, Nicola L; Ronckers, Cecile M; Rajaraman, Preetha; Craft, Alan W; Parker, Louise; de González, Amy Berrington

    2012-01-01

    Summary Background Although CT scans are very useful clinically, potential cancer risks exist from associated ionising radiation, in particular for children who are more radiosensitive than adults. We aimed to assess the excess risk of leukaemia and brain tumours after CT scans in a cohort of children and young adults. Methods In our retrospective cohort study, we included patients without previous cancer diagnoses who were first examined with CT in National Health Service (NHS) centres in England, Wales, or Scotland (Great Britain) between 1985 and 2002, when they were younger than 22 years of age. We obtained data for cancer incidence, mortality, and loss to follow-up from the NHS Central Registry from Jan 1, 1985, to Dec 31, 2008. We estimated absorbed brain and red bone marrow doses per CT scan in mGy and assessed excess incidence of leukaemia and brain tumours cancer with Poisson relative risk models. To avoid inclusion of CT scans related to cancer diagnosis, follow-up for leukaemia began 2 years after the first CT and for brain tumours 5 years after the first CT. Findings During follow-up, 74 of 178 604 patients were diagnosed with leukaemia and 135 of 176 587 patients were diagnosed with brain tumours. We noted a positive association between radiation dose from CT scans and leukaemia (excess relative risk [ERR] per mGy 0·036, 95% CI 0·005–0·120; p=0·0097) and brain tumours (0·023, 0·010–0·049; p<0·0001). Compared with patients who received a dose of less than 5 mGy, the relative risk of leukaemia for patients who received a cumulative dose of at least 30 mGy (mean dose 51·13 mGy) was 3·18 (95% CI 1·46–6·94) and the relative risk of brain cancer for patients who received a cumulative dose of 50–74 mGy (mean dose 60·42 mGy) was 2·82 (1·33–6·03). Interpretation Use of CT scans in children to deliver cumulative doses of about 50 mGy might almost triple the risk of leukaemia and doses of about 60 mGy might triple the risk of brain

  17. Heterogeneity in the therapeutic approach to relapsed elderly patients with acute myeloid leukaemia: a survey from the Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Acute Leukaemia Working Party.

    PubMed

    Ferrara, Felicetto; Fazi, Paola; Venditti, Adriano; Pagano, Livio; Amadori, Sergio; Mandelli, Franco

    2008-06-01

    The percentage of long-term survivors in acute myeloid leukaemia (AML) in the elderly does not exceed 10-15% of patients enrolled into clinical trials because of lower complete remission (CR) rates and higher incidence of relapse. However, few data are available as the treatment of elderly patients with relapsed disease is concerned. The aim of this study was of collecting data on criteria adopted for the treatment of these patients. A questionnaire was e-mailed to 32 haematologic institutions involved in the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) group. Questions to be addressed regarded: (1) per cent of relapsed elderly patients treated with aggressive salvage chemotherapy; (2) the selection criteria adopted for inclusion into intensive reinduction; (3) the specific treatment adopted; (4) the treatment given to patients not eligible for intensive salvage. Per cent of patients enrolled into aggressive salvage regimens varied from 10 to 80% (median 50%). The most frequent factor influencing the therapeutic choice was performance status (97%). Additional factors were age >70 years (44%) and duration of first CR (53%). Fludarabine including regimens were most frequently used as aggressive salvage therapy (59%), while gemtuzumab ozogamicin was adopted in various combinations at 11 out of 32 institutions (34%). For patients not eligible to aggressive therapy, the most frequent approach included hydroxyurea (59%). Low dose ARA-C (LDARA-C) was adopted at five centres: as single agent (n = 1), with 6-thioguanine (n = 1), with vitamin D3 and all-trans retinoic acid (ATRA) (n = 2), or with ATRA alone (n = 1). The FLT3 inhibitor CEP-701 was used at one centre. We conclude that the treatment of AML in elderly relapsed patients is extremely heterogeneous. A marked selection is operated as to inclusion into aggressive salvage regimens and only a small minority of patients are offered experimental approaches. PMID:18271064

  18. Cryo-electron tomography: moving towards revealing the viral life cycle of Rice dwarf virus

    PubMed Central

    Miyazaki, Naoyuki; Akita, Fusamichi; Nakagawa, Atsushi; Murata, Kazuyoshi; Omura, Toshihiro; Iwasaki, Kenji

    2013-01-01

    It is well known that viruses utilize the host cellular systems for their infection and replication processes. However, the molecular mechanisms underlying these processes are poorly understood for most viruses. To understand these molecular mechanisms, it is essential to observe the viral and virus-related structures and analyse their molecular interactions within a cellular context. Cryo-electron microscopy and tomography offer the potential to observe macromolecular structures and to analyse their molecular interactions within the cell. Here, using cryo-electron microscopy and tomography, the structures of Rice dwarf virus are reported within fully hydrated insect vector cells grown on electron microscopy grids towards revealing the viral infection and replication mechanisms. PMID:24121321

  19. Chemical sensitization and regulation of TRAIL-induced apoptosis in a panel of B-lymphocytic leukaemia cell lines.

    PubMed

    Kang, Jian; Kisenge, Rodrick R; Toyoda, Hidemi; Tanaka, Shigeki; Bu, Jun; Azuma, Eiichi; Komada, Yoshihiro

    2003-12-01

    Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively kills tumour cells but not normal cells. We investigated TRAIL sensitivity and the TRAIL-induced apoptosis signalling pathway in a panel of B-lymphocytic leukaemia cell lines. Depending upon TRAIL sensitivity, leukaemia cells could be divided into three groups: highly sensitive, moderately sensitive and resistant. TRAIL receptor-2 (DR5) plays an important role in transducing apoptosis signals. DR5 was internalized into the cytoplasm where it recruited FAS-associated death domain protein (FADD) under TRAIL stimulation in both sensitive and resistant cells. However, the active form of caspase-8 was recruited to FADD and only sensitive cells showed increased caspase-8 activity upon TRAIL stimulation. The caspase-8 specific inhibitor, Z-IETD, impaired caspase-8 activation and completely abrogated TRAIL-induced apoptosis. These results suggest that TRAIL resistance in B-lymphocytic leukaemia cells is due to negative regulation at the level of caspase-8 activation and that caspase-8 activation is an indispensable process in TRAIL-induced apoptosis. However, FADD-like interleukin-1 beta-converting enzyme inhibitory protein (c-FLIPL) was similarly expressed and down-regulated after TRAIL stimulation in both sensitive and resistant cells. Interestingly, in some cell lines, TRAIL sensitivity and caspase-8 activity was enhanced or restored with the treatment of cycloheximide (CHX). In addition, X-linked inhibitor of apoptosis (XIAP) levels decreased significantly and rapidly following treatment with CHX. Down-regulation of XIAP may be responsible for enhancement or restoration of TRAIL sensitivity after CHX treatment in B-lymphocytic leukaemia cells. PMID:14632785

  20. [Results of the treatment of myelodysplastic syndrome (MDS)obtained by the Polish Paediatric Leukaemia /Lymphoma Study Group].

    PubMed

    Chybicka, A; Wójcik, D; Pietras, W; Bogusławska-Jaworska, J; Kolecki, P; Balcerska, A; Balwierz, W; Bubała, H; Eliasinska, A; Kowalczyk, J; Jackowska, T; Klus, K; Krenke, K; Kurylak, A; Malinowska, I; Matysiak, M; Stefańska, K; Stefaniak, M J; Rokicka-Milewska, R; Wiśniewska-Slusarz, H; Sońta-Jakimczyk, D; Wysocki, M

    2000-01-01

    Sixty children with MDS treated in six centres of the Polish Paediatric Leukaemia/Lymphoma Study Group in the period 1975-1999 were included in the study. In 20 children RAEB-T, in 13 RA, in 21 RAEB and in 6 CMML were diagnosed. Our own and literature data showed that BMT is the best therapy for children with MDS. We need a new comprehensive protocol for the diagnosis and treatment of children with MDS in Poland. PMID:12021466

  1. Induction of apoptosis and bcl-2 expression in acute lymphoblastic leukaemia and non-Hodgkin's lymphoma in children.

    PubMed

    Pituch-Noworolska, A; Hajto, B; Balwierz, W; Klus, K

    2001-01-01

    bcl-2 expression is associated with the expression of the multidrug resistance molecule (p-gp) and the resistance of leukaemia cells to the induction of apoptosis. The activity of p-gp is the main mechanism of resistance of leukaemia cells to chemotherapy. This study assessed the induction of apoptosis of acute lymphoblastic leukaemia (ALL) and non-Hodgkin's lymphoma (NHL) blastic cells following in vitro treatment with dexamethasone (DXM), vincristine (VCR), and tumour necrosis factor (TNF) in relation to the expression of bcl-2 and p-gp. Common ALL (cALL; n = 24 patients), common ALL with co-expression of myeloid antigens (cALL + My; n = 9), ALL-T (n = 9), and NHL [n = 6 (T type, n = 2; B type, n = 4)] were included. The expression of bcl-2 and p-gp and apoptosis were assayed by flow cytometry. Spontaneous apoptosis was low (< 5%) in cALL and ALL-T and higher (> 8%) in NHL and cALL + My. A high frequency of bcl-2 expression was noted in cALL and cALL + My. A high frequency of p-gp expression was observed in cALL + My, ALL-T, and NHL. There was a reverse association between bcl-2 expression and spontaneous apoptosis. DXM-induced apoptosis was observed in 52.63%, TNF-induced in 42.85%, VCR-induced in 36.36%, and GM-CSF-induced in 33.3% of leukaemia and lymphoma cases. DXM and GM-CSF-driven apoptosis was reversibly associated with bcl-2-expression (bcl-2-dependent mechanism). VCR and TNF-driven apoptosis was not associated with bcl-2 expression, suggesting a different, bcl-2-independent, mechanism(s) of its induction. The in vitro induction of apoptosis was not associated with expression of p-gp. PMID:11855781

  2. Zika virus.

    PubMed

    2016-02-10

    Essential facts Zika virus disease is caused by a virus that is transmitted by the Aedes mosquito. While it generally causes a mild illness, there is increasing concern that it is harmful in pregnancy and can cause congenital abnormalities in infants born to women infected with the virus. There is no antiviral treatment or vaccine currently available. The best form of prevention is protection against mosquito bites. PMID:26860150

  3. CHLORELLA VIRUSES

    PubMed Central

    Yamada, Takashi; Onimatsu, Hideki; Van Etten, James L.

    2007-01-01

    Chlorella viruses or chloroviruses are large, icosahedral, plaque‐forming, double‐stranded‐DNA—containing viruses that replicate in certain strains of the unicellular green alga Chlorella. DNA sequence analysis of the 330‐kbp genome of Paramecium bursaria chlorella virus 1 (PBCV‐1), the prototype of this virus family (Phycodnaviridae), predict ∼366 protein‐encoding genes and 11 tRNA genes. The predicted gene products of ∼50% of these genes resemble proteins of known function, including many that are completely unexpected for a virus. In addition, the chlorella viruses have several features and encode many gene products that distinguish them from most viruses. These products include: (1) multiple DNA methyltransferases and DNA site‐specific endonucleases, (2) the enzymes required to glycosylate their proteins and synthesize polysaccharides such as hyaluronan and chitin, (3) a virus‐encoded K+ channel (called Kcv) located in the internal membrane of the virions, (4) a SET domain containing protein (referred to as vSET) that dimethylates Lys27 in histone 3, and (5) PBCV‐1 has three types of introns; a self‐splicing intron, a spliceosomal processed intron, and a small tRNA intron. Accumulating evidence indicates that the chlorella viruses have a very long evolutionary history. This review mainly deals with research on the virion structure, genome rearrangements, gene expression, cell wall degradation, polysaccharide synthesis, and evolution of PBCV‐1 as well as other related viruses. PMID:16877063

  4. The Anti-cancer Activity of Vernonia divaricata Sw against Leukaemia, Breast and Prostate Cancers In Vitro

    PubMed Central

    Lowe, HIC; Daley-Beckford, D; Toyang, NJ; Watson, C; Hartley, S; Bryant, J

    2014-01-01

    Background: Vernonia divaricata is one of five endemic Vernonia species of Jamaica. The ethnomedicinal uses of other species have been established, however, scientific validation of this species has not yet been done and as such this paper is aimed at identifying the anti-cancer activity of V divaricata against leukaemia, breast and prostate cancer cell lines. Methods: Leaves and stems of V divaricata were dried and milled into powder. The crude hexane and methanol extracts of the leaves and stems were obtained and bio-assayed using WST-1 cell proliferation assay against leukaemia, breast and prostate cancer cell lines. Results: The crude hexane and methanol extracts of V divaricata were able to significantly retard the growth of the MCF-7 (breast), HL-60 (leukaemia) and the PC-3 (prostate) cancer cell lines. The crude methanol extract of the stem was the strongest, exhibiting anti-proliferation activity with IC50 values of 10.14, 12.63 and 9.894 μg/ml for the HL-60, MCF-7 and PC-3 cancer cell lines, respectively, with the most potent toward prostate cancer. Conclusion: The medicinal use of V divaricata as an anti-cancer agent was corroborated as the crude hexane and methanol extracts demonstrated potent anti-proliferation activity and as such hold potential for further research and development into a drug to prevent or treat various cancers. PMID:25429469

  5. Management of adult and paediatric acute lymphoblastic leukaemia in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013

    PubMed Central

    Yeoh, Allen EJ; Tan, Daryl; Li, Chi-Kong; Hori, Hiroki; Tse, Eric; Pui, Ching-Hon

    2014-01-01

    The survival rates for both adult and children with acute lymphoblastic leukaemia have improved substantially in recent years with wider use of improved risk-directed therapy and supportive care. In nearly all developed countries, clinical practice guidelines have been formulated by multidisciplinary panels of leukaemia experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. However, those guidelines do not take into account resource limitations in low-income countries, including financial and technical challenges. In Asia, there are huge disparities in economy and infrastructure among the countries, and even among different regions in some large countries. This review summarizes the recommendations developed for Asian countries by a panel of adult and paediatric leukaemia therapists, based on the availability of financial, skill and logistical resources, at a consensus session held as part of the 2013 Asian Oncology Summit in Bangkok, Thailand. The management strategies described here are stratified by a four-tier system (basic, limited, enhanced and maximum) based on the resources available to a particular country or region. PMID:24176570

  6. miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia.

    PubMed

    Jiang, Xi; Hu, Chao; Arnovitz, Stephen; Bugno, Jason; Yu, Miao; Zuo, Zhixiang; Chen, Ping; Huang, Hao; Ulrich, Bryan; Gurbuxani, Sandeep; Weng, Hengyou; Strong, Jennifer; Wang, Yungui; Li, Yuanyuan; Salat, Justin; Li, Shenglai; Elkahloun, Abdel G; Yang, Yang; Neilly, Mary Beth; Larson, Richard A; Le Beau, Michelle M; Herold, Tobias; Bohlander, Stefan K; Liu, Paul P; Zhang, Jiwang; Li, Zejuan; He, Chuan; Jin, Jie; Hong, Seungpyo; Chen, Jianjun

    2016-01-01

    MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy. PMID:27116251

  7. A Case Report on the Progression of Myeloid Sarcoma to Form Multiple Metastatic Deposits without Developing Acute Myeloid Leukaemia.

    PubMed

    Kohli, Sunita; Lee, Mark; Marshall, Scott

    2015-01-01

    Introduction. Myeloid sarcomas (MS) are rare tumours occurring at extramedullary sites. They are usually associated with other haematology disorders such as acute myeloid leukaemia, myelodysplastic syndrome, and chronic myeloproliferative neoplasms. They frequently occur with a diagnosis of acute myeloid leukaemia (AML) or with relapse of preexisting disease. Patients with myeloid sarcomas without history or evidence of myeloid leukaemia typically progress to form AML. Case Presentation. A case report of a patient diagnosed with an isolated myeloid sarcoma that rarely did not transform to AML but instead spread to form multiple myeloid sarcomas throughout the body. Discussion. This case identifies the risk of metastatic spread of these tumours rather than the development of AML which is poorly documented in the literature, due to the rarity of cases, and may be significant in the investigation and management of isolated myeloid sarcomas. This case highlights the need for clinicians to consider repeat cross-sectional imaging to investigate unexplained clinical decline or symptoms, when there is no sign of AML progression and to consider radiotherapy treatment early. PMID:26491577

  8. Dietary Phenolic Acids Act as Effective Antioxidants in Membrane Models and in Cultured Cells, Exhibiting Proapoptotic Effects in Leukaemia Cells

    PubMed Central

    Zambonin, Laura; Caliceti, Cristiana; Vieceli Dalla Sega, Francesco; Fiorentini, Diana; Hrelia, Silvana; Landi, Laura; Prata, Cecilia

    2012-01-01

    Caffeic, syringic, and protocatechuic acids are phenolic acids derived directly from food intake or come from the gut metabolism of polyphenols. In this study, the antioxidant activity of these compounds was at first evaluated in membrane models, where caffeic acid behaved as a very effective chain-breaking antioxidant, whereas syringic and protocatechuic acids were only retardants of lipid peroxidation. However, all three compounds acted as good scavengers of reactive species in cultured cells subjected to exogenous oxidative stress produced by low level of H2O2. Many tumour cells are characterised by increased ROS levels compared with their noncancerous counterparts. Therefore, we investigated whether phenolic acids, at low concentrations, comparable to those present in human plasma, were able to decrease basal reactive species. Results show that phenolic acids reduced ROS in a leukaemia cell line (HEL), whereas no effect was observed in normal cells, such as HUVEC. The compounds exhibited no toxicity to normal cells while they decreased proliferation in leukaemia cells, inducing apoptosis. In the debate on optimal ROS-manipulating strategies in cancer therapy, our work in leukaemia cells supports the antioxidant ROS-depleting approach. PMID:22792417

  9. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia

    PubMed Central

    Irvine, David A.; Zhang, Bin; Kinstrie, Ross; Tarafdar, Anuradha; Morrison, Heather; Campbell, Victoria L.; Moka, Hothri A.; Ho, Yinwei; Nixon, Colin; Manley, Paul W.; Wheadon, Helen; Goodlad, John R.; Holyoake, Tessa L.; Bhatia, Ravi; Copland, Mhairi

    2016-01-01

    Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34+ CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34+ CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34+ CP-CML cell engraftment in NSG mice and, upon administration to EGFP+ /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells. PMID:27157927

  10. Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation.

    PubMed

    Steffen, Leta S; Bacher, Jeffery W; Peng, Yuanlin; Le, Phuong N; Ding, Liang-Hao; Genik, Paula C; Ray, F Andrew; Bedford, Joel S; Fallgren, Christina M; Bailey, Susan M; Ullrich, Robert L; Weil, Michael M; Story, Michael D

    2013-01-01

    Exposure to sparsely ionising gamma- or X-ray irradiation is known to increase the risk of leukaemia in humans. However, heavy ion radiotherapy and extended space exploration will expose humans to densely ionising high linear energy transfer (LET) radiation for which there is currently no understanding of leukaemia risk. Murine models have implicated chromosomal deletion that includes the hematopoietic transcription factor gene, PU.1 (Sfpi1), and point mutation of the second PU.1 allele as the primary cause of low-LET radiation-induced murine acute myeloid leukaemia (rAML). Using array comparative genomic hybridisation, fluorescence in situ hybridisation and high resolution melt analysis, we have confirmed that biallelic PU.1 mutations are common in low-LET rAML, occurring in 88% of samples. Biallelic PU.1 mutations were also detected in the majority of high-LET rAML samples. Microsatellite instability was identified in 42% of all rAML samples, and 89% of samples carried increased microsatellite mutant frequencies at the single-cell level, indicative of ongoing instability. Instability was also observed cytogenetically as a 2-fold increase in chromatid-type aberrations. These data highlight the similarities in molecular characteristics of high-LET and low-LET rAML and confirm the presence of ongoing chromosomal and microsatellite instability in murine rAML. PMID:22987027

  11. Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation

    PubMed Central

    Bacher, Jeffery W.

    2013-01-01

    Exposure to sparsely ionising gamma- or X-ray irradiation is known to increase the risk of leukaemia in humans. However, heavy ion radiotherapy and extended space exploration will expose humans to densely ionising high linear energy transfer (LET) radiation for which there is currently no understanding of leukaemia risk. Murine models have implicated chromosomal deletion that includes the hematopoietic transcription factor gene, PU.1 (Sfpi1), and point mutation of the second PU.1 allele as the primary cause of low-LET radiation-induced murine acute myeloid leukaemia (rAML). Using array comparative genomic hybridisation, fluorescence in situ hybridisation and high resolution melt analysis, we have confirmed that biallelic PU.1 mutations are common in low-LET rAML, occurring in 88% of samples. Biallelic PU.1 mutations were also detected in the majority of high-LET rAML samples. Microsatellite instability was identified in 42% of all rAML samples, and 89% of samples carried increased microsatellite mutant frequencies at the single-cell level, indicative of ongoing instability. Instability was also observed cytogenetically as a 2-fold increase in chromatid-type aberrations. These data highlight the similarities in molecular characteristics of high-LET and low-LET rAML and confirm the presence of ongoing chromosomal and microsatellite instability in murine rAML. PMID:22987027

  12. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia.

    PubMed

    Irvine, David A; Zhang, Bin; Kinstrie, Ross; Tarafdar, Anuradha; Morrison, Heather; Campbell, Victoria L; Moka, Hothri A; Ho, Yinwei; Nixon, Colin; Manley, Paul W; Wheadon, Helen; Goodlad, John R; Holyoake, Tessa L; Bhatia, Ravi; Copland, Mhairi

    2016-01-01

    Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34(+) CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34(+) CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34(+) CP-CML cell engraftment in NSG mice and, upon administration to EGFP(+) /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells. PMID:27157927

  13. Live Virus Smallpox Vaccine

    MedlinePlus

    ... Index SMALLPOX FACT SHEET The Live Virus Smallpox Vaccine The vaccinia virus is the "live virus" used ... cannot cause smallpox. What is a "live virus" vaccine? A "live virus" vaccine is a vaccine that ...

  14. Genetic diversity and temporal dynamics of phytoplankton viruses in East Lake, China.

    PubMed

    Wang, Mei-Niang; Ge, Xing-Yi; Wu, Yong-Quan; Yang, Xing-Lou; Tan, Bing; Zhang, Yu-Ji; Shi, Zheng-Li

    2015-08-01

    Phytoplankton viruses are important components of aquatic ecosystems. However, their prevalence and genetic diversity in marine and freshwater systems are largely under estimated owing to the immense size of water bodies and limitations in virus discovery techniques. In this study, we conducted a 1-year survey of phytoplankton virus communities by collecting surface water monthly from an inland lake (East Lake) in China between May 2012 and April 2013. We examined four phytoplankton viruses, i.e., myoviruses, podoviruses, siphoviruses, and phycodnaviruses, and seven sets of primers were used to target conserved genes within these four species. In this year-long investigation, a total of 358 different virus-related sequences from four virus families were obtained. All virus families were detected in all months, except for cyanopodoviruses, which were only identified during eight of the 12 months surveyed. Moreover, virus abundance and diversity changed dynamically over time. Phylogenetic analysis revealed that the majority of viral sequences from East Lake, China displayed distinct clustering patterns compared with published sequences. These results supported the existence of a highly diverse and unique phytoplankton virus community in East Lake, China. PMID:26248585

  15. Epstein-Barr Virus Encephalitis in an Immunocompetent Child: A Case Report and Management of Epstein-Barr Virus Encephalitis

    PubMed Central

    Akkoc, Gulsen; Kadayifci, Eda Kepenekli; Karaaslan, Ayse; Atici, Serkan; Yakut, Nurhayat; Ocal Demir, Sevliya; Soysal, Ahmet; Bakir, Mustafa

    2016-01-01

    Epstein-Barr virus (EBV) usually causes mild, asymptomatic, and self-limited infections in children and adults; however, it may occasionally lead to severe conditions such as neurological diseases, malignant diseases, hepatic failure, and myocarditis. Epstein-Barr virus-related neurological disorders include meningitis, encephalitis, and cranial or peripheral neuritis, which are mostly seen in immunocompromised patients. The therapeutic modalities for EBV-related severe organ damage including central nervous system manifestations are still uncertain. Herein, we describe a seven-year-old boy with EBV encephalitis who presented with prolonged fever, exudative pharyngitis, reduced consciousness, and neck stiffness. Cranial magnetic resonance imaging showed contrast enhancement in the bilateral insular cortex and the right hypothalamus. The diagnosis was made by EBV-DNA amplification in both the blood and cerebrospinal fluid samples. He was discharged with acyclovir therapy without any sequelae. PMID:27213062

  16. Epstein-Barr Virus Encephalitis in an Immunocompetent Child: A Case Report and Management of Epstein-Barr Virus Encephalitis.

    PubMed

    Akkoc, Gulsen; Kadayifci, Eda Kepenekli; Karaaslan, Ayse; Atici, Serkan; Yakut, Nurhayat; Ocal Demir, Sevliya; Soysal, Ahmet; Bakir, Mustafa

    2016-01-01

    Epstein-Barr virus (EBV) usually causes mild, asymptomatic, and self-limited infections in children and adults; however, it may occasionally lead to severe conditions such as neurological diseases, malignant diseases, hepatic failure, and myocarditis. Epstein-Barr virus-related neurological disorders include meningitis, encephalitis, and cranial or peripheral neuritis, which are mostly seen in immunocompromised patients. The therapeutic modalities for EBV-related severe organ damage including central nervous system manifestations are still uncertain. Herein, we describe a seven-year-old boy with EBV encephalitis who presented with prolonged fever, exudative pharyngitis, reduced consciousness, and neck stiffness. Cranial magnetic resonance imaging showed contrast enhancement in the bilateral insular cortex and the right hypothalamus. The diagnosis was made by EBV-DNA amplification in both the blood and cerebrospinal fluid samples. He was discharged with acyclovir therapy without any sequelae. PMID:27213062

  17. The origin of hepatitis C virus.

    PubMed

    Simmonds, Peter

    2013-01-01

    The origin of hepatitis C virus (HCV) can be conceptualised at several levels. Firstly, origins might refer to its dramatic spread throughout the Western world and developing countries throughout the twentieth century. As a blood-borne virus, this epidemic was fuelled by new parenteral transmission routes associated with medical treatments, immunisation, blood transfusion and more recently injecting drug use. At another level, however, origins might refer to the immediate sources of HCV associated with its pandemic spread, now identified as areas in Central and West sub-Saharan Africa and South and South East Asia where genetically diverse variants of HCV appear to have circulated for hundreds of years. Going back a final step to the actual source of HCV infection in these endemic areas, non-human primates have been long suspected as harbouring viruses related to HCV with potential cross-species transmission of variants corresponding to the 7 main genotypes into humans. Although there is tempting analogy between this and the clearly zoonotic origin of HIV-1 from chimpanzees in Central Africa, no published evidence to date has been obtained for infection of HCV-like viruses in either apes or Old World monkey species. Indeed, a radical re-think of both the host range and host-specificity of hepaciviruses is now required following the very recent findings of a non-primate hepacivirus (NPHV) in horses and potentially in dogs. Further research on a much wider range of mammals is needed to better understand the true genetic diversity of HCV-like viruses and their host ranges in the search for the ultimate origin of HCV in humans. PMID:23463195

  18. Childhood leukaemia and ordnance factories in west Cumbria during the Second World War

    PubMed Central

    Kinlen, L

    2006-01-01

    Much evidence has accumulated that childhood leukaemia (CL) is a rare response to a common, but unidentified, infection and in particular that situations involving the unusual mixing of urban and rural groups (approximating to, respectively, groups infected with, and susceptible to, the relevant microorganism) can produce localised epidemics with consequent increases of the infrequent leukaemic complication. During the Second World War, explosives production factories were built and operated at Drigg and Sellafield, and a shell filling factory at Bootle, in west Cumbria, England, requiring substantial numbers of construction workers to be brought into this remote and isolated area. Following the design of an earlier study of CL near large (post-war) rural construction sites, mortality from this disease was investigated with the help of the Office of National Statistics, in the area around these Cumbrian factories where local workers largely lived, during the construction period and with particular reference to the overlapping construction and operational phase when the mixing of local and migrant workers would have been greatest. An excess of leukaemia deaths at ages 1–14 was found during the construction period (observed 3; observed/expected (O/E) 2.2, 95% confidence interval (CI): 0.6, 6.0), which was more marked and statistically significant during the overlap with operations (O 3; O/E 4.5, 95% CI: 1.1, 12.2), especially at ages 1–4 (O 2; O/E 7.1, CI: 1.2, 23.6). A previous investigation did not detect this excess because it considered only a small part of west Cumbria that omitted the communities where most of the workforce lived, having incorrectly attributed the post-war expansion of the village of Seascale (situated between Drigg and Sellafield) to the wartime ordnance factories. The present findings are consistent with the results of the earlier study of rural construction projects and with the general evidence that marked rural–urban population

  19. Childhood leukaemia and ordnance factories in west Cumbria during the Second World War.

    PubMed

    Kinlen, L

    2006-07-01

    Much evidence has accumulated that childhood leukaemia (CL) is a rare response to a common, but unidentified, infection and in particular that situations involving the unusual mixing of urban and rural groups (approximating to, respectively, groups infected with, and susceptible to, the relevant microorganism) can produce localised epidemics with consequent increases of the infrequent leukaemic complication. During the Second World War, explosives production factories were built and operated at Drigg and Sellafield, and a shell filling factory at Bootle, in west Cumbria, England, requiring substantial numbers of construction workers to be brought into this remote and isolated area. Following the design of an earlier study of CL near large (post-war) rural construction sites, mortality from this disease was investigated with the help of the Office of National Statistics, in the area around these Cumbrian factories where local workers largely lived, during the construction period and with particular reference to the overlapping construction and operational phase when the mixing of local and migrant workers would have been greatest. An excess of leukaemia deaths at ages 1-14 was found during the construction period (observed 3; observed/expected (O/E) 2.2, 95% confidence interval (CI): 0.6, 6.0), which was more marked and statistically significant during the overlap with operations (O 3; O/E 4.5, 95% CI: 1.1, 12.2), especially at ages 1-4 (O 2; O/E 7.1, CI: 1.2, 23.6). A previous investigation did not detect this excess because it considered only a small part of west Cumbria that omitted the communities where most of the workforce lived, having incorrectly attributed the post-war expansion of the village of Seascale (situated between Drigg and Sellafield) to the wartime ordnance factories. The present findings are consistent with the results of the earlier study of rural construction projects and with the general evidence that marked rural-urban population mixing

  20. ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling

    PubMed Central

    Goossens, Steven; Radaelli, Enrico; Blanchet, Odile; Durinck, Kaat; Van der Meulen, Joni; Peirs, Sofie; Taghon, Tom; Tremblay, Cedric S.; Costa, Magdaline; Ghahremani, Morvarid Farhang; De Medts, Jelle; Bartunkova, Sonia; Haigh, Katharina; Schwab, Claire; Farla, Natalie; Pieters, Tim; Matthijssens, Filip; Van Roy, Nadine; Best, J. Adam; Deswarte, Kim; Bogaert, Pieter; Carmichael, Catherine; Rickard, Adam; Suryani, Santi; Bracken, Lauryn S.; Alserihi, Raed; Canté-Barrett, Kirsten; Haenebalcke, Lieven; Clappier, Emmanuelle; Rondou, Pieter; Slowicka, Karolina; Huylebroeck, Danny; Goldrath, Ananda W.; Janzen, Viktor; McCormack, Matthew P.; Lock, Richard B.; Curtis, David J.; Harrison, Christine; Berx, Geert; Speleman, Frank; Meijerink, Jules P. P.; Soulier, Jean; Van Vlierberghe, Pieter; Haigh, Jody J.

    2015-01-01

    Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model. PMID:25565005

  1. ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling.

    PubMed

    Goossens, Steven; Radaelli, Enrico; Blanchet, Odile; Durinck, Kaat; Van der Meulen, Joni; Peirs, Sofie; Taghon, Tom; Tremblay, Cedric S; Costa, Magdaline; Farhang Ghahremani, Morvarid; De Medts, Jelle; Bartunkova, Sonia; Haigh, Katharina; Schwab, Claire; Farla, Natalie; Pieters, Tim; Matthijssens, Filip; Van Roy, Nadine; Best, J Adam; Deswarte, Kim; Bogaert, Pieter; Carmichael, Catherine; Rickard, Adam; Suryani, Santi; Bracken, Lauryn S; Alserihi, Raed; Canté-Barrett, Kirsten; Haenebalcke, Lieven; Clappier, Emmanuelle; Rondou, Pieter; Slowicka, Karolina; Huylebroeck, Danny; Goldrath, Ananda W; Janzen, Viktor; McCormack, Matthew P; Lock, Richard B; Curtis, David J; Harrison, Christine; Berx, Geert; Speleman, Frank; Meijerink, Jules P P; Soulier, Jean; Van Vlierberghe, Pieter; Haigh, Jody J

    2015-01-01

    Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model. PMID:25565005

  2. Effectiveness of HB2 (anti-CD7)--saporin immunotoxin in an in vivo model of human T-cell leukaemia developed in severe combined immunodeficient mice.

    PubMed Central

    Morland, B. J.; Barley, J.; Boehm, D.; Flavell, S. U.; Ghaleb, N.; Kohler, J. A.; Okayama, K.; Wilkins, B.; Flavell, D. J.

    1994-01-01

    The transplantation of the human T-cell acute lymphoblastic leukaemia (T-ALL) cell line HSB-2 into severe combined immunodeficient (SCID) mice was found to produce a disseminated pattern of leukaemia similar to that seen in man. The intravenous injection of 10(7) HSB-2 cells was associated with a universally fatal leukaemia. Histopathological examination of animals revealed the spread of leukaemia initially from bone marrow to involve all major organs including the meninges. An immunotoxin (HB2-Sap) was constructed by conjugating the anti-CD7 MAb HB2 to the ribosome-inactivating protein saporin. An in vitro protein synthesis inhibition assay revealed specific delivery of HB2-Sap immunotoxin (IT) to CD7+ HSB-2 target cells with an IC50 of 4.5 pM. When SCID mice were injected with 10(6) HSB-2 cells and then treated 8 days later with a single intravenous dose of 10 micrograms of immunotoxin there was a significant therapeutic effect evidenced by the numbers of animals surviving in the therapy group compared with untreated controls (chi 2 = 5.348, P = 0.021). These results demonstrate the useful application of human leukaemia xenografts in SCID mice and the potential therapeutic effect of an anti-CD7 immunotoxin in human T-ALL. Images Figure 1 PMID:7507691

  3. Diseases Caused by Viruses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The symptoms, causal agents, epidemiology and management of important virus diseases in chickpea and lentil crops were reviewed in depth. The virus diseases include.Alflafa mosaic virus, Cucumber mosaiv virus, Faba bean necrotic yellows virus, Pea enation mosaic virus, Pea seed-borne mosaci virus,...

  4. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

    DOE PAGESBeta

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; Meldi, Kristen; Yoshida, Kenichi; Morabito, Margot; Chautard, Emilie; Auboeuf, Didier; Fenaux, Pierre; Braun, Thorsten; et al

    2016-02-24

    The cytidine analogues azacytidine and 5-aza-2’-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14 ± 5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents ismore » associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Lastly, our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.« less

  5. Fractional model for pharmacokinetics of high dose methotrexate in children with acute lymphoblastic leukaemia

    NASA Astrophysics Data System (ADS)

    Popović, Jovan K.; Spasić, Dragan T.; Tošić, Jela; Kolarović, Jovanka L.; Malti, Rachid; Mitić, Igor M.; Pilipović, Stevan; Atanacković, Teodor M.

    2015-05-01

    The aim of this study is to promote a model based on the fractional differential calculus related to the pharmacokinetic individualization of high dose methotrexate treatment in children with acute lymphoblastic leukaemia, especially in high risk patients. We applied two-compartment fractional model on 8 selected cases with the largest number (4-19) of measured concentrations, among 43 pediatric patients received 24-h methotrexate 2-5 g/m2 infusions. The plasma concentrations were determined by fluorescence polarization immunoassay. Our mathematical procedure, designed by combining Post's and Newton's method, was coded in Mathematica 8.0 and performed on Fujicu Celsius M470-2 PC. Experimental data show that most of the measured values of methotrexate were in decreasing order. However, in certain treatments local maximums were detected. On the other hand, integer order compartmental models do not give values which fit well with the observed data. By the use of our model, we obtained better results, since it gives more accurate behavior of the transmission, as well as the local maximums which were recognized in methotrexate monitoring. It follows from our method that an additional test with a small methotrexate dose can be suggested for the fractional system parameter identification and the prediction of a possible pattern with a full dose in the case of high risk patients. A special feature of the fractional model is that it can also recognize and better fit an observed non-monotonic behavior. A new parameter determination procedure can be successfully used.

  6. Subgroups of Paediatric Acute Lymphoblastic Leukaemia Might Differ Significantly in Genetic Predisposition to Asparaginase Hypersensitivity.

    PubMed

    Kutszegi, Nóra; Semsei, Ágnes F; Gézsi, András; Sági, Judit C; Nagy, Viktória; Csordás, Katalin; Jakab, Zsuzsanna; Lautner-Csorba, Orsolya; Gábor, Krisztina Míta; Kovács, Gábor T; Erdélyi, Dániel J; Szalai, Csaba

    2015-01-01

    L-asparaginase (ASP) is a key element in the treatment of paediatric acute lymphoblastic leukaemia (ALL). However, hypersensitivity reactions (HSRs) to ASP are major challenges in paediatric patients. Our aim was to investigate genetic variants that may influence the risk to Escherichia coli-derived ASP hypersensitivity. Sample and clinical data collection was carried out from 576 paediatric ALL patients who were treated according to protocols from the Berlin-Frankfurt-Münster Study Group. A total of 20 single nucleotide polymorphisms (SNPs) in GRIA1 and GALNT10 genes were genotyped. Patients with GRIA1 rs4958351 AA/AG genotype showed significantly reduced risk to ASP hypersensitivity compared to patients with GG genotype in the T-cell ALL subgroup (OR = 0.05 (0.01-0.26); p = 4.70E-04), while no such association was found in pre-B-cell ALL. In the medium risk group two SNPs of GRIA1 (rs2055083 and rs707176) were associated significantly with the occurrence of ASP hypersensitivity (OR = 0.21 (0.09-0.53); p = 8.48E-04 and OR = 3.02 (1.36-6.73); p = 6.76E-03, respectively). Evaluating the genders separately, however, the association of rs707176 with ASP HSRs was confined only to females. Our results suggest that genetic variants of GRIA1 might influence the risk to ASP hypersensitivity, but subgroups of patients can differ significantly in this respect. PMID:26457809

  7. Authenticity and drug resistance in a panel of acute lymphoblastic leukaemia cell lines

    PubMed Central

    Beesley, A H; Palmer, M-L; Ford, J; Weller, R E; Cummings, A J; Freitas, J R; Firth, M J; Perera, K U; de Klerk, N H; Kees, U R

    2006-01-01

    Cell lines are important models for drug resistance in acute lymphoblastic leukaemia (ALL), but are often criticised as being unrepresentative of primary disease. There are also doubts regarding the authenticity of many lines. We have characterised a panel of ALL cell lines for growth and drug resistance and compared data with that published for primary patient specimens. In contrast to the convention that cell lines are highly proliferative, those established in our laboratory grow at rates similar to estimates of leukaemic cells in vivo (doubling time 53–442 h). Authenticity was confirmed by genetic fingerprinting, which also demonstrated the potential stability of long-term cultures. In vitro glucocorticoid resistance correlated well with that measured ex vivo, but all lines were significantly more sensitive to vincristine than primary specimens. Sensitivity to methotrexate was inversely correlated to that of glucocorticoids and L-asparaginase, indicating possible reciprocity in resistance mechanisms. A cell line identified as highly methotrexate resistant (IC50 >8000-fold higher than other lines) was derived from a patient receiving escalating doses of the drug, indicating in vivo selection of resistance as a cause of relapse. Many of these lines are suitable as models to study naturally occurring resistance phenotypes in paediatric ALL. PMID:17117183

  8. Biphosphinic palladacycle complex mediates lysosomal-membrane permeabilization and cell death in K562 leukaemia cells.

    PubMed

    Barbosa, Christiano M V; Oliveira, Carlos R; Nascimento, Fábio D; Smith, Mickaela C M; Fausto, Daniela M; Soufen, Marco Antonio; Sena, Eliana; Araújo, Ronaldo C; Tersariol, Ivarne L S; Bincoletto, Claudia; Caires, Antonio C F

    2006-08-01

    The cell death mechanism of cytotoxicity induced by the Biphosphinic Palladacycle Complex (BPC) was studied using a K562 leukaemia cell line. The IC50 values obtained for K562 cells post-72 h of BPC were less than 5.0 microM by using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue assays. Using the Acridine Orange vital staining combining fluorescence microscopy it was observed that the complex triggers apoptosis in K562 cells, inducing DNA fragmentation, as analysed through electrophoresis. Lysosomal-membrane permeabilization was also observed in K562 cells post-5 h of BPC, which suggests intralysosomal accumulation by proton-trapping, since its pKa value ranged from 5.1 to 6.5. Caspase-3, and -6 activity induced by BPC in K562 cells was prevented by the cathepsin-B inhibitor [N-(L-3-trans-propylcarbamoyl-oxirane-2-carbonyl)-L-isoleucyl-L-proline] (CA074). These events occurred in the presence of endogenous bcl-2 and bax expression. Acute toxicological studies demonstrated that BPC produces no lesions for liver and kidney fourteen-days after drug administration (100 mg/kg--i.p.). White and red blood cells of BPC-treated mice presented normal morphological characteristics. Taken together, these data suggest a novel lysosomal pathway for BPC-induced apoptosis, in which lysosomes are the primary target and cathepsin B acts as death mediator. PMID:16831419

  9. Different reactivity of monoclonal antibodies against common acute lymphoblastic leukaemia antigen (CD10).

    PubMed Central

    Haralambidou, S; Melo, J V; Catovsky, D

    1987-01-01

    The reactivity of five monoclonal antibodies J5, OKB-cALLA, Nu-N1, Nu-N2 and VIL-A1 against the common acute lymphoblastic leukaemia (common-ALL) antigen (glycoprotein 100, CD10); was investigated by indirect immunofluorescence in cell suspensions, and by immunoperoxidase in cytocentrifuge slides of ALL, chronic B cell lymphoproliferative disorders, and plasma cell dyscrasias. The five monoclonal antibodies gave similar positive results with both techniques only in samples of ALL. J5 was positive in variable degrees by immunofluorescence in the majority of B cell disorders examined but this was not confirmed by immunoperoxidase. OKB-cALLA reacted in a similar way to J5 in both techniques, although with a lower percentage of cells by immunofluorescence. Nu-N1, Nu-N2, and VIL-A1 were mainly negative when tested by both immunofluorescence and immunoperoxidase in B cell disorders other than ALL and therefore seemed to be more specific for the diagnosis of common-ALL. PMID:2953763

  10. Identification of Arsenic Direct-Binding Proteins in Acute Promyelocytic Leukaemia Cells

    PubMed Central

    Zhang, Tao; Lu, Haojie; Li, Weijun; Hu, Ronggui; Chen, Zi

    2015-01-01

    The identification of arsenic direct-binding proteins is essential for determining the mechanism by which arsenic trioxide achieves its chemotherapeutic effects. At least two cysteines close together in the amino acid sequence are crucial to the binding of arsenic and essential to the identification of arsenic-binding proteins. In the present study, arsenic binding proteins were pulled down with streptavidin and identified using a liquid chromatograph-mass spectrometer (LC-MS/MS). More than 40 arsenic-binding proteins were separated, and redox-related proteins, glutathione S-transferase P1 (GSTP1), heat shock 70 kDa protein 9 (HSPA9) and pyruvate kinase M2 (PKM2), were further studied using binding assays in vitro. Notably, PKM2 has a high affinity for arsenic. In contrast to PKM2, GSTP1and HSPA9 did not combine with arsenic directly in vitro. These observations suggest that arsenic-mediated acute promyelocytic leukaemia (APL) suppressive effects involve PKM2. In summary, we identified several arsenic binding proteins in APL cells and investigated the therapeutic mechanisms of arsenic trioxide for APL. Further investigation into specific signal pathways by which PKM2 mediates APL developments may lead to a better understanding of arsenic effects on APL. PMID:26569224

  11. Chronic lymphocytic leukaemia: could immunological tolerance mechanisms be the origin of lymphoid neoplasms?

    PubMed

    García-Muñoz, Ricardo; Llorente, Luis

    2014-08-01

    Immunological tolerance theory in chronic lymphocytic leukaemia (CLL): we suggest that B cells that express B-cell receptors (BCR) that recognize their own BCR epitopes are viewed by immune system as 'dangerous cells'. BCR autonomous signalling may induce constant receptor editing and mistakes in allelic exclusion. The fact that whole BCR recognizes a self-antigen or foreing antigen may be irrelevant in early B cell development. In early B cells, autonomous signalling induced by recognition of the BCR's own epitopes simulates an antigen-antibody engagement. In the bone marrow this interaction is viewed as recognition of self-molecules and induces receptor editing. In mature B cells autonomous signalling by the BCR may promote 'reversible anergy' and also may correct self-reactivity induced by the somatic hypermutation mechanisms in mutated CLL B cells. However, in unmutated CLL B cells, BCR autonomous signalling in addition to self-antigen recognition augments B cell activation, proliferation and genomic instability. We suggest that CLL originates from a coordinated normal immunologic tolerance mechanism to destroy self-reactive B cells. Additional genetic damage induced by tolerance mechanisms may immortalize self-reactive B cells and transform them into a leukemia. PMID:24645778

  12. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia

    PubMed Central

    Cowan-Jacob, Sandra W.; Fendrich, Gabriele; Floersheimer, Andreas; Furet, Pascal; Liebetanz, Janis; Rummel, Gabriele; Rheinberger, Paul; Centeleghe, Mario; Fabbro, Doriano; Manley, Paul W.

    2007-01-01

    Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery. PMID:17164530

  13. Targeting survivin with YM155 (Sepantronium Bromide): a novel therapeutic strategy for paediatric acute myeloid leukaemia.

    PubMed

    Smith, Amanda M; Little, Erica B; Zivanovic, Andjelija; Hong, Priscilla; Liu, Alfred K S; Burow, Rachel; Stinson, Caedyn; Hallahan, Andrew R; Moore, Andrew S

    2015-04-01

    Despite aggressive chemotherapy, approximately one-third of children with acute myeloid leukaemia (AML) relapse. More effective treatments are urgently needed. Survivin is an inhibitor-of-apoptosis protein with key roles in regulating cell division, proliferation and apoptosis. Furthermore, high expression of Survivin has been associated with poor clinical outcome in AML. The survivin suppressant YM155 (Sepantronium Bromide) has pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited. Therefore, we undertook a comprehensive pre-clinical evaluation of YM155 in paediatric AML. YM155 potently inhibited cell viability in a diverse panel of AML cell lines. All paediatric cell lines were particularly sensitive, with a median IC50 of 0.038 μM. Cell cycle analyses demonstrated concentration-dependent increases in a sub-G1 population with YM155 treatment, suggestive of apoptosis that was subsequently confirmed by an increase in annexin-V positivity. YM155-mediated apoptosis was confirmed across a panel of 8 diagnostic bone marrow samples from children with AML. Consistent with the proposed mechanism of action, YM155 treatment was associated with down-regulation of survivin mRNA and protein expression and induction of DNA damage. These data suggest that YM155-mediated inhibition of survivin is a potentially beneficial therapeutic strategy for AML, particularly paediatric disease, and warrants further evaluation. PMID:25659731

  14. Tyrosine kinase inhibitors in Ph+ acute lymphoblastic leukaemia: facts and perspectives.

    PubMed

    Malagola, Michele; Papayannidis, Cristina; Baccarani, Michele

    2016-04-01

    Two tyrosine kinase inhibitors (TKIs), imatinib and dasatinib, are registered for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) in adults. Other two TKIs (nilotinib and ponatinib) have been tested in the second-line, can offer an alternative in the patients who fail the first-line, and can acquire a role also in the first-line. Here, we provide a summary of the reports of TKIs, used alone, and in combination with chemotherapy. TKIs are very effective alone and with corticosteroids and are likely to improve substantially the outcome when they are combined with standard or dose-adapted chemotherapy. While the complete haematologic remission rate is always very high, close to 100 %, the cytogenetic and molecular remission rates are lower, so that TKIs are still considered as a complement to chemotherapy and as a bridge to allogeneic stem cell transplantation (allo-SCT). However, many patients relapse before transplant, and many patients still relapse, even if they have been submitted to allo-SCT. A proper use of TKIs, the introduction of ponatinib, and of "new generation" TKIs should improve further on the outcome of Ph+ ALL. PMID:26891878

  15. A multi-state model approach for prediction in chronic myeloid leukaemia.

    PubMed

    Lauseker, Michael; Hasford, Joerg; Hoffmann, Verena S; Müller, Martin C; Hehlmann, Rüdiger; Pfirrmann, Markus

    2015-06-01

    Multi-state models support prediction in medicine. With different states of disease, chronic myeloid leukaemia (CML) is particularly suited for the application of multi-state models. In this article, we tried to find a model for CML that allows predicting the prevalence of three different states (initial state of disease, remission and progression) in dependence on treatment, adjusted for age, sex and risk score. Based on the German CML Study IV, one of the largest randomised studies in CML, the model was able to represent the known effects of age and risk score on the probabilities of remission and progression. Patients achieving a major molecular remission had a better chance of surviving without progression, but this effect was not significant. Comparing treatments, patient of the high-dose arm had the greatest chance to be in the state "remission" at 5 years but did not seem to have an advantage considering "progression". The proposed illness-death model can be useful for predicting the course of CML based on the patient's individual covariates (trial registration: this is an explorative analysis of ClinicalTrials.gov Identifier: NCT00055874). PMID:25465231

  16. Dasatinib improves insulin sensitivity and affects lipid metabolism in a patient with chronic myeloid leukaemia.

    PubMed

    Iizuka, Katsumi; Niwa, Hiroyuki; Kato, Takehiro; Takeda, Jun

    2016-01-01

    A 65-year-old woman had been visiting our department for the treatment of type-2 diabetes mellitus since December 2012. Her glycated haemoglobin levels were well controlled (≈5.8% (40 mmol/mol)) by metformin (500 mg). In July 2014, her white cell count increased suddenly to 33 530 cells/μL and she was diagnosed with Ph+ chronic myeloid leukaemia. She was started on dasatinib (100 mg), which immediately normalised plasma levels of WCC. Dasatinib improved the glycaemic index to <6.0% and also improved plasma levels of triglycerides (TGs) and high-density lipoprotein-cholesterol (HDL-c). Levels of low-density lipoprotein-cholesterol were increased but remained within the normal range. The TG:HDL-c ratio and Quantitative Insulin Sensitivity Check Index rapidly improved. Followed by an improvement in insulin sensitivity, plasma levels of adiponectin and leptin were increased. This case study suggests that dasatinib might have positive as well as negative effects on the metabolism of glucose and lipids. PMID:26873919

  17. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.

    PubMed

    Burger, Jan A; Landau, Dan A; Taylor-Weiner, Amaro; Bozic, Ivana; Zhang, Huidan; Sarosiek, Kristopher; Wang, Lili; Stewart, Chip; Fan, Jean; Hoellenriegel, Julia; Sivina, Mariela; Dubuc, Adrian M; Fraser, Cameron; Han, Yulong; Li, Shuqiang; Livak, Kenneth J; Zou, Lihua; Wan, Youzhong; Konoplev, Sergej; Sougnez, Carrie; Brown, Jennifer R; Abruzzo, Lynne V; Carter, Scott L; Keating, Michael J; Davids, Matthew S; Wierda, William G; Cibulskis, Kristian; Zenz, Thorsten; Werner, Lillian; Dal Cin, Paola; Kharchencko, Peter; Neuberg, Donna; Kantarjian, Hagop; Lander, Eric; Gabriel, Stacey; O'Brien, Susan; Letai, Anthony; Weitz, David A; Nowak, Martin A; Getz, Gad; Wu, Catherine J

    2016-01-01

    Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance. PMID:27199251

  18. Economic impact of genomic diagnostics for intermediate-risk acute myeloid leukaemia.

    PubMed

    Cressman, Sonya; Karsan, Aly; Hogge, Donna E; McPherson, Emily; Bolbocean, Corneliu; Regier, Dean A; Peacock, Stuart J

    2016-08-01

    Acute Myeloid Leukaemia (AML) is a rare but serious group of diseases that require critical decision-making for curative treatment. Over the past decade, scientific discovery has revealed dozens of prognostic gene mutations for AML while sequencing costs have plummeted. In this study, we compared the cost-effectiveness of multigene integrative analysis (genomic analysis) with the standard molecular testing currently used for diagnosis of intermediate-risk AML. We used a decision analytic model with data for costs and outcomes from British Columbia, Canada, to assess the long-term (10-year) economic impacts. Our results suggest that genomic analysis would result in a 26% increase in the use of first-remission allogeneic stem cell transplantation. The resulting treatment decisions and downstream effects would come at an additional cost of $12 556 [2013 Canadian dollars (CAD)] per person and the incremental cost-effectiveness ratio would be $49 493 per quality-adjusted life-year gained. Cost-effectiveness was dependent on quality of life during the long-term (5-10) years of survival, relapse rates following first-remission chemotherapy and the upfront cost of transplantation. Non-relapse mortality rates, short-term quality of life and the cost of genomic sequencing had only minor impacts. Further research on post-remission outcomes can lead to improvements in the cost-effectiveness of curative treatments for AML. PMID:27098559

  19. Multiple cotton wool spots following bone marrow transplantation for treatment of acute lymphatic leukaemia.

    PubMed Central

    Gloor, B; Gratwohl, A; Hahn, H; Kretzschmar, S; Robert, Y; Speck, B; Daicker, B

    1985-01-01

    Three patients with acute lymphatic leukaemia developed visual impairment due to occlusion of small retinal vessels with multiple cotton wool spots after treatment which included whole body and skull irradiation followed by bone marrow transplantation and cyclosporin A. Withdrawal of cyclosporin A and treatment with corticosteroids was followed by recovery of visual acuity. This retinopathy and the retinal changes seen in the immunodeficiency syndrome are thought to be closely related. The possible role of cyclosporin A is discussed, though cotton wool spots and retinal haemorrhages have never been described in renal transplant patients during treatment with this drug. Withdrawal of cyclosporin A, which is highly effective in preventing graft-versus-host disease, can be fatal. Irradiation of the skull prior to bone marrow transplantation and intrathecal administration of methotrexate may be the most important factors causing the retinal ischaemic signs described here. The inclusion of an ophthalmologist in the team monitoring transplant patients would lead to increased documentation and a better understanding of this disease. Images PMID:3888252

  20. Chronic lymphocytic leukaemia induces an exhausted T cell phenotype in the TCL1 transgenic mouse model.

    PubMed

    Gassner, Franz J; Zaborsky, Nadja; Catakovic, Kemal; Rebhandl, Stefan; Huemer, Michael; Egle, Alexander; Hartmann, Tanja N; Greil, Richard; Geisberger, Roland

    2015-08-01

    Although chronic lymphocytic leukaemia (CLL) is a B cell malignancy, earlier studies have indicated a role of T cells in tumour growth and disease progression. In particular, the functional silencing of antigen-experienced T cells, called T cell exhaustion, has become implicated in immune evasion in CLL. In this study, we tested whether T cell exhaustion is recapitulated in the TCL1(tg) mouse model for CLL. We show that T cells express high levels of the inhibitory exhaustion markers programmed cell death 1 (PDCD1, also termed PD-1) and lymphocyte-activation gene 3 (LAG3), whereas CLL cells express high levels of CD274 (also termed PD-ligand 1). In addition, the fraction of exhausted T cells increases with CLL progression. Finally, we demonstrate that exhausted T cells are reinvigorated towards CLL cytotoxicity by inhibition of PDCD1/CD274 interaction in vivo. These results suggest that T cell exhaustion contributes to CLL pathogenesis and that interference with PDCD1/CD274 signalling holds high potential for therapeutic approaches. PMID:25940792

  1. Chronic Lymphocytic Leukaemia: Census of Patients Treated in Italian Haematology Units

    PubMed Central

    Salvi, Gianfranco; Innocenti, Idanna; Autore, Francesco; Laurenti, Luca

    2015-01-01

    This study was conducted by contacting the population of the Italian haematology units and collecting from 68% of them data concerning the number of patients with chronic lymphocytic leukaemia visited over the previous 12 months, with the aim of obtaining an overview of the treatment of this disease and comparing the results with the prevalence estimates found in literature. The projection obtained (about 17,000 patients visited in the previous 12 months) is probably overestimated because of double-counting of patients who may have been treated at two different facilities during the year, although it is also underestimated since the internal medicine units were not involved. The balance of these two opposite factors is not known. It is important to bear in mind the approximation with which the count was performed in facilities for which no official data were available. Albeit with these limits, the results obtained are in line with some existing prevalence data and make it possible to determine the portion of patients at different Binet stages and in the various age ranges, identifying the corresponding therapeutic treatments. Use of the CIRS scale to classify patients as FIT and UNFIT was seen to be still somewhat limited. PMID:26543525

  2. Mechanisms of tumour cell escape encountered in treating lymphocytic leukaemia with anti-idiotypic antibody.

    PubMed Central

    Gordon, J.; Abdul-Ahad, A. K.; Hamblin, T. J.; Stevenson, F. K.; Stevenson, G. T.

    1984-01-01

    Four patients with chronic lymphocytic leukaemia were treated by one or more infusions of polyclonal antibody specific for the immunoglobulin idiotype expressed on their leukaemic cells. The antibody was in the form of IgG from sheep antiserum. Three of the 4 cases showed a significant fall in blood lymphocyte count. On one occasion most of the residual circulating lymphocytes were apparently dead. However on all occasions the cell counts rebounded to near pre-infusion levels within one week. Viable lymphocytes recovered from the blood after infusion always showed evidence of antigenic modulation: a diminished level of surface idiotype in a patched distribution, with an accompanying refractoriness to lysis by anti-idiotype plus complement. When cultured in vitro blood lymphocytes from three of the four patients revealed an appreciable export of idiotypic Ig. These 3 patients showed plasma levels of idiotypic Ig up to 400 micrograms ml-1, reduced by plasma exchange prior to infusion. The fourth patient had a level of less than 4 micrograms ml-1, and was the only one in whom free antibody could be found in the plasma after infusion. These cases demonstrate two major factors which thwart antibody attack on leukaemic cells--extracellular antigen and antigenic modulation--as well as problems relating to sparseness of surface antigen, recruitment of effectors, and exhaustion of effectors. PMID:6722005

  3. Thiopurine methyltransferase and treatment outcome in the UK acute lymphoblastic leukaemia trial ALL2003

    PubMed Central

    Lennard, Lynne; Cartwright, Cher S; Wade, Rachel; Vora, Ajay

    2015-01-01

    The influence of thiopurine methyltransferase (TPMT) genotype on treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia trial ALL2003, a trial in which treatment intensity was adjusted based on minimal residual disease (MRD). TPMT genotype was measured in 2387 patients (76% of trial entrants): 2190 were homozygous wild-type, 189 were heterozygous for low activity TPMT alleles (166 TPMT*1/*3A, 19 TPMT*1/*3C, 3 TPMT*1/*2 and 1 TPMT*1/*9) and 8 were TPMT deficient. In contrast to the preceding trial ALL97, there was no difference in event-free survival (EFS) between the TPMT genotypes. The 5-year EFS for heterozygous TPMT*1/*3A patients was the same in both trials (88%), but for the homozygous wild-type TPMT*1/*1 patients, EFS improved from 80% in ALL97% to 88% in ALL2003. Importantly, the unexplained worse outcome for heterozygous TPMT*1/*3C patients observed in ALL97 (5-year EFS 53%) was not seen in ALL2003 (5-year EFS 94%). In a multivariate Cox regression analysis the only significant factor affecting EFS was MRD status (hazard ratio for high-risk MRD patients 4·22, 95% confidence interval 2·97–5·99, P < 0·0001). In conclusion, refinements in risk stratification and treatment have reduced the influence of TPMT genotype on treatment outcome in a contemporary protocol. PMID:25940902

  4. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing.

    PubMed

    Ding, Li; Ley, Timothy J; Larson, David E; Miller, Christopher A; Koboldt, Daniel C; Welch, John S; Ritchey, Julie K; Young, Margaret A; Lamprecht, Tamara; McLellan, Michael D; McMichael, Joshua F; Wallis, John W; Lu, Charles; Shen, Dong; Harris, Christopher C; Dooling, David J; Fulton, Robert S; Fulton, Lucinda L; Chen, Ken; Schmidt, Heather; Kalicki-Veizer, Joelle; Magrini, Vincent J; Cook, Lisa; McGrath, Sean D; Vickery, Tammi L; Wendl, Michael C; Heath, Sharon; Watson, Mark A; Link, Daniel C; Tomasson, Michael H; Shannon, William D; Payton, Jacqueline E; Kulkarni, Shashikant; Westervelt, Peter; Walter, Matthew J; Graubert, Timothy A; Mardis, Elaine R; Wilson, Richard K; DiPersio, John F

    2012-01-26

    Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions. PMID:22237025

  5. Managing chronic myeloid leukaemia in the elderly with intermittent imatinib treatment.

    PubMed

    Russo, D; Malagola, M; Skert, C; Cancelli, V; Turri, D; Pregno, P; Bergamaschi, M; Fogli, M; Testoni, N; De Vivo, A; Castagnetti, F; Pungolino, E; Stagno, F; Breccia, M; Martino, B; Intermesoli, T; Cambrin, G R; Nicolini, G; Abruzzese, E; Tiribelli, M; Bigazzi, C; Usala, E; Russo, S; Russo-Rossi, A; Lunghi, M; Bocchia, M; D'Emilio, A; Santini, V; Girasoli, M; Lorenzo, R Di; Bernardi, S; Palma, A Di; Cesana, B M; Soverini, S; Martinelli, G; Rosti, G; Baccarani, M

    2015-01-01

    The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged ⩾65 years in optimal and stable response with ⩾2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% confidence interval 35-59%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response. PMID:26383820

  6. Managing chronic myeloid leukaemia in the elderly with intermittent imatinib treatment

    PubMed Central

    Russo, D; Malagola, M; Skert, C; Cancelli, V; Turri, D; Pregno, P; Bergamaschi, M; Fogli, M; Testoni, N; De Vivo, A; Castagnetti, F; Pungolino, E; Stagno, F; Breccia, M; Martino, B; Intermesoli, T; Cambrin, G R; Nicolini, G; Abruzzese, E; Tiribelli, M; Bigazzi, C; Usala, E; Russo, S; Russo-Rossi, A; Lunghi, M; Bocchia, M; D'Emilio, A; Santini, V; Girasoli, M; Lorenzo, R Di; Bernardi, S; Palma, A Di; Cesana, B M; Soverini, S; Martinelli, G; Rosti, G; Baccarani, M

    2015-01-01

    The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged ⩾65 years in optimal and stable response with ⩾2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% confidence interval 35–59%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response. PMID:26383820

  7. Natural killer cell function and lymphoid subpopulations in acute non-lymphoblastic leukaemia in complete remission.

    PubMed Central

    Pizzolo, G.; Trentin, L.; Vinante, F.; Agostini, C.; Zambello, R.; Masciarelli, M.; Feruglio, C.; Dazzi, F.; Todeschini, G.; Chilosi, M.

    1988-01-01

    A long term follow-up study has been undertaken in 33 patients with acute non-lymphoblastic leukaemia (ANLL) in order to establish whether a correlation exists between the clinical course and the immunologic pattern of lymphoid subpopulations. Peripheral blood lymphoid cells have been investigated longitudinally (each 1 to 4 months) during complete remission (CR), by morphologic, phenotypic and functional analyses. Particular attention has been paid to the evaluation of the natural killer (NK) cell compartment, by the detection of cells expressing an NK-related phenotype and by NK in vitro assay. Among the patients so far evaluable, 20 relapsed (R) and 10 are long survivors in CR 'off therapy' (LS). The most relevant finding was represented by statistically higher values of NK activity observed in LS vs. R patients (P less than 0.01). The removal of adherent cells before the NK assay, performed to investigate the possible inhibitory effect on NK function played by the macrophage component, abolished this difference, due to a selective increase of NK function in the R group. The longitudinal study revealed that NK activity tended to decrease in individual patients who subsequently relapsed. These data suggest a possible role of NK cells in the relapse control of ANLL, although it cannot be excluded that the low level of NK activity observed in the R group is the result of impending relapse rather than its cause. PMID:3179190

  8. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

    PubMed Central

    Burger, Jan A.; Landau, Dan A.; Taylor-Weiner, Amaro; Bozic, Ivana; Zhang, Huidan; Sarosiek, Kristopher; Wang, Lili; Stewart, Chip; Fan, Jean; Hoellenriegel, Julia; Sivina, Mariela; Dubuc, Adrian M.; Fraser, Cameron; Han, Yulong; Li, Shuqiang; Livak, Kenneth J.; Zou, Lihua; Wan, Youzhong; Konoplev, Sergej; Sougnez, Carrie; Brown, Jennifer R.; Abruzzo, Lynne V.; Carter, Scott L.; Keating, Michael J.; Davids, Matthew S.; Wierda, William G.; Cibulskis, Kristian; Zenz, Thorsten; Werner, Lillian; Cin, Paola Dal; Kharchencko, Peter; Neuberg, Donna; Kantarjian, Hagop; Lander, Eric; Gabriel, Stacey; O'Brien, Susan; Letai, Anthony; Weitz, David A.; Nowak, Martin A.; Getz, Gad; Wu, Catherine J.

    2016-01-01

    Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance. PMID:27199251

  9. Chronic lymphocytic leukaemia induces an exhausted T cell phenotype in the TCL1 transgenic mouse model

    PubMed Central

    Gassner, Franz J; Zaborsky, Nadja; Catakovic, Kemal; Rebhandl, Stefan; Huemer, Michael; Egle, Alexander; Hartmann, Tanja N; Greil, Richard; Geisberger, Roland

    2015-01-01

    Although chronic lymphocytic leukaemia (CLL) is a B cell malignancy, earlier studies have indicated a role of T cells in tumour growth and disease progression. In particular, the functional silencing of antigen-experienced T cells, called T cell exhaustion, has become implicated in immune evasion in CLL. In this study, we tested whether T cell exhaustion is recapitulated in the TCL1tg mouse model for CLL. We show that T cells express high levels of the inhibitory exhaustion markers programmed cell death 1 (PDCD1, also termed PD-1) and lymphocyte-activation gene 3 (LAG3), whereas CLL cells express high levels of CD274 (also termed PD-ligand 1). In addition, the fraction of exhausted T cells increases with CLL progression. Finally, we demonstrate that exhausted T cells are reinvigorated towards CLL cytotoxicity by inhibition of PDCD1/CD274 interaction in vivo. These results suggest that T cell exhaustion contributes to CLL pathogenesis and that interference with PDCD1/CD274 signalling holds high potential for therapeutic approaches. PMID:25940792

  10. An Intelligent Decision Support System for Leukaemia Diagnosis using Microscopic Blood Images

    NASA Astrophysics Data System (ADS)

    Chin Neoh, Siew; Srisukkham, Worawut; Zhang, Li; Todryk, Stephen; Greystoke, Brigit; Peng Lim, Chee; Alamgir Hossain, Mohammed; Aslam, Nauman

    2015-10-01

    This research proposes an intelligent decision support system for acute lymphoblastic leukaemia diagnosis from microscopic blood images. A novel clustering algorithm with stimulating discriminant measures (SDM) of both within- and between-cluster scatter variances is proposed to produce robust segmentation of nucleus and cytoplasm of lymphocytes/lymphoblasts. Specifically, the proposed between-cluster evaluation is formulated based on the trade-off of several between-cluster measures of well-known feature extraction methods. The SDM measures are used in conjuction with Genetic Algorithm for clustering nucleus, cytoplasm, and background regions. Subsequently, a total of eighty features consisting of shape, texture, and colour information of the nucleus and cytoplasm sub-images are extracted. A number of classifiers (multi-layer perceptron, Support Vector Machine (SVM) and Dempster-Shafer ensemble) are employed for lymphocyte/lymphoblast classification. Evaluated with the ALL-IDB2 database, the proposed SDM-based clustering overcomes the shortcomings of Fuzzy C-means which focuses purely on within-cluster scatter variance. It also outperforms Linear Discriminant Analysis and Fuzzy Compactness and Separation for nucleus-cytoplasm separation. The overall system achieves superior recognition rates of 96.72% and 96.67% accuracies using bootstrapping and 10-fold cross validation with Dempster-Shafer and SVM, respectively. The results also compare favourably with those reported in the literature, indicating the usefulness of the proposed SDM-based clustering method.

  11. Suppressed spontaneous secretion of growth hormone in girls after treatment for acute lymphoblastic leukaemia.

    PubMed Central

    Moëll, C; Garwicz, S; Westgren, U; Wiebe, T; Albertsson-Wikland, K

    1989-01-01

    The spontaneous secretion of growth hormone during a 24 hour period and the response of growth hormone to growth hormone releasing hormone was studied in 13 girls who had received treatment for acute lymphoblastic leukemia that included cranial irradiation with 20-24 Gy in 12-14 fractions. At the time of investigation the girls were at varying stages of puberty and had normal concentrations of thyroid hormones. The mean interval between the end of treatment and investigation was 4.6 years. The mean age at onset of the disease was 3.2 years and at investigation 10.7 years. The average attained height equalled -0.3 SD at onset, and -1.0 SD at the time of investigation. Secretion of growth hormone was substantially reduced compared with controls and did not increase during puberty. A prompt rise in growth hormone secretion was seen after injection of growth hormone releasing hormone, but the mean maximum growth hormone concentration was, however, only 25 mU/l. There was no correlation between the 24 hour secretion and growth hormone response to growth hormone releasing hormone, or the time since irradiation. These results confirm earlier work that suggested that girls who had received treatment for acute lymphoblastic leukaemia, that included cranial irradiation, have a comparative growth hormone insufficiency characterised by normal prepubertal growth and slow growth during puberty because of an inability to respond to the increased demands for growth hormone at that time. PMID:2494952

  12. Evans syndrome secondary to chronic lymphocytic leukaemia: presentation, treatment, and outcome.

    PubMed

    Carli, Giuseppe; Visco, Carlo; Falisi, Erika; Perbellini, Omar; Novella, Elisabetta; Giaretta, Ilaria; Ferrarini, Isacco; Sandini, Alessandra; Alghisi, Alberta; Ambrosetti, Achille; Rodeghiero, Francesco

    2016-05-01

    Evans syndrome (ES) is defined by the combination (either simultaneous or sequential) of immune thrombocytopenia (ITP) and autoimmune haemolytic anaemia (AIHA). When related to secondary conditions, ES may arise in patients with chronic lymphocytic leukaemia (CLL), which is frequently associated to autoimmune cytopenias (AIC). We analysed 25 patients with ES secondary to CLL, which were identified from a large series of consecutive patients with CLL, diagnosed and followed up in two institutions. They represented 2.9 % of the whole series. Thirteen patients presented with concurrent ITP and AIHA (simultaneous ES), while others developed the two AIC sequentially. Occurrence of ES was associated with unfavourable biological prognostic factors like ZAP-70 expression, unmutated immunoglobulin heavy chain variable region gene status, 17-p13 deletion and TP53 gene mutations. Of note, the majority of patients with ES (66 %) had stereotyped B cell receptor configuration. Most patients had short-lasting remissions and required second-line treatments to control the autoimmune manifestations of ES. Patients with ES were associated with inferior survival compared to patients not developing AIC, especially when ES developed early in the course of CLL, although the reduced survival was not confirmed by multivariate analysis. In conclusion, ES secondary to CLL is a difficult-to-treat complication, characterised by adverse biological features and clinical outcome. PMID:27001309

  13. Site- and allele-specific polycomb dysregulation in T-cell leukaemia.

    PubMed

    Navarro, Jean-Marc; Touzart, Aurore; Pradel, Lydie C; Loosveld, Marie; Koubi, Myriam; Fenouil, Romain; Le Noir, Sandrine; Maqbool, Muhammad Ahmad; Morgado, Ester; Gregoire, Claude; Jaeger, Sebastien; Mamessier, Emilie; Pignon, Charles; Hacein-Bey-Abina, Salima; Malissen, Bernard; Gut, Marta; Gut, Ivo G; Dombret, Hervé; Macintyre, Elizabeth A; Howe, Steven J; Gaspar, H Bobby; Thrasher, Adrian J; Ifrah, Norbert; Payet-Bornet, Dominique; Duprez, Estelle; Andrau, Jean-Christophe; Asnafi, Vahid; Nadel, Bertrand

    2015-01-01

    T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1(+) cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1(+) T-ALLs. Sequencing reveals that >20% of monoallelic TAL1(+) patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5' to TAL1. Using 'allelic-ChIP' and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation. PMID:25615415

  14. Transcriptional and functional defects of dendritic cells derived from the MUTZ-3 leukaemia line

    PubMed Central

    Rasaiyaah, Jane; Noursadeghi, Mahdad; Kellam, Paul; Chain, Benjamin

    2009-01-01

    Dendritic cells (DC) generated from MUTZ-3, an immortalized acute myeloid leukaemia-derived cell line, have potential application as a model for the study of human DC, and as a tool with which to stimulate immunotherapeutic responses to cancer. However, the relationship of MUTZ-3 DC to their non-transformed counterparts remains incompletely understood. Immunoselected CD14+ MUTZ-3 cells were used to generate a homogeneous population of DC (M3DC). These cells had a cell surface phentoype and morphology characteristic of conventional monocyte-derived DC (MDDC). Whole genome transcriptome comparison of M3DC and MDDC however, revealed extensive differences between these two cell types. Functional ontology-based data analysis revealed three enriched clusters of genes downregulated in M3DC, with functions in pathogen recognition, DC maturation and cytokine/chemokine signalling. Downregulation of protein expression was confirmed for several of these genes. The molecular differences were accompanied by a profoundly impaired phenotypic and functional response of M3DC to microbial stimulation. The immortalized phenotype of MUTZ-3 therefore reflects not only deregulated proliferative capacity, but substantial perturbation of normal antigen-presenting cell function. These results have important implications for studies using MUTZ-3 as a model of MDDC or for cancer immunotherapy. PMID:19538250

  15. Transcriptional and functional defects of dendritic cells derived from the MUTZ-3 leukaemia line.

    PubMed

    Rasaiyaah, Jane; Noursadeghi, Mahdad; Kellam, Paul; Chain, Benjamin

    2009-07-01

    Dendritic cells (DC) generated from MUTZ-3, an immortalized acute myeloid leukaemia-derived cell line, have potential application as a model for the study of human DC, and as a tool with which to stimulate immunotherapeutic responses to cancer. However, the relationship of MUTZ-3 DC to their non-transformed counterparts remains incompletely understood. Immunoselected CD14+ MUTZ-3 cells were used to generate a homogeneous population of DC (M3DC). These cells had a cell surface phentoype and morphology characteristic of conventional monocyte-derived DC (MDDC). Whole genome transcriptome comparison of M3DC and MDDC however, revealed extensive differences between these two cell types. Functional ontology-based data analysis revealed three enriched clusters of genes downregulated in M3DC, with functions in pathogen recognition, DC maturation and cytokine/chemokine signalling. Downregulation of protein expression was confirmed for several of these genes. The molecular differences were accompanied by a profoundly impaired phenotypic and functional response of M3DC to microbial stimulation. The immortalized phenotype of MUTZ-3 therefore reflects not only deregulated proliferative capacity, but substantial perturbation of normal antigen-presenting cell function. These results have important implications for studies using MUTZ-3 as a model of MDDC or for cancer immunotherapy. PMID:19538250

  16. Chronic lymphocytic leukaemia: could immunological tolerance mechanisms be the origin of lymphoid neoplasms?

    PubMed Central

    García-Muñoz, Ricardo; Llorente, Luis

    2014-01-01

    Immunological tolerance theory in chronic lymphocytic leukaemia (CLL): we suggest that B cells that express B-cell receptors (BCR) that recognize their own BCR epitopes are viewed by immune system as ‘dangerous cells’. BCR autonomous signalling may induce constant receptor editing and mistakes in allelic exclusion. The fact that whole BCR recognizes a self-antigen or foreing antigen may be irrelevant in early B cell development. In early B cells, autonomous signalling induced by recognition of the BCR’s own epitopes simulates an antigen-antibody engagement. In the bone marrow this interaction is viewed as recognition of self-molecules and induces receptor editing. In mature B cells autonomous signalling by the BCR may promote ‘reversible anergy’ and also may correct self-reactivity induced by the somatic hypermutation mechanisms in mutated CLL B cells. However, in unmutated CLL B cells, BCR autonomous signalling in addition to self-antigen recognition augments B cell activation, proliferation and genomic instability. We suggest that CLL originates from a coordinated normal immunologic tolerance mechanism to destroy self-reactive B cells. Additional genetic damage induced by tolerance mechanisms may immortalize self-reactive B cells and transform them into a leukemia. PMID:24645778

  17. Childhood acute lymphoblastic leukaemia and indicators of early immune stimulation: the Estelle study (SFCE)

    PubMed Central

    Ajrouche, R; Rudant, J; Orsi, L; Petit, A; Baruchel, A; Lambilliotte, A; Gambart, M; Michel, G; Bertrand, Y; Ducassou, S; Gandemer, V; Paillard, C; Saumet, L; Blin, N; Hémon, D; Clavel, J

    2015-01-01

    Background: Factors related to early stimulation of the immune system (breastfeeding, proxies for exposure to infectious agents, normal delivery, and exposure to animals in early life) have been suggested to decrease the risk of childhood acute lymphoblastic leukaemia (ALL). Methods: The national registry-based case–control study, ESTELLE, was carried out in France in 2010–2011. Population controls were frequency matched with cases on age and gender. The participation rates were 93% for cases and 86% for controls. Data were obtained from structured telephone questionnaires administered to mothers. Odds ratios (OR) were estimated using unconditional regression models adjusted for age, gender, and potential confounders. Results: In all, 617 ALL and 1225 controls aged ⩾1 year were included. Inverse associations between ALL and early common infections (OR=0.8, 95% confidence interval (CI): 0.6, 1.0), non-first born (⩾3 vs 1; OR=0.7, 95% CI: 0.5, 1.0), attendance of a day-care centre before age 1 year (OR=0.7, 95% CI: 0.5, 1.0), breastfeeding (OR=0.8, 95% CI: 0.7, 1.0), and regular contact with pets (OR=0.8, 95% CI: 0.7, 1.0) in infancy were observed. Conclusions: The results support the hypothesis that conditions promoting the maturation of the immune system in infancy have a protective role with respect to ALL. PMID:25675150

  18. A high rate of telomeric sister chromatid exchange occurs in chronic lymphocytic leukaemia B-cells.

    PubMed

    Medves, Sandrine; Auchter, Morgan; Chambeau, Laetitia; Gazzo, Sophie; Poncet, Delphine; Grangier, Blandine; Verney, Aurélie; Moussay, Etienne; Ammerlaan, Wim; Brisou, Gabriel; Morjani, Hamid; Géli, Vincent; Palissot, Valérie; Berchem, Guy; Salles, Gilles; Wenner, Thomas

    2016-07-01

    Cancer cells protect their telomere ends from erosion through reactivation of telomerase or by using the Alternative Lengthening of Telomere (ALT) mechanism that depends on homologous recombination. Chronic lymphocytic leukaemia (CLL) B cells are characterized by almost no telomerase activity, shelterin deregulation and telomere fusions. To characterize telomeric maintenance mechanisms in B-CLL patients, we measured their telomere length, telomerase expression and the main hallmarks of the ALT activity i.e. C-circle concentration, an extra-chromosomal telomere repeat (ECTR), and the level of telomeric sister chromatid exchange (T-SCE) rate. Patients showed relative homogenous telomere length although almost no TERT transcript and nearly no C-circle were evidenced. Nevertheless, compared with normal B cells, B-CLL cells showed an increase in T-SCE rate that was correlated with a strong down-regulation of the topoisomerase III alpha (TOP3A) expression, involved in the dissolution of Holliday Junctions (HJ), together with an increased expression of SLX1A, SLX4, MUS81 and GEN1, involved in the resolution of HJ. Altogether, our results suggest that the telomere maintenance mechanism of B-CLL cells do not preferentially use telomerase or ALT. Rather, the rupture of the dissolvasome/resolvasome balance may increase telomere shuffling that could homogenize telomere length, slowing telomere erosion in this disease. PMID:26970083

  19. An Intelligent Decision Support System for Leukaemia Diagnosis using Microscopic Blood Images.

    PubMed

    Chin Neoh, Siew; Srisukkham, Worawut; Zhang, Li; Todryk, Stephen; Greystoke, Brigit; Peng Lim, Chee; Alamgir Hossain, Mohammed; Aslam, Nauman

    2015-01-01

    This research proposes an intelligent decision support system for acute lymphoblastic leukaemia diagnosis from microscopic blood images. A novel clustering algorithm with stimulating discriminant measures (SDM) of both within- and between-cluster scatter variances is proposed to produce robust segmentation of nucleus and cytoplasm of lymphocytes/lymphoblasts. Specifically, the proposed between-cluster evaluation is formulated based on the trade-off of several between-cluster measures of well-known feature extraction methods. The SDM measures are used in conjuction with Genetic Algorithm for clustering nucleus, cytoplasm, and background regions. Subsequently, a total of eighty features consisting of shape, texture, and colour information of the nucleus and cytoplasm sub-images are extracted. A number of classifiers (multi-layer perceptron, Support Vector Machine (SVM) and Dempster-Shafer ensemble) are employed for lymphocyte/lymphoblast classification. Evaluated with the ALL-IDB2 database, the proposed SDM-based clustering overcomes the shortcomings of Fuzzy C-means which focuses purely on within-cluster scatter variance. It also outperforms Linear Discriminant Analysis and Fuzzy Compactness and Separation for nucleus-cytoplasm separation. The overall system achieves superior recognition rates of 96.72% and 96.67% accuracies using bootstrapping and 10-fold cross validation with Dempster-Shafer and SVM, respectively. The results also compare favourably with those reported in the literature, indicating the usefulness of the proposed SDM-based clustering method. PMID:26450665

  20. Childhood leukaemia close to high-voltage power lines – the Geocap study, 2002–2007

    PubMed Central

    Sermage-Faure, C; Demoury, C; Rudant, J; Goujon-Bellec, S; Guyot-Goubin, A; Deschamps, F; Hemon, D; Clavel, J

    2013-01-01

    Background: High-voltage overhead power lines (HVOLs) are a source of extremely low-frequency magnetic fields (ELF-MFs), which are classified as possible risk factors for childhood acute leukaemia (AL). The study was carried out to test the hypothesis of an increased AL incidence in children living close to HVOL of 225–400 kV (VHV-HVOL) and 63–150 kV (HV-HVOL). Methods: The nationwide Geocap study included all the 2779 cases of childhood AL diagnosed in France over 2002–2007 and 30 000 contemporaneous population controls. The addresses at the time of inclusion were geocoded and precisely located around the whole HVOL network. Results: Increased odds ratios (ORs) were observed for AL occurrence and living within 50 m of a VHV-HVOL (OR=1.7 (0.9–3.6)). In contrast, there was no association with living beyond that distance from a VHV-HVOL or within 50 m of a HV-HVOL. Conclusion: The present study, free from any participation bias, supports the previous international findings of an increase in AL incidence close to VHV-HVOL. In order to investigate for a potential role of ELF-MF in the results, ELF-MF at the residences close to HVOL are to be estimated, using models based on the annual current loads and local characteristics of the lines. PMID:23558899

  1. Perspectives for therapeutic targeting of gene mutations in acute myeloid leukaemia with normal cytogenetics.

    PubMed

    Falini, Brunangelo; Sportoletti, Paolo; Brunetti, Lorenzo; Martelli, Maria Paola

    2015-08-01

    The acute myeloid leukaemia (AML) genome contains more than 20 driver recurrent mutations. Here, we review the potential for therapeutic targeting of the most common mutations associated with normal cytogenetics AML, focusing on those affecting the FLT3, NPM1 and epigenetic modifier genes (DNMT3A, IDH1/2, TET2). As compared to early compounds, second generation FLT3 inhibitors are more specific and have better pharmacokinetics. They also show higher anti-leukaemic activity, leading to about 50% of composite complete remissions in refractory/relapsed FLT3-internal tandem duplication-mutated AML. However, rapid relapses invariably occur due to various mechanisms of resistance to FLT3 inhibitors. This issue and the best way for using FLT3 inhibitors in combination with other therapeutic modalities are discussed. Potential approaches for therapeutic targeting of NPM1-mutated AML include: (i) reverting the aberrant nuclear export of NPM1 mutant using exportin-1 inhibitors; (ii) disruption of the nucleolus with drugs blocking the oligomerization of wild-type nucleophosmin or inducing nucleolar stress; and (iii) immunotherapeutic targeting of highly expressed CD33 and IL3RA (CD123) antigens. Finally, we discuss the role of demethylating agents (decitabine and azacitidine) and IDH1/2 inhibitors in the treatment of AML patients carrying mutations of genes (DNMT3A, IDH1/2 and TET2) involved in the epigenetic regulation of transcription. PMID:25891481

  2. Chronic Lymphocytic Leukaemia: Census of Patients Treated in Italian Haematology Units.

    PubMed

    Salvi, Gianfranco; Innocenti, Idanna; Autore, Francesco; Laurenti, Luca

    2015-01-01

    This study was conducted by contacting the population of the Italian haematology units and collecting from 68% of them data concerning the number of patients with chronic lymphocytic leukaemia visited over the previous 12 months, with the aim of obtaining an overview of the treatment of this disease and comparing the results with the prevalence estimates found in literature. The projection obtained (about 17,000 patients visited in the previous 12 months) is probably overestimated because of double-counting of patients who may have been treated at two different facilities during the year, although it is also underestimated since the internal medicine units were not involved. The balance of these two opposite factors is not known. It is important to bear in mind the approximation with which the count was performed in facilities for which no official data were available. Albeit with these limits, the results obtained are in line with some existing prevalence data and make it possible to determine the portion of patients at different Binet stages and in the various age ranges, identifying the corresponding therapeutic treatments. Use of the CIRS scale to classify patients as FIT and UNFIT was seen to be still somewhat limited. PMID:26543525

  3. The potential of clofarabine in MLL-rearranged infant acute lymphoblastic leukaemia.

    PubMed

    Stumpel, Dominique J P M; Schneider, Pauline; Pieters, Rob; Stam, Ronald W

    2015-09-01

    MLL-rearranged acute lymphoblastic leukaemia (ALL) in infants is the most difficult-to-treat type of childhood ALL, displaying a chemotherapy-resistant phenotype, and unique histone modifications, gene expression signatures and DNA methylation patterns. MLL-rearranged infant ALL responds remarkably well to nucleoside analogue drugs in vitro, such as cytarabine and cladribine, and to the demethylating agents decitabine and zebularine as measured by cytotoxicity assays. These observations led to the inclusion of cytarabine into the treatment regimens currently used for infants with ALL. However, survival chances for infants with MLL-rearranged ALL do still not exceed 30-40%. Here we explored the in vitro potential of the novel nucleoside analogue clofarabine for MLL-rearranged infant ALL. Therefore we used both cell line models as well as primary patient cells. Compared with other nucleoside analogues, clofarabine effectively targeted primary MLL-rearranged infant ALL cells at the lowest concentrations, with median LC50 values of ∼25 nM. Interestingly, clofarabine displayed synergistic cytotoxic effects in combination with cytarabine. Furthermore, at concentrations of 5-10nM clofarabine induced demethylation of the promoter region of the tumour suppressor gene FHIT (Fragile Histidine Triad), a gene typically hypermethylated in MLL-rearranged ALL. Demethylation of the FHIT promoter region was accompanied by subtle re-expression of this gene both at the mRNA and protein level. We conclude that clofarabine is an interesting candidate for further studies in MLL-rearranged ALL in infants. PMID:26188848

  4. Developing "Care Assistant": A smartphone application to support caregivers of children with acute lymphoblastic leukaemia.

    PubMed

    Wang, Jingting; Yao, Nengliang; Wang, Yuanyuan; Zhou, Fen; Liu, Yanyan; Geng, Zhaohui; Yuan, Changrong

    2016-04-01

    Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy. Caring for children with ALL is an uncommon experience for parents without medical training. They urgently need professional assistance when their children are recovering at home. This paper documents the process of developing an Android application (app) "Care Assistant" for family caregivers of children with ALL. Key informant interviews and focus group studies were used before programming the app. The key informants and focus group members included: caregivers of children with ALL, cancer care physicians and nurses, and software engineers. We found several major challenges faced by caregivers: limited access to evidence-based clinic information, lack of financial and social assistance, deficient communications with doctors or nurses, lack of disease-related knowledge, and inconvenience of tracking treatments and testing results. This feedback was used to develop "Care Assistant". This app has eight modules: personal information, treatment tracking, family care, financial and social assistance, knowledge centre, self-assessment questionnaires, interactive platform, and reminders. We have also developed a web-based administration portal to manage the app. The usability and effectiveness of "Care Assistant" will be evaluated in future studies. PMID:26271029

  5. Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol.

    PubMed

    Raja, Raheel A; Schmiegelow, Kjeld; Albertsen, Birgitte K; Prunsild, Kaie; Zeller, Bernward; Vaitkeviciene, Goda; Abrahamsson, Jonas; Heyman, Mats; Taskinen, Mervi; Harila-Saari, Arja; Kanerva, Jukka; Frandsen, Thomas L

    2014-04-01

    L-asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Treatment is associated with several toxicities, including acute pancreatitis. Clinical course, presentation, re-exposure to L-asparginase after pancreatitis and risk of recurrent pancreatitis within an asparaginase-intensive protocol has been poorly reported. Children (1-17 years) on the ongoing Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol with asparaginase-associated pancreatitis (AAP) diagnosed between 2008 and 2012 were identified through the online NOPHO ALL toxicity registry. NOPHO ALL2008 includes eight or 15 doses of intramuscular pegylated L-asparginase (PEG-asparaginase) 1000 iu/m(2) /dose at 2-6 weeks intervals, with a total of 30 weeks of exposure to PEG-asparaginase (clinicaltrials.gov no: NCT00819351). Of 786 children, 45 were diagnosed with AAP with a cumulative risk of AAP of 5·9%. AAP occurred after a median of five doses (range 1-13), and 11 d (median) from the latest administration of PEG-Asparaginase. Thirteen patients developed pseudocysts (30%) and 11 patients developed necrosis (25%). One patient died from pancreatitis. Twelve AAP patients were re-exposed to L-asparginase, two of whom developed mild AAP once more, after four and six doses respectively. In conclusion, re-exposure to PEG-asparaginase in ALL patients with mild AAP seems safe. PMID:24428625

  6. Awareness of acute myeloid leukaemia risk induced by diagnosis of a myelodysplastic syndrome.

    PubMed

    Ousseine, Youssoufa M; Butow, Phyllis N; Julian-Reynier, Claire; Dring, Rebecca; Festy, Patrick; Fenaux, Pierre; Vey, Norbert; Mancini, Julien

    2016-07-01

    Myelodysplastic syndromes (MDS) can evolve to acute myeloid leukaemia (AML) in approximately 30% of cases. Knowing their AML risk is important for patients because it might impact adherence to care and psychological health. The aim of this study was to evaluate the awareness of AML risk among MDS patients and to study the factors associated with this awareness. A self-administered questionnaire was mailed to all members of French and Australian patients' national MDS associations. Data of 301 patients were analysed. Patients were satisfied with the information they had received, but 33.2% did not know that they had an increased risk of developing AML. Younger age, higher-risk MDS treatment, preferences for health-related information and satisfaction with information provided about treatment were the factors independently associated with awareness of AML risk. Compared to unaware patients, patients knowing their risk were more likely to participate in a hypothetical clinical trial (83.0% vs 72.4%, p=0.043). More efforts are needed to provide more systematic information about AML risk to patients wishing to know it. More research is needed to study if increasing awareness can lead to more active engagement of MDS patients in their care and can increase the rate of clinical trial participation. PMID:27173089

  7. The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukaemia.

    PubMed

    Franco, R F; Simões, B P; Tone, L G; Gabellini, S M; Zago, M A; Falcão, R P

    2001-12-01

    We have determined the prevalence of methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C in 71 children (< or = 15 years) with acute lymphoblastic leukaemia (ALL) and in 71 control subjects. Odds ratio (OR) for ALL linked to MTHFR C677T was 0.4 (95% CI 0.2-0.8); for heterozygotes it was 0.5 (95% CI 0.2-0.9) and for homozygotes it was 0.3 (95%CI 0.09-0.8). MTHFR A1298C yielded an overall OR for ALL of 1.3 (95% CI: 0.7-2.6); for heterozygotes it was 1.3 (95% CI: 0.7-7.6) and for homozygotes it was 2.8 (95% CI 0.5-15.6). In conclusion, MTHFR C677T was linked to a significant 2.4-fold decreased risk of developing childhood ALL, whereas MTHFR A1298C did not significantly affect the risk of ALL in our population. PMID:11736945

  8. [Detection of the level of antibodies against bovine leucosis virus in the cow milk by immune sensor].

    PubMed

    Pyrohova, L V; Starodub, M F; Nahaeva, L I

    2005-01-01

    An immune sensor based on the surface plasmon resonance (SPR) was developed for express diagnostics of bovine leucosis. Sensor used for detection of the level of antibodies against bovine leukaemia virus (BLV) in the milk serum. It was shown that immune sensor analysis is more sensitive, rapid and simple in comparison with the traditional AGID test. It was stated that the developed immune sensor may be used for performance of screening of bovine leucosis at the farms and the minimal dilution of the milk serum should be 1:20. PMID:16335252

  9. Computer viruses

    NASA Technical Reports Server (NTRS)

    Denning, Peter J.

    1988-01-01

    The worm, Trojan horse, bacterium, and virus are destructive programs that attack information stored in a computer's memory. Virus programs, which propagate by incorporating copies of themselves into other programs, are a growing menace in the late-1980s world of unprotected, networked workstations and personal computers. Limited immunity is offered by memory protection hardware, digitally authenticated object programs,and antibody programs that kill specific viruses. Additional immunity can be gained from the practice of digital hygiene, primarily the refusal to use software from untrusted sources. Full immunity requires attention in a social dimension, the accountability of programmers.

  10. Hendra virus.

    PubMed

    Middleton, Deborah

    2014-12-01

    Hendra virus infection of horses occurred sporadically between 1994 and 2010 as a result of spill-over from the viral reservoir in Australian mainland flying-foxes, and occasional onward transmission to people also followed from exposure to affected horses. An unprecedented number of outbreaks were recorded in 2011 leading to heightened community concern. Release of an inactivated subunit vaccine for horses against Hendra virus represents the first commercially available product that is focused on mitigating the impact of a Biosafety Level 4 pathogen. Through preventing the development of acute Hendra virus disease in horses, vaccine use is also expected to reduce the risk of transmission of infection to people. PMID:25281398

  11. Risk of leukaemia and residential exposure to air pollution in an industrial area in Northern Italy: a case-control study.

    PubMed

    Parodi, Stefano; Santi, Irene; Casella, Claudia; Puppo, Antonella; Montanaro, Fabio; Fontana, Vincenzo; Pescetto, Massimiliano; Stagnaro, Emanuele

    2015-01-01

    Leukaemia risk in adult populations exposed to environmental air pollution is poorly investigated. We have carried out a population-based case-control study in an area that included a fossil fuel power plant, a coke oven and two big chemical industries. Information on residential history and several risk factors for leukaemia was obtained from 164 cases, diagnosed between 2002 and 2005, and 279 controls. A higher risk for subjects residing in polluted areas was observed, but statistical significance was not reached (adjusted OR = 1.11 and 1.56 for subjects living in moderately and in heavily polluted zones, respectively, p = 0.190). Results suggest a possible aetiological role of residential air pollution from industrial sites on the risk of developing leukaemia in adult populations. However, the proportion of eligible subjects excluded from the study and the lack of any measure of air pollution prevent definitive conclusions from being drawn. PMID:25245102

  12. Marrow matrix metalloproteinases (MMPs) and tissue inhibitors of MMP in acute leukaemia: potential role of MMP-9 as a surrogate marker to monitor leukaemic status in patients with acute myelogenous leukaemia.

    PubMed

    Lin, Liang-In; Lin, Dong-Tsamn; Chang, Chi-Jen; Lee, Cheng-Yeh; Tang, Jih-Luh; Tien, Hwei-Fang

    2002-06-01

    Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were demonstrated to have important implications in the progression and invasiveness of many malignant disorders. In contrast, the biological significance of these molecules in human leukaemias is not clear. We determined the levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 in the bone marrow of 37 patients with acute myelogenous leukaemia (AML) and 18 patients with acute lymphoblastic leukaemia (ALL) before chemotherapy. Nineteen bone marrow donors served as normal controls. After chemotherapy, sequential measurements were done during the course in 19 AML patients. The levels of TIMP-1 and TIMP-2 were significantly higher and MMP-9 levels were significantly lower in the AML and ALL patients than in the normal controls. MMP-2 levels were higher in ALL, but not AML patients, compared with controls. Moreover, the levels of marrow MMP-2 and MMP-9 did not parallel the numbers of leukaemic blasts in the peripheral blood. MMP-9 levels were significantly lower in the AML patients who achieved a complete remission (CR) than in those who did not (8.71 +/- 8.15 ng/ml vs 26.13 +/- 27.75 ng/ml, P < 0.05). The AML patients with lower MMP-9 levels (< or = 4.4 ng/ml) tended to have longer survival time than those with higher levels (> 12 months vs 4 months, P = 0.12). In addition, MMP-9 levels in the AML patients at CR rose to the same range as the controls, but dropped again at relapse, demonstrating a close relationship of marrow MMP-9 with disease status of AML. Therefore, we conclude that the level of marrow MMP-9 may be a useful surrogate marker for monitoring disease status in AML and propose it as a potential prognostic factor. PMID:12060118

  13. Zika Virus

    MedlinePlus

    ... be at risk for developing fetal complications. Blood, organ and tissue donor screening tests are also needed to assure the safety of transfusion and transplantation in areas of active mosquito-borne virus transmission. ...

  14. Zika Virus.

    PubMed

    Phillips, Jennan A; Neyland, Anavernyel

    2016-08-01

    Zika virus (ZIKV) infections are the latest global public health emergency. Occupational health nurses can protect society by educating workers, women of childbearing age, and others traveling in ZIKV-infected areas about prevention strategies. PMID:27411846

  15. CD33 monoclonal antibody conjugated Au cluster nano-bioprobe for targeted flow-cytometric detection of acute myeloid leukaemia

    NASA Astrophysics Data System (ADS)

    Retnakumari, Archana; Jayasimhan, Jasusri; Chandran, Parwathy; Menon, Deepthy; Nair, Shantikumar; Mony, Ullas; Koyakutty, Manzoor

    2011-07-01

    Protein stabilized gold nanoclusters (Au-NCs) are biocompatible, near-infrared (NIR) emitting nanosystems having a wide range of biomedical applications. Here, we report the development of a Au-NC based targeted fluorescent nano-bioprobe for the flow-cytometric detection of acute myeloid leukaemia (AML) cells. Au-NCs with ~ 25-28 atoms showing bright red-NIR fluorescence (600-750 nm) and average size of ~ 0.8 nm were prepared by bovine serum albumin assisted reduction-cum-stabilization in aqueous phase. The protein protected clusters were conjugated with monoclonal antibody against CD33 myeloid antigen, which is overexpressed in ~ 99.2% of the primitive population of AML cells, as confirmed by immunophenotyping using flow cytometry. Au-NC-CD33 conjugates having average size of ~ 12 nm retained bright fluorescence over an extended duration of ~ a year, as the albumin protein protects Au-NCs against degradation. Nanotoxicity studies revealed excellent biocompatibility of Au-NC conjugates, as they showed no adverse effect on the cell viability and inflammatory response. Target specificity of the conjugates for detecting CD33 expressing AML cells (KG1a) in flow cytometry showed specific staining of ~ 95.4% of leukaemia cells within 1-2 h compared to a non-specific uptake of ~ 8.2% in human peripheral blood cells (PBMCs) which are CD33low. The confocal imaging also demonstrated the targeted uptake of CD33 conjugated Au-NCs by leukaemia cells, thus confirming the flow cytometry results. This study demonstrates that novel nano-bioprobes can be developed using protein protected fluorescent nanoclusters of Au for the molecular receptor targeted flow cytometry based detection and imaging of cancer cells.

  16. Case-control study of leukaemia among young people near La Hague nuclear reprocessing plant: the environmental hypothesis revisited.

    PubMed Central

    Pobel, D.; Viel, J. F.

    1997-01-01

    OBJECTIVE: To investigate the association between childhood leukaemia and established risk factors or other factors related to La Hague nuclear waste reprocessing plant. DESIGN: Case-control study. SETTING: Area within a 35 km radius of La Hague, Normandy, France. SUBJECTS: Twenty seven cases of leukaemia diagnosed during the period 1978-93 in people aged under 25 years and 192 controls matched for sex, age, place of birth, and residence at time of diagnosis. MAIN OUTCOME MEASURES: Antenatal and postnatal exposure to x rays and viral infections, occupational exposure of parents (particularly ionising radiation), living conditions, lifestyle of parents and children. RESULTS: Increased trends were found for use of local beaches by mothers and children (P < or = 0.01); relative risks 2.87 (95% confidence intervals 1.05 to 8.72) and 4.49 (1.52 to 15.23) when categories were aggregated in two levels (more or less than once a month). Consumption of local fish and shellfish also showed an increased trend (P 0.01); relative risk 2.66 (0.91 to 9.51) when categories were grouped in two levels (more or less than once a week). A relative risk of 1.18 a year (1.03 to 1.42) was observed for length of residence in a granite-built house or in a granitic area. No association was shown with occupational radiation exposure in parents. CONCLUSIONS: There is some convincing evidence in childhood leukaemia of a causal role for environmental radiation exposure from recreational activities on beaches. New methods for identifying the environmental pathways, focusing on marine ecosystems, are warranted. PMID:9006467

  17. Evolution of procalcitonin, C-reactive protein and fibrinogen levels in neutropenic leukaemia patients with invasive pulmonary aspergillosis or mucormycosis.

    PubMed

    Roques, Marjorie; Chretien, Marie Lorraine; Favennec, Camille; Lafon, Ingrid; Ferrant, Emmanuelle; Legouge, Caroline; Plocque, Alexia; Golfier, Camille; Duvillard, Laurence; Amoureux, Lucie; Bastie, Jean Noel; Maurin-Bernier, Lory; Dalle, Frederic; Caillot, Denis

    2016-06-01

    Unlike bacterial infections, the value of procalcitonin (PCT) in detecting fungal infections in leukaemia patients is not clear. To determine whether the monitoring of PCT coupled with C-reactive protein (CRP) and fibrinogen (Fib) could be helpful in the management of pulmonary aspergillosis (IPA) or mucormycosis (PM), we retrospectively analysed the evolution of PCT, CRP and Fib levels in 94 leukaemia patients with proven/probable IPA (n = 77) or PM (n = 17) from D-12 to D12 relative to IFI onset defined as D0. Overall, 2140 assays were performed. From D-12 to D0, 12%, 5% and 1.4% of patients had PCT >0.5, 1 and 1.5 μg l(-1) , respectively, while CRP was >50, 75 and 100 mg l(-1) in 84%, 70% and 57% and Fib was >4, 5 and 6 g l(-1) in 96%, 80% and 61% of cases respectively (P < 10(-7) ). The same trends were observed from D1 to D12. Overall, between D-12 and D12, only 6.4% of patients had PCT >1.5 μg l(-1) , while CRP >100 mg l(-1) and Fib >6 g l(-1) were observed in 80% and 75% of cases respectively (P < 10(-7) ). In leukaemia patients, IPA or PM was accompanied by a significant increase in CRP and Fib while PCT remained low. PMID:26931315

  18. Plasma High Sensitivity Troponin T Levels in Adult Survivors of Childhood Leukaemias: Determinants and Associations with Cardiac Function

    PubMed Central

    Cheung, Yiu-fai; Yu, Wei; Cheuk, Daniel Ka-leung; Cheng, Frankie Wai-tsoi; Yang, Janet Yee-kwan; Yau, Jeffrey Ping-wa; Ho, Karin Ka-huen; Li, Chi-kong; Li, Rever Chak-ho; Yuen, Hui-leung; Ling, Alvin Siu-cheung; Li, Vivian Wing-yi; Wong, Wai-keung; Tsang, Kwong-cheong; Chan, Godfrey Chi-fung

    2013-01-01

    Background We sought to quantify plasma high sensitivity cardiac troponin (hs-cTnT) levels, their determinants, and their associations with left ventricular (LV) myocardial deformation in adult survivors of childhood acute leukaemias. Methods and Results One hundred adult survivors (57 males) of childhood acute leukaemias, aged 24.1±4.2 years, and 42 age-matched controls (26 males) were studied. Plasma cTnT was determined using a highly sensitive assay. Genotyping of NAD(P)H oxidase and multidrug resistance protein polymorphisms was performed. Left ventricular function was assessed by conventional, three-dimensional, and speckle tracking echocardiography. The medians (interquartile range) of hs-cTnT in male and female survivors were 4.9 (4.2 to 7.2) ng/L and 1.0 (1.0 to 3.5) ng/L, respectively. Nineteen survivors (13 males, 6 females) (19%) had elevated hs-cTnT (>95th centile of controls). Compared to those without elevated hs-TnT levels, these subjects had received larger cumulative anthracycline dose and were more likely to have leukaemic relapse, stem cell transplant, and cardiac irradiation. Their LV systolic and early diastolic myocardial velocities, isovolumic acceleration, and systolic longitudinal strain rate were significantly lower. Survivors having CT/TT at CYBA rs4673 had higher hs-cTnT levels than those with CC genotype. Functionally, increased hs-cTnT levels were associated with worse LV longitudinal systolic strain and systolic and diastolic strain rates. Conclusions Increased hs-cTnT levels occur in a significant proportion of adult survivors of childhood acute leukaemias and are associated with larger cumulative anthracycline dose received, history of leukaemic relapse, stem cell transplant, and cardiac irradiation, genetic variants in free radical metabolism, and worse LV myocardial deformation. PMID:24204736

  19. Development of chronic lymphocytic leukaemia in a case of Sjögren's syndrome with systemic lupus erythematosus.

    PubMed

    Ho, C H; Chiang, Y M; Chong, L L; Lin, H Y; Hwang, T S

    1985-08-01

    Persistent lymphocytosis and intermittent fever were found in a 68-yr-old Chinese woman 5 yr after the diagnosis of Sjögren's syndrome with systemic lupus erythematosus (SLE). A series of examinations--including virology, bone marrow aspiration and surface markers of lymphocytes--was made to evaluate the nature of the lymphocytosis which had not been found previously. All of the results were consistent with the diagnosis of B-cell chronic lymphocytic leukaemia (CLL). Development of CLL in Sjögren's syndrome has seldom been described before and may be added to other malignancies associated with Sjögren's syndrome. PMID:3876599

  20. An unusual indication for splenectomy in hairy cell leukaemia: a report of three cases with persistent splenomegaly after chemoimmunotherapy.

    PubMed

    Sarid, Nadav; Ahmad, Humayun N; Wotherspoon, Andrew; Dearden, Claire E; Else, Monica; Catovsky, Daniel

    2015-12-01

    We describe three cases of relapsed hairy cell leukaemia (HCL) treated with pentostatin plus rituximab. All three achieved bone marrow complete remission but had persistent splenomegaly and hypersplenism. Because of the clinical uncertainty of its significance, they were all splenectomized. The spleen histology showed no evidence of HCL, but a five-fold thickening of the splenic capsule and areas of fibrosis in the red pulp. This process may have contributed to the lack of elasticity and caused the persistent splenomegaly. We discuss the clinical implications for future patient management. The three patients remain in remission at 1 + , 5 + and 9 + years. PMID:26403440