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Sample records for leukaemia virus-related virus

  1. Ebola Virus-Related Encephalitis.

    PubMed

    de Greslan, Thierry; Billhot, Magali; Rousseau, Claire; Mac Nab, Christine; Karkowski, Ludovic; Cournac, Jean-Marie; Bordes, Julien; Gagnon, Nicolas; Dubrous, Philippe; Duron, Sandrine; Moroge, Sophie; Quentin, Benoit; Koulibaly, Fassou; Bompaire, Flavie; Renard, Jean-Luc; Cellarier, Gilles

    2016-10-15

    Ebola patients frequently exhibit behavioral modifications with ideation slowing and aggressiveness, sometimes contrasting with mild severity of Ebola disease. We performed lumbar punctures in 3 patients with this presentation and found Ebola virus in all cerebrospinal fluid samples. This discovery helps to discuss the concept of a specific Ebola virus encephalitis. PMID:27418576

  2. [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

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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

  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. [Pathogenesis of hepatitis B virus-related hepatocellular carcinoma].

    PubMed

    Zhang, Yuanqing; Guo, Jinsheng

    2016-02-01

    Hepatocellular carcinoma (HCC) is one of the most common cancer worldwide. Most of the HCC occur in developing countries. Chronic hepatitis B virus (HBV) infection is an important risk factor for HCC development. HBV induces immune-mediated chronic hepatitis, liver injury, regeneration and scar forming responses, leading to an inflammatory, fibrotic and immune deficient microenvironment. HBV may integrate into host genome, inducing genetic abnormality and altering the expression of HCC-related genes. HBV also expresses active proteins such as X (HBx) and S proteins, which may trans-activate HCC-related proteins expression, interact with intracellular specific proteins, activate a variety of signaling pathways, and induce aberrant epigenetic modifications. HBV mutation also has impact on HBV related HCC development. PMID:26983488

  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. Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase.

    PubMed

    Ndongwe, Tanyaradzwa P; Adedeji, Adeyemi O; Michailidis, Eleftherios; Ong, Yee Tsuey; Hachiya, Atsuko; Marchand, Bruno; Ryan, Emily M; Rai, Devendra K; Kirby, Karen A; Whatley, Angela S; Burke, Donald H; Johnson, Marc; Ding, Shilei; Zheng, Yi-Min; Liu, Shan-Lu; Kodama, Ei-Ichi; Delviks-Frankenberry, Krista A; Pathak, Vinay K; Mitsuya, Hiroaki; Parniak, Michael A; Singh, Kamalendra; Sarafianos, Stefan G

    2012-01-01

    We report key mechanistic differences between the reverse transcriptases (RT) of human immunodeficiency virus type-1 (HIV-1) and of xenotropic murine leukemia virus-related virus (XMRV), a gammaretrovirus that can infect human cells. Steady and pre-steady state kinetics demonstrated that XMRV RT is significantly less efficient in DNA synthesis and in unblocking chain-terminated primers. Surface plasmon resonance experiments showed that the gammaretroviral enzyme has a remarkably higher dissociation rate (k(off)) from DNA, which also results in lower processivity than HIV-1 RT. Transient kinetics of mismatch incorporation revealed that XMRV RT has higher fidelity than HIV-1 RT. We identified RNA aptamers that potently inhibit XMRV, but not HIV-1 RT. XMRV RT is highly susceptible to some nucleoside RT inhibitors, including Translocation Deficient RT inhibitors, but not to non-nucleoside RT inhibitors. We demonstrated that XMRV RT mutants K103R and Q190M, which are equivalent to HIV-1 mutants that are resistant to tenofovir (K65R) and AZT (Q151M), are also resistant to the respective drugs, suggesting that XMRV can acquire resistance to these compounds through the decreased incorporation mechanism reported in HIV-1. PMID:21908397

  14. Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase

    PubMed Central

    Ndongwe, Tanyaradzwa P.; Adedeji, Adeyemi O.; Michailidis, Eleftherios; Ong, Yee Tsuey; Hachiya, Atsuko; Marchand, Bruno; Ryan, Emily M.; Rai, Devendra K.; Kirby, Karen A.; Whatley, Angela S.; Burke, Donald H.; Johnson, Marc; Ding, Shilei; Zheng, Yi-Min; Liu, Shan-Lu; Kodama, Ei-Ichi; Delviks-Frankenberry, Krista A.; Pathak, Vinay K.; Mitsuya, Hiroaki; Parniak, Michael A.; Singh, Kamalendra; Sarafianos, Stefan G.

    2012-01-01

    We report key mechanistic differences between the reverse transcriptases (RT) of human immunodeficiency virus type-1 (HIV-1) and of xenotropic murine leukemia virus-related virus (XMRV), a gammaretrovirus that can infect human cells. Steady and pre-steady state kinetics demonstrated that XMRV RT is significantly less efficient in DNA synthesis and in unblocking chain-terminated primers. Surface plasmon resonance experiments showed that the gammaretroviral enzyme has a remarkably higher dissociation rate (koff) from DNA, which also results in lower processivity than HIV-1 RT. Transient kinetics of mismatch incorporation revealed that XMRV RT has higher fidelity than HIV-1 RT. We identified RNA aptamers that potently inhibit XMRV, but not HIV-1 RT. XMRV RT is highly susceptible to some nucleoside RT inhibitors, including Translocation Deficient RT inhibitors, but not to non-nucleoside RT inhibitors. We demonstrated that XMRV RT mutants K103R and Q190M, which are equivalent to HIV-1 mutants that are resistant to tenofovir (K65R) and AZT (Q151M), are also resistant to the respective drugs, suggesting that XMRV can acquire resistance to these compounds through the decreased incorporation mechanism reported in HIV-1. PMID:21908397

  15. Detection of transient and persistent feline leukaemia virus infections.

    PubMed

    Jarrett, O; Golder, M C; Stewart, M F

    1982-03-01

    A study was made of cats persistently or transiently viraemic with feline leukaemia virus (FeLV) following experimental oronasal infection. Cats of two ages were exposed to the virus. One group was infected when eight weeks old in the expectation that most of the cats would become persistently viraemic, and the second group when 16 weeks old, so that some would show signs of a transient infection and then recover. The periods following infection when virus was detectable in the blood and in the oropharynx were determined for each group. Three methods for detecting viraemia were compared: virus isolation, immunofluorescence on blood smears and an enzyme-linked immunosorbent assay (ELISA). There was good overall agreement among the three tests in detecting virus-positive cats. Virus was found sooner after infection by virus isolation than by the other methods, and virus appeared in the blood slightly sooner in cats which developed persistent viraemia than in transiently viraemic cats. Infectious FeLV was isolated from the oropharynx of all of the persistently viraemic cats, in most cases simultaneously with virus in the plasma. Virus was also isolated from the mouth of most transiently viraemic cats. Under field conditions such transient excretion of virus lasting only a few days would rarely be detected in a single sampling. This might explain how FeLV is maintained in free range urban cats in the absence of a large number of cats with persistent active FeLV infection. For routine diagnosis, immunofluorescence would appear to offer the best chance of differentiating transient and persistent infections by FeLV.

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

    PubMed

    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

    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 (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 [(1)H, (15)N] HSQC resonances were automatically identified using the five samples (Wu et al., 2006) [14]. 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 been observed not only at the interface with APV but also in regions apart from the interface. This indicates that the structural heterogeneity induced by the asymmetry of the binding of APV to the XMRV PR dimer is transmitted to distant regions. This is in contrast to the case of the APV:HIV-1 PR complex, in which the structural heterogeneity is only localized at the interface. Long-range transmission of the structural change identified for the XMRV PR complex might be utilized for the discovery of a new type of drug. PMID:22842568

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

    PubMed

    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

    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 (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 [(1)H, (15)N] HSQC resonances were automatically identified using the five samples (Wu et al., 2006) [14]. 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 been observed not only at the interface with APV but also in regions apart from the interface. This indicates that the structural heterogeneity induced by the asymmetry of the binding of APV to the XMRV PR dimer is transmitted to distant regions. This is in contrast to the case of the APV:HIV-1 PR complex, in which the structural heterogeneity is only localized at the interface. Long-range transmission of the structural change identified for the XMRV PR complex might be utilized for the discovery of a new type of drug.

  18. Immune control strategies for vaccinia virus-related laboratory-acquired infections.

    PubMed

    Wei, Qiang; Jiang, Meng Nan; Han, Jun; Wang, Zi Jun

    2014-02-01

    While presenting biological characteristics of vaccinia virus and laboratory-acquired infections during related research processes, this paper focuses on benefits and risks of vaccinia virus immunization in relation to laboratory-acquired infections, describes characteristics and the adaptation of vaccinia virus vaccine, analyses the role vaccinia virus immunization plays in the prevention and control of laboratory-acquired infections, and finally proposes solutions and countermeasures to further promote and implement immune control strategies. The problem related to immune strategy and laboratory- acquired infections which is being raised, analyzed and explored plays an active and instructive role in vaccinia virus related researches and laboratory- acquired infections, and also helps to recommend and develop relevant immune strategy for future vaccine control of such infections.

  19. 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.

  20. 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

  1. Hepatitis B virus-related polyarteritis nodosa presenting with multiple lung nodules and cavitary lesions.

    PubMed

    Naniwa, Taio; Maeda, Tomoyo; Shimizu, Shigeki; Ito, Rei

    2010-07-01

    The patient presented here is a 59-year-old Japanese man with active chronic hepatitis B with precore and core promoter mutated virus, presenting with high fever, bloody sputum, and multiple lung nodules with excavation. Surgical biopsy of the lung nodule showed necrotizing vasculitis affecting pulmonary arteries without granulomatous changes. The pulmonary manifestations of this patient resembled Wegener granulomatosis. However, the pathologic findings showing nongranulomatous necrotizing vasculitis involving the small pulmonary arteries, presence of circulating immune complex, absence of antineutrophil cytoplasmic antibodies, and excellent response to the combination therapy of corticosteroid and an anti-hepatitis B virus agent, entecavir, led us to the diagnosis of hepatitis B virus-related polyarteritis nodosa (PAN). Radiographic evidence of lung nodules or cavitations seen in systemic vasculitis patients has been considered a sign suggestive of granulomatous disease and a diagnostic surrogate marker for necrotizing granulomatous vasculitis, but a clinical relevance to hepatitis B virus-related PAN has not been reported before this case. PMID:20605819

  2. Polymorphonuclear leukocyte dysfunction associated with feline leukaemia virus infection.

    PubMed

    Lewis, M G; Duska, G O; Stiff, M I; Lafrado, L J; Olsen, R G

    1986-10-01

    The chemiluminescent characteristics of enriched (greater than 95%) peripheral blood polymorphonuclear leukocyte populations (PMN) from normal and feline leukaemia virus (FeLV)-infected cats were investigated. FeLV-infected cats demonstrated a significantly lower (P less than 0.001) PMN chemiluminescent response when compared to the response of normal age-matched controls. Normal PMN treated with FeLV-infected cat serum exhibited a depressed response in comparison to control cells. A titration of serum from infected cats supplemented with normal serum revealed a titratable suppression of chemiluminescence with increasing concentration of serum from the infected cats. However, PMN from FeLV-infected cats treated with normal serum displayed a slight increase in chemiluminescence over the same cells in autologous serum. The addition of inactivated FeLV to normal PMN caused a titratable decrease in chemiluminescence.

  3. Human herpes virus-6 seroprevalence and leukaemias: a case-control study

    PubMed Central

    Gentile, G; Mele, A; Ragona, G; Faggioni, A; Zompetta, C; Tosti, M E; Visani, G; Castelli, G; Pulsoni, A; Monarca, B; Martino, P; Mandelli, F

    1999-01-01

    The relationships between acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL), chronic myeloid leukaemia (CML) and refractory anaemia with excess of blasts (RAEB) and human herpes virus (HHV)-6 antibody level were investigated in a multicentre case-control study. An association between increased HHV-6 seropositivity and geometric mean titre ratio with AML was shown: P for trend = 0.022, adjusted odds ratio 1.20, 95% confidence interval 1.07–1.33 respectively. No association was found between HHV-6 and ALL, CML or RAEB. © 1999 Cancer Research Campaign PMID:10362124

  4. Evaluation of the natural perinatal transmission of bovine leukaemia virus.

    PubMed

    Mekata, Hirohisa; Sekiguchi, Satoshi; Konnai, Satoru; Kirino, Yumi; Honkawa, Kazuyuki; Nonaka, Nariaki; Horii, Yoichiro; Norimine, Junzo

    2015-03-01

    The perinatal transmission of bovine leukaemia virus (BLV) plays a critical role in the spread and persistence of BLV infection in cattle herds. The purpose of this study was to examine the frequency of perinatal infections in an area in Japan and investigate some risk factors associated with infection. Altogether, 129 calves born to BLV-infected cows in a herd in Japan were tested for infection immediately after birth and again at one month of age using nested PCR. Twenty-four calves (18.6 per cent) were infected with BLV, of which 14 (10.8 per cent) and 10 (7.7 per cent) calves were infected via the transplacental and the birth canal routes, respectively. Maternal viral loads, breed, the presence or absence of assistance during parturition and the number of births per dam were evaluated to investigate risk factors associated with infection. Maternal viral load was significantly correlated with the frequency of perinatal infection, and more than 40 per cent of newborn calves born to dams with high viral loads were infected with BLV. The results of this study could contribute towards developing effective eradication programmes by providing necessary data for replacement of breeding cow in the field.

  5. Variation of the Virus-Related Elements within Syntenic Genomes of the Hyperthermophilic Archaeon Aeropyrum

    PubMed Central

    Daifuku, Takashi; Yoshida, Takashi; Kitamura, Takayuki; Kawaichi, Satoshi; Inoue, Takahiro; Nomura, Keigo; Yoshida, Yui; Kuno, Sotaro

    2013-01-01

    The increasing number of genome sequences of archaea and bacteria show their adaptation to different environmental conditions at the genomic level. Aeropyrum spp. are aerobic and hyperthermophilic archaea. Aeropyrum camini was isolated from a deep-sea hydrothermal vent, and Aeropyrum pernix was isolated from a coastal solfataric vent. To investigate the adaptation strategy in each habitat, we compared the genomes of the two species. Shared genome features were a small genome size, a high GC content, and a large portion of orthologous genes (86 to 88%). The genomes also showed high synteny. These shared features may have been derived from the small number of mobile genetic elements and the lack of a RecBCD system, a recombinational enzyme complex. In addition, the specialized physiology (aerobic and hyperthermophilic) of Aeropyrum spp. may also contribute to the entire-genome similarity. Despite having stable genomes, interference of synteny occurred with two proviruses, A. pernix spindle-shaped virus 1 (APSV1) and A. pernix ovoid virus 1 (APOV1), and clustered regularly interspaced short palindromic repeat (CRISPR) elements. Spacer sequences derived from the A. camini CRISPR showed significant matches with protospacers of the two proviruses infecting A. pernix, indicating that A. camini interacted with viruses closely related to APSV1 and APOV1. Furthermore, a significant fraction of the nonorthologous genes (41 to 45%) were proviral genes or ORFans probably originating from viruses. Although the genomes of A. camini and A. pernix were conserved, we observed nonsynteny that was attributed primarily to virus-related elements. Our findings indicated that the genomic diversification of Aeropyrum spp. is substantially caused by viruses. PMID:23872576

  6. The xenotropic murine leukemia virus-related retrovirus debate continues at first international workshop.

    PubMed

    Stoye, Jonathan P; Silverman, Robert H; Boucher, Charles A; Le Grice, Stuart F J

    2010-12-22

    The 1st International Workshop on Xenotropic Murine Leukemia Virus-Related Retrovirus (XMRV), co-sponsored by the National Institutes of Health, The Department of Health and Human Services and Abbott Diagnostics, was convened on September 7/8, 2010 on the NIH campus, Bethesda, MD. Attracting an international audience of over 200 participants, the 2-day event combined a series of plenary talks with updates on different aspects of XMRV research, addressing basic gammaretrovirus biology, host response, association of XMRV with chronic fatigue syndrome and prostate cancer, assay development and epidemiology. The current status of XMRV research, concerns among the scientific community and suggestions for future actions are summarized in this meeting report.

  7. Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy

    PubMed Central

    Song, Il Han; Kim, So Mi; Choo, Young Kwang

    2013-01-01

    Hepatocellular carcinoma (HCC) is a grave primary liver cancer that has a limited therapeutic option because it is generally diagnosed later in an advanced stage due to its aggressive biologic behavior. The early detection of HCC has a great impact on the treatment efficacy and survival of patients at high risk for cancer. Potential host, environmental, and virus-related risk factors have been introduced. Hepatitis B virus (HBV) is a major cause of end-stage liver diseases such as liver cirrhosis or HCC in endemic areas, and its serologic or virologic status is considered an important risk factor. HCC risk prediction derived from the identification of major risk factors is necessary for providing adequate screening/surveillance strategies to high-risk individuals. Several risk prediction models for HBV-related HCC have been presented recently with simple, efficient, and readily available to use parameters applicable to average- or unknown-risk populations as well as high-risk individuals. Predictive scoring systems of risk estimation to assess HCC development can provide the way to an evidence-based clinical approach for cost- and effort-effective outcomes, capable of inducing a personalized surveillance program according to risk stratification. In this review, the concepts and perspectives of the risk prediction of HCC are discussed through the analysis of several risk prediction models of HBV-related HCC. PMID:24379609

  8. 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

  9. The role of viruses in the origin of leukaemia in animals and man

    PubMed Central

    Zilber, L. A.

    1962-01-01

    In the course of the last decade intensive research has been conducted in many laboratories on the role of viruses in the etiology of various forms of animal and human leukaemia. This research has led to the accumulation of substantial experimental material, several reviews of which have been published. This article discusses the more important data obtained from study of the etiology of leukaemia in animals and man and attempts to evaluate them and to outline the pathways of study of problems still unsolved. It also contains information on the induction of leukaemia and tumours by means of nucleic acids isolated from neoplastic tissues, and some general problems of the pathogenesis of cancer caused by viruses are discussed in this connexion. PMID:20604114

  10. Prevention of contamination by xenotropic murine leukemia virus-related virus: susceptibility to alcohol-based disinfectants and environmental stability.

    PubMed

    Palesch, David; Khalid, Mohammad; Stürzel, Christina M; Münch, Jan

    2014-04-01

    Xenotropic murine leukemia virus-related virus (XMRV) represents a novel γ-retrovirus that is capable of infecting human cells and has been classified as a biosafety level 2 (BSL-2) organism. Hence, XMRV represents a potential risk for personnel in laboratories worldwide. Here, we measured the stability of XMRV and its susceptibility to alcohol-based disinfectants. To this end, we exposed an infectious XMRV reporter virus encoding a secretable luciferase to different temperatures, pH values, and disinfectants and infected XMRV-permissive Raji B cells to measure residual viral infectivity. We found that 1 min treatment of XMRV particles at 60°C is sufficient to reduce infectivity by 99.9%. XMRV infectivity was maximal at a neutral pH but was reduced by 86% at pH 4 and 99.9% at pH 10. The common hand and surface disinfectants ethanol and isopropanol as well as the cell fixation reagent paraformaldehyde abrogated XMRV infectivity entirely, as indicated by a reduction of infectivity exceeding 99.99%. Our findings provide evidence of specific means to inactivate XMRV. Their application will help to prevent unintended XMRV contamination of cell cultures in laboratories and minimize the risk for laboratory personnel and health care workers to become infected with this biosafety level 2 organism.

  11. 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.

  12. 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.

  13. Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma.

    PubMed

    Kubo, Shoji; Takemura, Shigekazu; Tanaka, Shogo; Shinkawa, Hiroji; Nishioka, Takayoshi; Nozawa, Akinori; Kinoshita, Masahiko; Hamano, Genya; Ito, Tokuji; Urata, Yorihisa

    2015-07-21

    Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC.

  14. Structural and Inhibition Studies of the RNase H Function of Xenotropic Murine Leukemia Virus-Related Virus Reverse Transcriptase

    PubMed Central

    Kirby, Karen A.; Marchand, Bruno; Ong, Yee Tsuey; Ndongwe, Tanyaradzwa P.; Hachiya, Atsuko; Michailidis, Eleftherios; Leslie, Maxwell D.; Sietsema, Daniel V.; Fetterly, Tracy L.; Dorst, Christopher A.; Singh, Kamalendra; Wang, Zhengqiang; Parniak, Michael A.

    2012-01-01

    RNase H inhibitors (RNHIs) have gained attention as potential HIV-1 therapeutics. Although several RNHIs have been studied in the context of HIV-1 reverse transcriptase (RT) RNase H, there is no information on inhibitors that might affect the RNase H activity of other RTs. We performed biochemical, virological, crystallographic, and molecular modeling studies to compare the RNase H function and inhibition profiles of the gammaretroviral xenotropic murine leukemia virus-related virus (XMRV) and Moloney murine leukemia virus (MoMLV) RTs to those of HIV-1 RT. The RNase H activity of XMRV RT is significantly lower than that of HIV-1 RT and comparable to that of MoMLV RT. XMRV and MoMLV, but not HIV-1 RT, had optimal RNase H activities in the presence of Mn2+ and not Mg2+. Using hydroxyl-radical footprinting assays, we demonstrated that the distance between the polymerase and RNase H domains in the MoMLV and XMRV RTs is longer than that in the HIV-1 RT by ∼3.4 Å. We identified one naphthyridinone and one hydroxyisoquinolinedione as potent inhibitors of HIV-1 and XMRV RT RNases H with 50% inhibitory concentrations ranging from ∼0.8 to 0.02 μM. Two acylhydrazones effective against HIV-1 RT RNase H were less potent against the XMRV enzyme. We also solved the crystal structure of an XMRV RNase H fragment at high resolution (1.5 Å) and determined the molecular details of the XMRV RNase H active site, thus providing a framework that would be useful for the design of antivirals that target RNase H. PMID:22252812

  15. Structural and inhibition studies of the RNase H function of xenotropic murine leukemia virus-related virus reverse transcriptase.

    PubMed

    Kirby, Karen A; Marchand, Bruno; Ong, Yee Tsuey; Ndongwe, Tanyaradzwa P; Hachiya, Atsuko; Michailidis, Eleftherios; Leslie, Maxwell D; Sietsema, Daniel V; Fetterly, Tracy L; Dorst, Christopher A; Singh, Kamalendra; Wang, Zhengqiang; Parniak, Michael A; Sarafianos, Stefan G

    2012-04-01

    RNase H inhibitors (RNHIs) have gained attention as potential HIV-1 therapeutics. Although several RNHIs have been studied in the context of HIV-1 reverse transcriptase (RT) RNase H, there is no information on inhibitors that might affect the RNase H activity of other RTs. We performed biochemical, virological, crystallographic, and molecular modeling studies to compare the RNase H function and inhibition profiles of the gammaretroviral xenotropic murine leukemia virus-related virus (XMRV) and Moloney murine leukemia virus (MoMLV) RTs to those of HIV-1 RT. The RNase H activity of XMRV RT is significantly lower than that of HIV-1 RT and comparable to that of MoMLV RT. XMRV and MoMLV, but not HIV-1 RT, had optimal RNase H activities in the presence of Mn²⁺ and not Mg²⁺. Using hydroxyl-radical footprinting assays, we demonstrated that the distance between the polymerase and RNase H domains in the MoMLV and XMRV RTs is longer than that in the HIV-1 RT by ∼3.4 Å. We identified one naphthyridinone and one hydroxyisoquinolinedione as potent inhibitors of HIV-1 and XMRV RT RNases H with 50% inhibitory concentrations ranging from ∼0.8 to 0.02 μM. Two acylhydrazones effective against HIV-1 RT RNase H were less potent against the XMRV enzyme. We also solved the crystal structure of an XMRV RNase H fragment at high resolution (1.5 Å) and determined the molecular details of the XMRV RNase H active site, thus providing a framework that would be useful for the design of antivirals that target RNase H. PMID:22252812

  16. No association of xenotropic murine leukemia virus-related virus with prostate cancer or chronic fatigue syndrome in Japan

    PubMed Central

    2011-01-01

    Background The involvement of xenotropic murine leukemia virus-related virus (XMRV) in prostate cancer (PC) and chronic fatigue syndrome (CFS) is disputed as its reported prevalence ranges from 0% to 25% in PC cases and from 0% to more than 80% in CFS cases. To evaluate the risk of XMRV infection during blood transfusion in Japan, we screened three populations--healthy donors (n = 500), patients with PC (n = 67), and patients with CFS (n = 100)--for antibodies against XMRV proteins in freshly collected blood samples. We also examined blood samples of viral antibody-positive patients with PC and all (both antibody-positive and antibody-negative) patients with CFS for XMRV DNA. Results Antibody screening by immunoblot analysis showed that a fraction of the cases (1.6-3.0%) possessed anti-Gag antibodies regardless of their gender or disease condition. Most of these antibodies were highly specific to XMRV Gag capsid protein, but none of the individuals in the three tested populations retained strong antibody responses to multiple XMRV proteins. In the viral antibody-positive PC patients, we occasionally detected XMRV genes in plasma and peripheral blood mononuclear cells but failed to isolate an infectious or full-length XMRV. Further, all CFS patients tested negative for XMRV DNA in peripheral blood mononuclear cells. Conclusion Our data show no solid evidence of XMRV infection in any of the three populations tested, implying that there is no association between the onset of PC or CFS and XMRV infection in Japan. However, the lack of adequate human specimens as a positive control in Ab screening and the limited sample size do not allow us to draw a firm conclusion. PMID:21414229

  17. 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

  18. Natural and Experimental Infection of Caenorhabditis Nematodes by Novel Viruses Related to Nodaviruses

    PubMed Central

    Wu, Guang; Nuez, Isabelle; Bélicard, Tony; Jiang, Yanfang; Zhao, Guoyan; Franz, Carl J.; Goldstein, Leonard D.; Sanroman, Mabel; Miska, Eric A.; Wang, David

    2011-01-01

    An ideal model system to study antiviral immunity and host-pathogen co-evolution would combine a genetically tractable small animal with a virus capable of naturally infecting the host organism. The use of C. elegans as a model to define host-viral interactions has been limited by the lack of viruses known to infect nematodes. From wild isolates of C. elegans and C. briggsae with unusual morphological phenotypes in intestinal cells, we identified two novel RNA viruses distantly related to known nodaviruses, one infecting specifically C. elegans (Orsay virus), the other C. briggsae (Santeuil virus). Bleaching of embryos cured infected cultures demonstrating that the viruses are neither stably integrated in the host genome nor transmitted vertically. 0.2 µm filtrates of the infected cultures could infect cured animals. Infected animals continuously maintained viral infection for 6 mo (∼50 generations), demonstrating that natural cycles of horizontal virus transmission were faithfully recapitulated in laboratory culture. In addition to infecting the natural C. elegans isolate, Orsay virus readily infected laboratory C. elegans mutants defective in RNAi and yielded higher levels of viral RNA and infection symptoms as compared to infection of the corresponding wild-type N2 strain. These results demonstrated a clear role for RNAi in the defense against this virus. Furthermore, different wild C. elegans isolates displayed differential susceptibility to infection by Orsay virus, thereby affording genetic approaches to defining antiviral loci. This discovery establishes a bona fide viral infection system to explore the natural ecology of nematodes, host-pathogen co-evolution, the evolution of small RNA responses, and innate antiviral mechanisms. PMID:21283608

  19. Natural and experimental infection of Caenorhabditis nematodes by novel viruses related to nodaviruses.

    PubMed

    Félix, Marie-Anne; Ashe, Alyson; Piffaretti, Joséphine; Wu, Guang; Nuez, Isabelle; Bélicard, Tony; Jiang, Yanfang; Zhao, Guoyan; Franz, Carl J; Goldstein, Leonard D; Sanroman, Mabel; Miska, Eric A; Wang, David

    2011-01-25

    An ideal model system to study antiviral immunity and host-pathogen co-evolution would combine a genetically tractable small animal with a virus capable of naturally infecting the host organism. The use of C. elegans as a model to define host-viral interactions has been limited by the lack of viruses known to infect nematodes. From wild isolates of C. elegans and C. briggsae with unusual morphological phenotypes in intestinal cells, we identified two novel RNA viruses distantly related to known nodaviruses, one infecting specifically C. elegans (Orsay virus), the other C. briggsae (Santeuil virus). Bleaching of embryos cured infected cultures demonstrating that the viruses are neither stably integrated in the host genome nor transmitted vertically. 0.2 µm filtrates of the infected cultures could infect cured animals. Infected animals continuously maintained viral infection for 6 mo (∼50 generations), demonstrating that natural cycles of horizontal virus transmission were faithfully recapitulated in laboratory culture. In addition to infecting the natural C. elegans isolate, Orsay virus readily infected laboratory C. elegans mutants defective in RNAi and yielded higher levels of viral RNA and infection symptoms as compared to infection of the corresponding wild-type N2 strain. These results demonstrated a clear role for RNAi in the defense against this virus. Furthermore, different wild C. elegans isolates displayed differential susceptibility to infection by Orsay virus, thereby affording genetic approaches to defining antiviral loci. This discovery establishes a bona fide viral infection system to explore the natural ecology of nematodes, host-pathogen co-evolution, the evolution of small RNA responses, and innate antiviral mechanisms.

  20. 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.

  1. Intravenous anti-D immune globulin-induced intravascular hemolysis in Epstein-Barr virus-related thrombocytopenia.

    PubMed

    Levendoglu-Tugal, O; Jayabose, S

    2001-10-01

    RhoD immune globulin intravenous (anti-D IGIV) increases platelet counts in patients who have not undergone splenectomy and are positive for RhoD with idiopathic thrombocytopenic purpura. After treatment, in most patients, anemia develops as a result of immune-mediated red cell destruction in the spleen. Although intravascular hemolysis (IVH) is not expected, life-threatening IVH has been recently reported by the Food and Drug Administration, and physicians are encouraged to report their experience with patients with idiopathic thrombocytopenic purpura in whom IVH develops after anti-D administration. Severe IVH was observed after treatment with anti-D IGIV in two adolescent girls with acute thrombocytopenia related to Epstein-Barr virus. They did not have hemolytic anemia before treatment. The authors believe that anti-D IGIV triggered an unusual virus-induced immune response causing hemolysis; therefore, anti-D IGIV should not be used in patients with Epstein-Barr virus-related thrombocytopenia, particularly during the acute phase of infection.

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

    PubMed

    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.

  3. Characterization of Rous sarcoma virus-related sequences in the Japanese quail.

    PubMed Central

    Chambers, J A; Cywinski, A; Chen, P J; Taylor, J M

    1986-01-01

    We detected sequences related to the avian retrovirus Rous sarcoma virus within the genome of the Japanese quail, a species previously considered to be free of endogenous avian leukosis virus elements. Using low-stringency conditions of hybridization, we screened a quail genomic library for clones containing retrovirus-related information. Of five clones so selected, one, lambda Q48, contained sequence information related to the gag, pol, and env genes of Rous sarcoma virus arranged in a contiguous fashion and spanning a distance of approximately 5.8 kilobases. This organization is consistent with the presence of an endogenous retroviral element within the Japanese quail genome. Use of this element as a high-stringency probe on Southern blots of genomic digests of several quail DNA demonstrated hybridization to a series of high-molecular-weight bands. By slot hybridization to quail DNA with a cloned probe, it was deduced that there were approximately 300 copies per diploid cell. In addition, the quail element also hybridized at low stringency to the DNA of the White Leghorn chicken and at high stringency to the DNAs of several species of jungle fowl and both true and ruffed pheasants. Limited nucleotide sequencing analysis of lambda Q48 revealed homologies of 65, 52, and 46% compared with the sequence of Rous sarcoma virus strain Prague C for the endonuclease domain of pol, the pol-env junction, and the 3'-terminal region of env, respectively. Comparisons at the amino acid level were also significant, thus confirming the retrovirus relatedness of the cloned quail element. Images PMID:3016302

  4. 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

  5. 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

  6. HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis.

    PubMed

    Pineda, Juan A; Romero-Gómez, Manuel; Díaz-García, Fernando; Girón-González, José A; Montero, José L; Torre-Cisneros, Julián; Andrade, Raúl J; González-Serrano, Mercedes; Aguilar, José; Aguilar-Guisado, Manuela; Navarro, José M; Salmerón, Javier; Caballero-Granado, Francisco J; García-García, José A

    2005-04-01

    The impact of human immunodeficiency virus (HIV) coinfection on the survival of patients with hepatitis C virus (HCV)-related end-stage liver disease (ESLD) is unknown. Because HIV infection is no longer considered an absolute contraindication for liver transplantation in some countries, it has become a priority to address this topic. The objective of this study was to compare the survival of HIV-infected and HIV-uninfected patients with decompensated cirrhosis due to HCV. In a retrospective cohort study, the survival of 1,037 HCV monoinfected and 180 HCV/HIV-coinfected patients with cirrhosis after the first hepatic decompensation was analyzed. Of the group, 386 (37%) HCV-monoinfected and 100 (56%) HCV/HIV-coinfected subjects died during the follow-up. The median survival time of HIV-infected and HIV-uninfected patients was 16 and 48 months, respectively (P < .001). The relative risk (95% CI) of death for HIV-infected patients was 2.26 (1.51-3.38). Other independent predictors of survival were age older than 63 years (2.25 [1.53-3.31]); Child-Turcotte-Pugh class B versus class A (1.95 [1.41-2.68]) and class C versus class A (2.78 [1.66-4.70]); hepatitis D virus infection (1.56 [1.12-4.77]); model for end-stage liver disease score, (1.05 [1.01-1-11]); more than one simultaneous decompensation (1.23 [1.12-3.33]); and the type of the first hepatic decompensation, with a poorer prognosis associated with encephalopathy compared with portal hypertensive gastrointestinal bleeding (2.03 [1.26-3.10]). In conclusion, HIV coinfection reduces considerably the survival of patients with HCV-related ESLD independently of other markers of poor prognosis. This fact must be taken into account to establish the adequate timing of liver transplantation in HIV-coinfected subjects.

  7. 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

  8. 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

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

    SciTech Connect

    Brozik, Susan M; Manginell, Ronald P; Moorman, Matthew W; 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.

  10. 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

  11. 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

  12. Autophagy and microRNA in hepatitis B virus-related hepatocellular carcinoma

    PubMed Central

    Wu, Shan-Ying; Lan, Sheng-Hui; Liu, Hsiao-Sheng

    2016-01-01

    Approximately 350 million people worldwide are chronically infected by hepatitis B virus (HBV). HBV causes severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). In about 25% of affected patients, HBV infection proceeds to HCC. Therefore, the mechanisms by which HBV affects the host cell to promote viral replication and its pathogenesis have been the subject of intensive research efforts. Emerging evidence indicates that both autophagy and microRNAs (miRNAs) are involved in HBV replication and HBV-related hepatocarcinogenesis. In this review, we summarize how HBV induces autophagy, the role of autophagy in HBV infection, and HBV-related tumorigenesis. We further discuss the emerging roles of miRNAs in HBV infection and how HBV affects miRNAs biogenesis. The accumulating knowledge pertaining to autophagy and miRNAs in HBV replication and its pathogenesis may lead to the development of novel strategies against HBV infection and HBV-related HCC tumorigenesis. PMID:26755869

  13. Metastasis occurring eleven years after diagnosis of human papilloma virus-related oropharyngeal squamous cell carcinoma

    PubMed Central

    Ley, Jessica; Wildes, Tanya; El-Mofty, Samir; Adkins, Douglas

    2014-01-01

    Human papilloma virus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favourable prognosis, although approximately 20–25% of patients ultimately develop recurrent cancer. Most disease recurrence events appear within 3 years; however, long-term follow-up of reported studies are limited, and the risk of late recurrence is unknown. We present a case report of a patient who developed distant metastases of HPV-related SCC 11 years after initial diagnosis and treatment of HPV-related OPSCC. Late disease recurrence may occur after initial diagnosis of HPV-related OPSCC. This observation has implications on the appropriate duration of follow-up and surveillance of these patients. PMID:25435908

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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

  19. Benefits of nucleos(t)ide analog treatments for hepatitis B virus-related cirrhosis.

    PubMed

    Honda, Koichi; Seike, Masataka; Murakami, Kazunari

    2015-10-01

    Chronic hepatitis B infection induces progressive liver disease. Before nucleos(t)ide analogs (NUCs) became established as a safe and effective treatment for hepatitis B, it was difficult to suppress the activity of the hepatitis B virus (HBV). Currently, many patients with hepatitis or cirrhosis associated with HBV are treated with NUCs for an extended period of time, and the effects, benefits, and limitations of these treatments have been apparent. This article reviews HBV-related cirrhosis, its natural course and survival, histological improvement after NUC treatments, treatment effects for decompensated cirrhosis, the incidence of hepatocellular carcinoma (HCC) after NUC treatments, and the efficacy of NUC treatments before and after the treatment of patients for HBV-related HCC. Of particular interest are the histological improvements, including regression of fibrosis, that have been achieved with NUC treatments. Liver function of patients with decompensated cirrhosis has significantly improved regardless of the type of NUC applied, and treatment with NUCs has reduced the incidence of HCC in cirrhotic patients. However, cirrhosis remains the strongest risk factor for HCC occurrence following NUC treatments, and the long-term cumulative incidence of HCC after NUC treatments remains high. When recurrence does occur, it is important to reconsider the treatment modality according to the degree of improved liver function that was achieved.

  20. MicroRNAs as new biomarkers for human papilloma virus related head and neck cancers.

    PubMed

    Wang, Yuhan; Wang, Jie; Huang, Yuanshuai

    2015-01-01

    Head and neck cancers are the sixth most common cancer in the world and the predominant type of which consist of squamous cell carcinomas (head and neck squamous cell carcinoma, HNSCC). Besides tobacco smoking and alcohol consumption, human papilloma virus (HPV) infection is the third leading cause of the occurrence of HNSCC. The presence of HPV is a distinct group of head and neck cancers exhibiting epidemiological, histopathological, clinical and prognostic differences opposed to the typical HNSCC. HPV positive HNSCC normally have a favorable prognosis compared with HPV negative HNSCC, so biomarkers suitable for the early detection of HPV positive HNSCC should be developed urgently to improve patient outcomes. HPV DNA screening is sensitive, but probably not useful because of the high prevalence of oral HPV and low risk of HNSCC. MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that act as post-transcriptional regulators of gene expression. Since miRNAs have a role in the cancer development and HPV status may affect the miRNAs expression pattern in HNSCC, the specific of miRNAs' expression in HPV positive HNSCC may expound the role of HPV in HNSCC and be new biomarkers for the early detection of HNSCC. More excitingly, saliva as proximal biofluid in the context of HNSCC contains a good deal of miRNAs. These miRNAs are stabile and may be suitable for noninvasive biomarkers of HNSCC.

  1. 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

  2. Restoring homeostasis of CD4+ T cells in hepatitis-B-virus-related liver fibrosis

    PubMed Central

    Cheng, Li-Sha; Liu, Yun; Jiang, Wei

    2015-01-01

    Immune-mediated liver injury is widely seen during hepatitis B virus (HBV) infection. Unsuccessful immune clearance of HBV results in chronic hepatitis and increases the risk of liver cirrhosis and hepatocellular carcinoma. HBV-related liver fibrosis (HBVLF), occurring as a result of HBV-induced chronic hepatitis, is a reversible, intermediate stage of chronic hepatitis B (CHB) and liver cirrhosis. Therefore, defining the pathogenesis of HBVLF is of practical significance for achieving better clinical outcomes. Recently, the homeostasis of CD4+ T cells was considered to be pivotal in the process of HBVLF. To better uncover the underlying mechanisms, in this review, we systematically retrospect the impacts of different CD4+ T-cell subsets on CHB and HBVLF. We emphasize CD4+ T-cell homeostasis and the important balance between regulatory T (Treg) and T helper 17 (Th17) cells. We discuss some cytokines associated with Treg and Th17 cells such as interleukin (IL)-17, IL-22, IL-21, IL-23, IL-10, IL-35 and IL-33, as well as surface molecules such as programmed cell death protein 1, cytotoxic T lymphocyte-associated antigen 4, T cell immunoglobulin domain and mucin domain-containing molecule 3 and cannabinoid receptor 2 that have potential therapeutic implications for the homeostasis of CD4+ T cells in CHB and HBVLF. PMID:26478664

  3. 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

  4. ISG15 as a novel prognostic biomarker for hepatitis B virus-related hepatocellular carcinoma

    PubMed Central

    Qiu, Xiaoxin; Hong, Yuan; Yang, Darong; Xia, Man; Zhu, Haizhen; Li, Qinglong; Xie, Hailong; Wu, Qunfeng; Liu, Chen; Zuo, Chaohui

    2015-01-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in prevention and treatment of HCC. IFN-stimulated gene 15 (ISG15) is an ubiquitin-like molecule that is strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. Several studies have shown that the overexpression of ISG15 is correlated with multiply tumor types. However, the role of ISG15 in hepatitis B virus (HBV)-related HCC remains undetermined. ISG15 expression was found to be obviously higher in HBV-related HCC tissues than that in non-tumor tissues. ISG15 is a novel prognostic marker for predicting 5-year overall survival of HBV-related HCC patients. Overexpression of ISG15 was associated with clinicopathological characteristics and poor patient outcomes. ISG15 may serve as a novel prognostic marker for HBV-related HCC. Therefore, ISG15 may represent a novel HCC marker with prognostic significance and may be helpful in selecting patients for and predicting response to the treatment of HBV-related HCC. PMID:26770308

  5. Lamivudine versus Entecavir for Newly Diagnosed Hepatitis B Virus-Related Hepatocellular Carcinoma

    PubMed Central

    Kim, Jung Hee; Sinn, Dong Hyun; Kim, Kyunga; Kim, Hyeseung; Gwak, Geum-Youn; Paik, Yong-Han; Choi, Moon Seok; Lee, Joon Hyeok; Koh, Kwang Cheol; Paik, Seung Woon

    2016-01-01

    Background/Aims Antiviral therapy is a key component in the management of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. However, whether the potent drug entecavir is more effective than a less potent drug, such as lamivudine, in HBV-related HCC is not clear. Methods A retrospective cohort of 451 newly diagnosed, HBV-related HCC patients without antiviral therapy at diagnosis, who started antiviral therapy with either entecavir (n=249) or lamivudine (n=202), were enrolled. Results The median survival was longer for the entecavir group than for the lamivudine group, and lamivudine use (vs entecavir) was an independent factor for mortality (hazard ratio [HR], 1.49; p=0.002). Lamivudine use (vs entecavir) was an independent risk factor for new-onset hepatic decompensation (HR, 1.67; p=0.010) in 318 patients without previous hepatic decompensation, and it was also an independent risk factor for recurrence after curative therapy (HR, 1.84; p=0.002) in 117 patients who received curative therapy. The findings were similar in a propensity score-matched cohort. Conclusions Overall survival, decompensation-free survival, and recurrence-free survival were better in the entecavir-treated patients than in the lamivudine treated-patients, indicating that the potent antiviral drug should be the preferred choice in HBV-related HCC patients. PMID:27282264

  6. 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

  7. Incidental Detection of Hairy Cell Leukaemia with Herpes Simplex Virus (HSV) Related Lip Ulcer Mimicking Carcinoma.

    PubMed

    Agrawal, Pallavi; Bhartiya, Richa; Singh, Ran Vijoy Narayan

    2016-08-01

    Hairy cell leukemia is a chronic lympho-proliferative disease. It is indolent but progressive in nature. It arises from B-cell lineage. We report an incidentally detected case of Hairy Cell Leukaemia (HCL) in a 55-year-old male patient with Herpes simplex virus (HSV) - related lip ulcer mimicking squamous cell carcinoma. Clinically the patient presented with lip ulceration without pain. He was found to have moderate hepatosplenomegaly and pancytopenia on general examination. Bone marrow aspiration and flow cytometric immunophenotyping revealed HCL. The oral lesion resolved after antiviral therapy. The intriguing possibility of a combined pathogenesis for the two disorders is considered, as HCL is known to be associated with immunosuppression, second malignancies and the production of cytokines promoting epithelial growth. PMID:27656454

  8. Detection of Bovine Leukaemia Virus Antibodies and Proviral DNA in Colostrum Replacers.

    PubMed

    Choudhury, B; Finnegan, C; Phillips, A; Horigan, M; Pollard, T; Steinbach, F

    2015-10-01

    Great Britain has been bovine leukaemia virus (BLV) disease free since 1999. We recently reported three separate incidents of BLV seropositivity on farms with home-reared cattle due to the use of colostrum replacer rather than infection with BLV (Emerg. Infect. Dis., 19, 2013, 1027). These cases were all linked via the use of the same brand of colostrum replacer. Here, we investigate further by examining multiple brands of colostrum replacer for proviral DNA and BLV antibodies. BLV antibodies were detected in 7 of the colostrum replacers tested, with PCR concurring in two cases. Thus, the use of these BLV antibody-positive colostrum replacers may also lead to false-positive serological diagnostics. PMID:24268042

  9. 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.

  10. 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.

  11. Mechanism of DNA-binding enhancement by the human T-cell leukaemia virus transactivator Tax.

    PubMed

    Baranger, A M; Palmer, C R; Hamm, M K; Giebler, H A; Brauweiler, A; Nyborg, J K; Schepartz, A

    1995-08-17

    Tax protein activates transcription of the human T-cell leukaemia virus type I (HTLV-I) genome through three imperfect cyclic AMP-responsive element (CRE) target sites located within the viral promoter. Previous work has shown that Tax interacts with the bZIP element of proteins that bind the CRE target site to promote peptide dimerization, suggesting an association between Tax and bZIP coiled coil. Here we show that the site of interaction with Tax is not the coiled coil, but the basic segment. This interaction increases the stability of the GCN4 bZIP dimer by 1.7 kcal mol-1 and the DNA affinity of the dimer by 1.9 kcal mol-1. The differential effect of Tax on several bZip-DNA complexes that differ in peptide sequence or DNA conformation suggests a model for Tax action based on stabilization of a distinct DNA-bound protein structure. This model may explain how Tax interacts with transcription factors of considerable sequence diversity to alter patterns of gene expression.

  12. 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.

  13. Comparison of Clinical Characteristics and Survival after Surgery in Patients with Non-B and Non-C Hepatocellular Carcinoma and Hepatitis 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 compared clinicopathologic data and long-term clinical outcomes among patients with non-B and non-C hepatocellular carcinoma (NBNC-HCC) who underwent curative resection (group A, n=129), those with hepatitis B virus-related HCC (group B, n=62) and those with hepatitis C virus-related HCC (group C, n=284). Methods: Clinicopathologic characteristics and cumulative overall survival (OS) and recurrence-free survival (RFS) after curative resection were compared among the three groups. Results: The proportion of patients with non-liver cirrhosis (LC) or diabetes mellitus in group A was significantly higher than that in group B or group C. The mean maximum tumor size in group A was significantly larger than that of group B or group C. Cumulative 3-year OS rates after resection were 76% in group A, 79% in group B and 72% in group C (A vs. B, P=0.638; A vs. C, P=0.090; B vs. C, P=0.091; overall significance, P=0.088). The corresponding RFS rates after resection were 38% in group A, 36% in group B and 36% in group C (A vs. B, P=0.528; A vs. C, P=0.281; B vs. C, P=0.944; overall significance, P=0.557). In subgroup analyses in patients with LC, in those without LC and in those who satisfied the Milan criteria, similar results were obtained, i.e., the difference among the three groups did not reach significance in terms of OS and RFS. Conclusion: Long-term clinical outcomes in patients NBNC-HCC after curative resection were comparable to those in patients with hepatitis virus-related HCC after curative resection. PMID:23901350

  14. 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

  15. Xenotropic Murine Leukemia Virus-Related Virus and RNase L R462Q Variants in Iranian Patients With Sporadic Prostate Cancer

    PubMed Central

    Babaei, Farhad; Ahmadi, Ali; Rezaei, Farhad; Jalilvand, Somayeh; Ghavami, Nastaran; Mahmoudi, Mahmoud; Abiri, Ramin; Kondori, Nasim; Nategh, Rakhshande; Mokhtari Azad, Talat

    2015-01-01

    Background: Although several studies have confirmed the association of xenotropic murine leukemia virus-related virus (XMRV) and prostate cancer, this association is still controversial, as most studies did not detect XMRV in prostate tissue samples. Furthermore, some genetic and epidemiological studies have highlighted a role for RNase L polymorphisms, particularly R462Q, in the progression of prostate cancer. Objectives: The focus of this study was on the association of XMRV and RNase L R462Q variants with the risk of prostate cancer in Iranian patients. Patients and Methods: In this case-control study, 40 and 80 individuals with sporadic prostate cancer and benign prostatic hyperplasia, respectively, were included. The presence of XMRV was evaluated by real-time polymerase chain reaction (PCR) of integrase and nested-PCR for the gag genes. The RNase L R462Q polymorphism analysis was carried out by PCR and sequencing. Results: In a total of 40 sporadic prostate cancer and 80 benign prostatic hyperplasia cases, no XMRV was detected by real-time PCR and nested-PCR. RNase L R462Q polymorphism analysis reveals that although there was an increase in the risk of prostate cancer correlated with the Q/Q allele of RNase L at position 462, the frequencies of the RNase L R462Q alleles were not statistically significant between the prostate cancer and benign prostatic hyperplasia groups (OR = 2.75 (95% CI = 0.67 - 11.3), P = 0.29). Conclusions: These results did not support the presence of XMRV in the samples with prostate cancer and showed that RNase L R462Q variants had relatively little or no impact on the risk of prostate cancer in Iranian population. PMID:26744630

  16. 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

  17. [Successful use of danaparoid in the treatment of portal vein thrombosis that developed in a warfarin-administered hepatitis C virus-related cirrhosis patient].

    PubMed

    Nawata, Yoshitaka; Hamada, Kouichi; Tajima, Hiroko; Nishino, Noriyuki; Nakazawa, Toshihiro; Tobayashi, Kenji; Saitoh, Satoshi

    2012-08-01

    An 84-year-old woman with hepatitis C virus-related cirrhosis, hepatocellular carcinoma and atrial fibrillation, who presented with hematemesis, was initially treated with endoscopic variceal ligation (EVL) for an esophageal varix hemorrhage. However, computed tomography (CT) upon admission had revealed portal vein thrombosis, despite having received warfarin for existing atrial fibrillation. We subsequently initiated a 2-week treatment with danaparoid;warfarin being discontinued in order to reduce the risk of re-hemorrhage. A follow-up CT after treatment revealed complete reduction of the portal vein thrombosis. This is the first successful report of danaparoid use in the treatment of portal vein thrombosis that developed in a patient who had received warfarin. PMID:22863964

  18. The effect of lipopolysaccharide-induced obesity and its chronic inflammation on influenza virus-related pathology.

    PubMed

    Ahn, Sun-Young; Sohn, Sung-Hwa; Lee, Sang-Yeon; Park, Hye-Lim; Park, Yong-Wook; Kim, Hun; Nam, Jae-Hwan

    2015-11-01

    Obese individuals show increased susceptibility to infection, low vaccine efficacy, and worse pathophysiology. However, it is unclear how obesity affects these events. The aim of this study was to investigate the effect of obesity-triggered chronic inflammation on immune cells after influenza virus infection. Control and lipopolysaccharide mice, in which an osmotic pump continually released Tween saline or lipopolysaccharide, were prepared and 3 weeks later were infected with pandemic H1N1 2009 influenza A virus. In lipopolysaccharide mice, we found a reduction in macrophage activation markers in the steady state, and reduced production of pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6, in restimulated peritoneal macrophages. Interestingly, lipopolysaccharide-triggered chronic inflammation exacerbated the severity of pathological symptoms in the lungs after challenge with influenza virus. Taken together, the increased severity of virus-induced symptoms in obese individuals with chronic inflammation may be, at least partially, caused by macrophage dysfunction.

  19. Degenerate and specific PCR assays for the detection of bovine leukaemia virus and primate T cell leukaemia/lymphoma virus pol DNA and RNA: phylogenetic comparisons of amplified sequences from cattle and primates from around the world.

    PubMed

    Dube, S; Bachman, S; Spicer, T; Love, J; Choi, D; Esteban, E; Ferrer, J F; Poiesz, B J

    1997-06-01

    Degenerate and specific PCR assays were developed for bovine leukaemia virus (BLV) and/or primate T cell leukaemia/lymphoma viruses (PTLV). The degenerate assays detected all major variants of the BLV/PTLV genus at a sensitivity of 10-100 copies of input DNA; the specific systems detected 1-10 copies of input target. Sensitivity was 100% in specific DNA-PCR assays done on peripheral blood from seropositive BLV-infected cattle and HTLV-I- or HTLV-II-infected humans, and 62% in RNA/DNA-PCR assays on sera from BLV seropositive cattle. The pol fragments from 21 different BLV strains, isolated from cattle in North and Central America, were cloned and sequenced, and compared to other published BLV and PTLV pol sequences. BLV and PTLV sequences differed by 42%. Sequence divergence was up to 6% among the BLV strains, and up to 36% among the PTLV strains (with PTLV-I and PTLV-II differing among themselves by 15% and 8%, respectively). Some cows were infected with several BLV strains. Among retroviruses, BLV and PTLV sequences formed a distinct clade. The data support the interpretation that BLV and PTLV evolved from a common ancestor many millennia ago, and some considerable time before the PTLV-I and PTLV-II strains diverged from each other. The dissemination of the BLV strains studied probably resulted from the export of European cattle throughout the world over the last 500 years. The relatively similar mutation rates of BLV and PTLV, after their various points of divergence, suggest that there could be a much wider genetic range of BLV than has currently been defined.

  20. Detection of IgG antibody to bovine leukaemia virus in urine and serum by two enzyme immunoassays.

    PubMed

    Carli, K T; Sen, A; Batmaz, H; Kennerman, E

    1999-06-01

    Four hundred blood sera from a cattle production unit were tested for BLV-(Bovine Leukaemia Virus) antibody with IP (Institut Porquier) and SB (Svanova Biotech) ELISA kits. Seventy-seven cattle with BLV-antibody (19.25%) and 77 without the antibody were used. No significant difference was found between O.D. of sera of PL+ (Persistent Lymphocytosis Positive) and PL- (Negative) cattle. The mean O.D. of urine samples of 77 seropositive cattle was significantly higher than that of 77 seronegative cattle (P < 0.01). There were also differences between urine O.D.s of seropositive (PL+) and seropositive (PL-) groups of cattle with IP (P < 0.05) and SB (P < 0.01) kits. All the results revealed the presence of BLV-antibody in the urine of the cattle without any urinary dysfunction. PMID:10389255

  1. 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…

  2. Anti-viral therapy to reduce recurrence and improve survival in hepatitis B virus-related hepatocellular carcinoma

    PubMed Central

    Ishikawa, Toru

    2013-01-01

    Hepatocellular carcinoma (HCC) is the most common malignancy and the third leading cause of cancer death worldwide. Chronic infection with hepatitis B virus (HBV) and hepatitis C virus accounts for approximately 75%-80% of HCC cases worldwide. In particular, chronic HBV infection is a predominant risk factor for HCC in Asia and Africa. Hepatic resection and radiofrequency ablation are increasingly used for the curative treatment of HCC, and good local control can be achieved. However, the high rate of recurrence is a major obstacle to improving prognosis. A high viral load of HBV DNA is the most important correctable risk factor for recurrence. Furthermore, interferon and/or nucleotide analogues may decrease HBV DNA. Therefore, these drugs may decrease recurrence. In this article, treatment strategies for HBV-related HCC are described in order to reduce recurrence and improve survival. PMID:24379608

  3.  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

  4. Immune responses to Epstein-Barr virus in atomic bomb survivors: study of precursor frequency of cytotoxic lymphocytes and titer levels of anti-Epstein-Barr virus-related antibodies.

    PubMed

    Kusunoki, Y; Kyoizumi, S; Fukuda, Y; Huang, H; Saito, M; Ozaki, K; Hirai, Y; Akiyama, M

    1994-04-01

    Precursor frequencies of cytotoxic lymphocytes to autologous Epstein-Barr virus-transformed B cells and serum titers of anti-Epstein-Barr virus-related antibodies were measured in 68 atomic bomb survivors to clarify the immune mechanism controlling Epstein-Barr virus infection. The precursor frequency was negatively correlated with the titer of anti-early antigen IgG, which is probably produced at the stage of viral reactivation. A positive correlation between the precursor frequency and titer of anti-Epstein-Barr virus-associated nuclear antigen antibody was also observed, indicating that the precursor frequency reflects the degree of in vivo destruction by T cells of the virus-infected cells. These results suggest that T-cell memory specific to Epstein-Barr virus keeps the virus under control and that the precursor frequency assay is useful for the evaluation of immune responses to Epstein-Barr virus. However, no significant effect of atomic bomb radiation on the precursor frequency was observed in the present study, probably due to the limited number of participants.

  5. Immune responses to epstein-barr virus in atomic bomb survivors: Study of precursor frequency of cytotoxic lymphocytes and titer levels of anti-Epstein-Barr virus-related antibodies

    SciTech Connect

    Kusunoki, Yoichiro; Kyoizumi, Seishi; Saito, Mayumi; Ozaki, Kyoko; Hirai, Yuko; Akiyama, Mitoshi ); Fukuda, Yasuko Children's Hospital Medical Center of Northern California, Oakland, CA ); Huang, Hua Univ. of Wisconsin, Madison, WI )

    1994-04-01

    Precursor frequencies of cytotoxic lymphocytes to autologous Epstein-Barr virus-transformed B cells and serum titers of anti-Epstein-Barr virus-related antibodies were measured in 68 atomic bomb survivors to clarify the immune mechanism controlling Epstein-Barr virus infection. The precursor frequency was negatively correlated with the titer of anti-early antigen lgG, which is probably produced at the stage of viral reactivation. A positive correlation between the precursor frequency and titer of anti-Epstein-Barr virus-associated nuclear antigen antibody was also observed, indicating that the precursor frequency reflects the degree of in vivo destruction by T cells of the virus-infected cells. These results suggest that T-cell memory specific to Epstein-Barr virus keeps the virus under control and that the precursor frequency assay is useful for the evaluation of immune responses to Epstein-Barr virus. However, no significant effect of atomic bomb radiation on the precursor frequency was observed in the present study, probably due to the limited number of participants. 24 refs., 4 figs., 2 tabs.

  6. Genital ulcers associated with human immunodeficiency virus-related immunosuppression in female sex workers in Abidjan, Ivory Coast.

    PubMed

    Ghys, P D; Diallo, M O; Ettiègne-Traoré, V; Yeboué, K M; Gnaoré, E; Lorougnon, F; Kalé, K; Van Dyck, E; Brettegaard, K; Hoyi, Y M

    1995-11-01

    A cross-sectional study among female sex workers in Abidjan was conducted to study the association between sexually transmitted diseases and human immunodeficiency virus (HIV) infection and HIV-related immunosuppression. Among 1209 women tested for HIV, 962 (80%) were seropositive. HIV infection was independently associated with a longer duration of sex work, a lower price for intercourse, being an immigrant, and having a positive Treponema pallidum hemagglutination test (P < .05). Genital ulcers (25% vs. 5%), genital warts (14% vs. 4%), Neisseria gonorrhoeae (32% vs. 16%), Trichomonas vaginalis (27% vs. 17%), and syphilis (27% vs. 17%) were more frequent (P < .05) in HIV-infected than -uninfected women. Among HIV-infected women, the proportions with a genital ulcer were 17%, 25%, and 36% for those with > 28%, 14%-28%, and < 14% CD4 cells, respectively (P < .001). This study suggests that genital ulcers are an opportunistic disease in female sex workers in Abidjan.

  7. 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

  8. 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.

  9. 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

  10. 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

  11. Impact of delayed diagnosis time in estimating progression rates to hepatitis C virus-related cirrhosis and death.

    PubMed

    Fu, Bo; Wang, Wenbin; Shi, Xin

    2015-12-01

    Delay of the diagnosis of hepatitis C virus (HCV), and its treatment to avert cirrhosis, is often present sincethe early stage of HCV progression is latent. Current methods to determine the incubation time to HCV-related cirrhosis and the duration time from cirrhosis to subsequent events (e.g. complications or death) used to be based on the time of liver biopsy diagnosis and ignore this delay which led to an interval censoring for the first event time and a double censoring for the subsequent event time. To investigate the impact of this delay in estimating HCV progression rates and relevant estimating bias, we present a correlated two-stage progression model for delayed diagnosis time and fit the developed model to the previously studied hepatitis C cohort data from Edinburgh. Our analysis shows that taking the delayed diagnosis into account gives a mildly different estimate of progression rate to cirrhosis and significantly lower estimated progression rate to HCV-related death in comparison with conventional modelling. We also find that when the delay increases, the bias in estimating progression increases significantly.

  12. 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

  13. 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

  14. Non-human Immunodeficiency Virus-related Ocular Syphilis in a Korean Population: Clinical Manifestations and Treatment Outcomes

    PubMed Central

    Kim, Yonguk; Kwak, Hyung Woo

    2016-01-01

    Purpose To describe the clinical manifestations and treatment outcomes of ocular syphilis in patients without human immunodeficiency virus (HIV) infection. Methods A total of 45 eyes from 39 patients with ocular syphilis confirmed by serologic tests were reviewed retrospectively. The included cases were all non-HIV-infected patients presenting with intraocular inflammation from 2002 to 2014 at Kyung Hee University Hospital. Medical records of 45 eyes were analyzed and included best-corrected visual acuity and ophthalmologic examination findings of the anterior and posterior segments to determine the focus of inflammation. Optical coherence tomography and fluorescein angiography findings as well as both medical and surgical management were also analyzed. Results The mean patient age was 61.0 years (range, 37 to 89 years). Bilateral ocular involvement occurred in 6 patients (15.4%), and diagnoses at presentation were most frequently related to posterior uveitis (38%), followed by panuveitis (29%) and optic neuritis (11%). Isolated interstitial keratitis and intermediate uveitis were uncommon (4%, both). Twenty-eight eyes (62.2%) were treated with penicillin, and 11 eyes (24.4%) underwent surgical treatment. The mean baseline best corrected visual acuity was 0.79 ± 0.59 (mean ± standard deviation, logarithm of the minimum angle of resolution) and significantly improved to 0.60 ± 0.63 at the final follow-up after treatment (p = 0.019). Mean visual improvement was significantly greater in the penicillin-treated group (p = 0.001). Visual impairment at the final visit occurred in 11 eyes (24.4%). Among the visual impairment group, 10 eyes (90.1%) had posterior segment-involving uveitis. Conclusions Visual outcomes of treated, non-HIV-related ocular syphilis were favorable regardless of time to presentation. Posterior segment-involving uveitis at presentation was associated with poor visual outcome. PMID:27729756

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. til-1: a novel proviral insertion locus for Moloney murine leukaemia virus in lymphomas of CD2-myc transgenic mice.

    PubMed

    Stewart, M; Terry, A; O'Hara, M; Cameron, E; Onions, D; Neil, J C

    1996-03-01

    Moloney murine leukaemia virus (MoMLV) markedly accelerates thymic lymphoma development in mice carrying a transgene in which the human c-myc gene is linked to the CD2 locus control region. To investigate the mechanism of synergy and identify the genes which collaborate with myc in these clonal tumours, we analysed the sites of MoMLV insertion. Analysis of known viral integration loci revealed only a small number of insertions at bmi-1, pim-1 and ahi-1. Further cloning and hybridization analysis revealed a new common integration locus, designated til-1, which was occupied in 25 out of 77 lymphomas examined, with evidence of multiple clonal insertions in some cases. Mapping relative to established chromosomal markers in interspecific backcross mice located til-1 to mouse chromosome 17, distal to pim-1 and tic-1. These results suggest that the til-1 locus may harbour a novel myc-collaborating gene which acts as a target for activation in T cell lymphomas. PMID:8601779

  4. 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

  5. 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

  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.

  7. A survey of human T-cell leukaemia virus type I antibodies in patients with malignant disease in the Witwatersrand area.

    PubMed

    Dansey, R D; Mansoor, N; Cohn, R J; MacDougall, L G; Bezwoda, W R

    1986-10-11

    The prevalence of antibodies to human T-cell leukaemia virus type I in Africa ranges from 2% to 21% according to the geographical area surveyed. Most studies suggest that the background infection rate in children is low. In paediatric patients with malignant disease in the Witwatersrand area the prevalence is low (1%), whereas a seemingly high rate is found in healthy black children from a restricted rural area (7%). Further, the antibody prevalence in adult whites with lymphoproliferative disease is low (1%) compared with that in blacks with malignant disease (6%). There also appears to be a higher prevalence of positive results in black women (7%) than in black men (4%).

  8. The N-Terminus of Murine Leukaemia Virus p12 Protein Is Required for Mature Core Stability

    PubMed Central

    Wight, Darren J.; Boucherit, Virginie C.; Wanaguru, Madushi; Elis, Efrat; Hirst, Elizabeth M. A.; Li, Wilson; Ehrlich, Marcelo; Bacharach, Eran; Bishop, Kate N.

    2014-01-01

    The murine leukaemia virus (MLV) gag gene encodes a small protein called p12 that is essential for the early steps of viral replication. The N- and C-terminal regions of p12 are sequentially acting domains, both required for p12 function. Defects in the C-terminal domain can be overcome by introducing a chromatin binding motif into the protein. However, the function of the N-terminal domain remains unknown. Here, we undertook a detailed analysis of the effects of p12 mutation on incoming viral cores. We found that both reverse transcription complexes and isolated mature cores from N-terminal p12 mutants have altered capsid complexes compared to wild type virions. Electron microscopy revealed that mature N-terminal p12 mutant cores have different morphologies, although immature cores appear normal. Moreover, in immunofluorescent studies, both p12 and capsid proteins were lost rapidly from N-terminal p12 mutant viral cores after entry into target cells. Importantly, we determined that p12 binds directly to the MLV capsid lattice. However, we could not detect binding of an N-terminally altered p12 to capsid. Altogether, our data imply that p12 stabilises the mature MLV core, preventing premature loss of capsid, and that this is mediated by direct binding of p12 to the capsid shell. In this manner, p12 is also retained in the pre-integration complex where it facilitates tethering to mitotic chromosomes. These data also explain our previous observations that modifications to the N-terminus of p12 alter the ability of particles to abrogate restriction by TRIM5alpha and Fv1, factors that recognise viral capsid lattices. PMID:25356837

  9. A Subclone of HuH-7 with Enhanced Intracellular Hepatitis C Virus Production and Evasion of Virus Related-Cell Cycle Arrest

    PubMed Central

    Murayama, Asako; Sugiyama, Nao; Yoshimura, Seiko; Ishihara-Sugano, Mitsuko; Masaki, Takahiro; Kim, Sulyi; Wakita, Takaji; Mishiro, Shunji; Kato, Takanobu

    2012-01-01

    Hepatitis C virus (HCV) cell culture system with JFH-1 strain and HuH-7 cells enabled us to produce infectious HCV particles in vitro, and such system is useful to explore the anti-HCV compounds and to develop the vaccine against HCV. In the present study, we describe the derivation of a cell line that permits improved production of HCV particles. Specifically, we characterized several subclones that were isolated from the original HuH-7 cell line by limiting dilution. These HuH-7 subclones displayed a notable range of HCV production levels following transfection by full-genome JFH-1 RNA. Among these subclones, HuH-7T1 produced HCV more efficiently than other subclones and Huh-7.5.1 that is known to be highly permissive for HCV replication. Upon transfection with full-genome RNA, HCV production was increased ten-fold in HuH-7T1 compared to Huh-7.5.1. This increase in viral production correlated with increased efficiency of intracellular infectious virus production. Furthermore, HCV replication did not induce cell cycle arrest in HuH-7T1, whereas it did in Huh-7.5.1. Consequently, the use of HuH-7T1 as host cells could provide increased population of HCV-positive cells and elevated viral titer. In conclusion, we isolated a HuH-7 subclone, HuH-7T1, that supports efficient HCV production. High efficiency of intracellular infectious virus production and evasion of cell cycle arrest were important for this phenotype. We expect that the use of this cell line will facilitate analysis of the underlying mechanisms for HCV particle assembly and the cell cycle arrest caused by HCV. PMID:23285155

  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

    Satterfield, Brent C; Garcia, Rebecca A; Jia, Hongwei; Tang, Shaohua; Zheng, Haoqiang; Switzer, William M

    2011-02-22

    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.

  11. 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

  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. 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

  14. 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

  15. Liver Fibrosis, Host Genetic and Hepatitis C Virus Related Parameters as Predictive Factors of Response to Therapy against Hepatitis C Virus in HIV/HCV Coinfected Patients

    PubMed Central

    Corchado, Sara; López-Cortés, Luis F.; Rivero-Juárez, Antonio; Torres-Cornejo, Almudena; Rivero, Antonio; Márquez-Coello, Mercedes; Girón-González, José-Antonio

    2014-01-01

    Objective To establish the role of liver fibrosis as a predictive tool of response to pegylated interferon alpha (Peg-IFN) and ribavirin (RBV) treatment in human immunodeficiency (HIV)/hepatitis C virus (HCV) coinfected patients, in addition to recognized predictive factors (HCV load, HCV genotype, IL-28B polymorphism). Patients and Methods A sample of 267 HIV/HCV coinfected patients was treated with Peg-IFN and RBV. Predictive factors of rapid (RVR) and sustained (SVR) virological response were analyzed. Independent variables were age, sex, IL28B, −238 TNF-α and −592 IL-10 polymorphisms, HCV genotype, HCV-RNA levels, significant fibrosis or cirrhosis and CD4+ T cell count. Results Patients infected by HCV genotype 1 (n = 187) showed RVR and SVR in 12% and 39% of cases, respectively. The parameters associated with RVR were IL28B genotype CC and plasma HCV-RNA levels <600000 IU/ml. Advanced liver fibrosis was negatively associated with SVR in patients without RVR. A SVR was obtained in 42% of subjects with HCV genotype 4, and the independent factors associated with SVR were IL28B genotype CC and an HCV-RNA <600000 IU/ml. A SVR was obtained in 66% of patients with HCV genotypes 2/3; in this case, the independent parameter associated with SVR was the absence of significant liver fibrosis. TNF-α and IL-10 polymorphisms were not associated with SVR, although a significantly higher percentage of −238 TNF-α genotype GG was detected in patients with significant liver fibrosis. Conclusions In HIV/HCV coinfected patients with HCV genotypes 1 or 4, RVR, mainly influenced by genotype IL28B and HCV-RNA levels, reliably predicted SVR after 4 weeks of therapy with Peg-IFN plus RBV. In patients infected by HCV genotype 3, an elevated relapse rate compromised the influence of RVR on SVR. Relapses were related to the presence of advanced liver fibrosis. Liver cirrhosis was associated with a −238 TNF-α polymorphism in these patients. PMID:25013899

  16. 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

  17. Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells

    PubMed Central

    Tomita, Mariko; Semenza, Gregg L.; Michiels, Canine; Matsuda, Takehiro; Uchihara, Jun-Nosuke; Okudaira, Taeko; Tanaka, Yuetsu; Taira, Naoya; Ohshiro, Kazuiku; Mori, Naoki

    2007-01-01

    HTLV-1 (human T-cell leukaemia virus type 1) is the causative agent for ATL (adult T-cell leukaemia). HTLV-1 Tax can activate the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway, which is responsible for survival of HTLV-1-infected T-cells. HIFs (hypoxia-inducible factors) are transcriptional regulators that play a central role in the response to hypoxia. Overexpression of HIF-1α in many cancers is associated with a poor response to treatment and increased patient mortality. Our objectives in the present study were to investigate whether HIF-1 was activated in HTLV-1-infected T-cells and to elucidate the molecular mechanisms of HIF-1 activation by focusing on the PI3K/Akt signalling pathway. We detected a potent pathway that activated HIF-1 in the HTLV-1-infected T-cells under a normal oxygen concentration. Enhanced HIF-1α protein expression and HIF-1 DNA-binding activity were exhibited in HTLV-1-infected T-cell lines. Knockdown of HIF-1α by siRNA (small interfering RNA) suppressed the growth and VEGF (vascular endothelial growth factor) expression of the HTLV-1-infected T-cell line. HIF-1 protein accumulation and transcriptional activity were enhanced by Tax, which was inhibited by dominant-negative Akt. Importantly, mutant forms of Tax that are defective in activation of the PI3K/Akt pathway failed to induce HIF-1 transcriptional activity. The PI3K inhibitor LY294002 suppressed HIF-1α protein expression, HIF-1 DNA-binding and HIF-1 transcriptional activity in HTLV-1-infected T-cell lines. In primary ATL cells, HIF-1α protein levels were strongly correlated with levels of phosphorylated Akt. The results of the present study suggest that PI3K/Akt activation induced by Tax leads to activation of HIF-1. As HIF-1 plays a major role in tumour progression, it may represent a molecular target for the development of novel ATL therapeutics. PMID:17576198

  18. 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

  19. Seroprevalence of human T cell leukaemia/lymphoma virus type I (HTLV-I) in pregnant women, patients attending venereological outpatient services and intravenous drug users from Slovenia.

    PubMed

    Poljak, M; Bednarik, J; Rednak, K; Seme, K; Kristancic, L; Celan-Lucu, B

    1998-01-01

    To establish current seroprevalence of human T cell leukaemia/lymphoma virus type I (HTLV-I) infection in some low- and high-risk populations from Slovenia, 10,369 and 869 serum samples collected during Slovenian 1994 unlinked surveys of human immunodeficiency viruses seroprevalence in pregnant women and patients attending venereological outpatient services, respectively, and 219 serum samples collected from Slovenian intravenous drug abusers during 1995 and 1996, were screened for the presence of anti-HTLV-I antibodies using commercial particle agglutination test Serodia HTLV-I (Fujirebio, Tokyo, Japan). Only one sample obtained from a pregnant woman was found repeatedly positive in the screening test. Presence of anti-HTLV-I antibodies in the reactive sample was undoubtedly confirmed with supplemental Western blot test. The prevalence of antibodies to HTLV-I in the Slovenian population might be somewhere between one in 10,000 (0.01%) and one in 15,000 (0.0066%), which is similar or even higher to prevalence rates in other European countries.

  20. 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

  1. An 8-year longitudinal sero-epidemiological study of bovine leukaemia virus (BLV) infection in dairy cattle in Turkey and analysis of risk factors associated with BLV seropositivity.

    PubMed

    Şevik, Murat; Avcı, Oğuzhan; İnce, Ömer Barış

    2015-04-01

    Enzootic bovine leukosis (EBL) which is caused by bovine leukaemia virus (BLV) has an important economic impact on dairy herds due to reduced milk production and restrictions on livestock exports. This study was conducted to determine the BLV infection status in Central Anatolia Region of Turkey, an important milk production centre, and to examine the risk factors such as purchasing cattle, increasing cattle age, cattle breed and herd size associated with transmission of BLV infection. To estimate the rate of BLV infection, a survey for specific antibodies in 28,982 serum samples from animals belonging to 1116 different herds situated in Central Anatolia Region of Turkey were tested from January 2006 to December 2013. A generalized mixed linear model was used to evaluate the risk factors that influenced BLV seroprevalence. Antibodies against BLV were detected in 431 (2.28 %) of 18,822 Holstein and 29 (0.28 %) of 10,160 Brown Swiss cows. Among 1116 herds, 132 herds (11.82 %) had one or more positive animals. Also results of our study show that the prevalence of BLV infection increased from 2006 to 2011, and it tends to reduce with BLV control programme. Furthermore, we found positive associations between percentage of seropositive animal and increasing cattle age, herd size, cattle breed and purchased cattle. Age-specific prevalence showed that BLV prevalence increased with age. These factors should be taken into consideration for control of BLV infection.

  2. 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

  3. Correlation of serum hepcidin levels with disease progression in hepatitis B virus-related disease assessed by nanopore film based assay

    PubMed Central

    Wang, Jing; Dong, Ailian; Liu, Gang; Anderson, Gregory J.; Hu, Tony Y.; Shi, Jian; Hu, Yulin; Nie, Guangjun

    2016-01-01

    Chronic hepatitis B virus (HBV) infection often develop into cirrhosis, and both are major risk factors of hepatocellular carcinoma. However, effective approaches for the monitoring of HBV-related disease progress are still in need. Increased iron storage has an important role in HBV-related diseases. Hepcidin is a key regulator of iron homeostasis whose expression changes are often indicative of abnormal iron metabolism. There are few reports of hepcidin levels in patients with HBV infections, and the available results are inconsistent. In this study, using a recently validated nanopore silica film based method, we measured serum hepcidin levels in 46 HBV-related patients and 20 healthy controls. Patients were divided into three groups: chronic hepatitis B without cirrhosis; HBV-related cirrhosis; and HBV-related cirrhosis with hepatocellular carcinoma. Compared to healthy controls, the mean serum hepcidin level was significantly higher in CHB patients without cirrhosis, and in those with hepatocellular carcinoma, but not in those with cirrhosis. Iron-loading, viral infection and liver dysfunction are determined to be the major regulators of hepcidin in these patients. These observations suggest correlations between serum hepcidin and progression of chronic HBV infection, and may shed a new light on the development of biomarkers for HBV-related disease surveillance. PMID:27694815

  4. Frequent disruption of the Nf1 gene by a novel murine AIDS virus-related provirus in BXH-2 murine myeloid lymphomas.

    PubMed Central

    Cho, B C; Shaughnessy, J D; Largaespada, D A; Bedigian, H G; Buchberg, A M; Jenkins, N A; Copeland, N G

    1995-01-01

    Evi-2, a common site of viral integration in BXH-2 myeloid lymphomas, is located within a large intron of the Nf1 tumor suppressor gene. Viral integration at Evi-2 appears to induce disease by disrupting normal Nf1 expression. During our attempts to characterize the nature of the proviruses located at Evi-2, we found that approximately half of the proviruses were defective nonecotropic proviruses (A. M. Buchberg, H. G. Bedigian, N. A. Jenkins, and N. G. Copeland, Mol. Cell. Biol. 10:4658-4666, 1990). This was surprising, since most proviruses characterized at other BXH-2 common integration sites are full-length ecotropic viruses. In the studies described here, we found that this defective provirus carries two large deletions, one in pol and one in env, and is structurally related to another murine retrovirus, the murine AIDS retrovirus. By using oligonucleotide probes specific for this defective provirus, designated MRV, we showed that MRV-related proviruses are carried as endogenous germ line proviruses in most inbred strains. In addition, we identified the endogenous MRV provirus that gives rise to the defective proviruses identified at Evi-2. We present a model that accounts for the positive selection of MRV proviruses at Evi-2, which may allow selective identification of common viral integration sites harboring tumor suppressor genes. PMID:7474134

  5. 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.

  6. Human T cell leukaemia virus type 2 tax protein mediates CC-chemokine expression in peripheral blood mononuclear cells via the nuclear factor kappa B canonical pathway.

    PubMed

    Barrios, C S; Castillo, L; Zhi, H; Giam, C-Z; Beilke, M A

    2014-01-01

    Retroviral co-infections with human immunodeficiency virus type-1 (HIV-1) and human T cell leukaemia virus type 1 (HTLV-1) or type 2 (HTLV-2) are prevalent in many areas worldwide. It has been observed that HIV-1/HTLV-2 co-infections are associated with slower rates of CD4(+) T cell decline and delayed progression to AIDS. This immunological benefit has been linked to the ability of Tax2, the transcriptional activating protein of HTLV-2, to induce the expression of macrophage inflammatory protein (MIP)-1α/CCL3, MIP-1β/CCL4 and regulated upon activation normal T cell expressed and secreted (RANTES)/CCL5 and to down-regulate the expression of the CCR5 co-receptor in peripheral blood mononuclear cells (PBMCs). This study aimed to assess the role of Tax2-mediated activation of the nuclear factor kappa B (NF-κB) signalling pathway on the production of the anti-viral CC-chemokines MIP-1α, MIP-1β and RANTES. Recombinant Tax1 and Tax2 proteins, or proteins expressed via adenoviral vectors used to infect cells, were tested for their ability to activate the NF-κB pathway in cultured PBMCs in the presence or absence of NF-κB pathway inhibitors. Results showed a significant release of MIP-1α, MIP-1β and RANTES by PBMCs after the activation of p65/RelA and p50. The secretion of these CC-chemokines was significantly reduced (P < 0·05) by canonical NF-κB signalling inhibitors. In conclusion, Tax2 protein may promote innate anti-viral immune responses through the activation of the canonical NF-κB pathway.

  7. 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

  8. Genetic polymorphisms of immune checkpoint proteins PD-1 and TIM-3 are associated with survival of patients with hepatitis B virus-related hepatocellular carcinoma

    PubMed Central

    Li, Zhu; Li, Na; Li, Fang; Zhou, Zhihua; Sang, Jiao; Jin, Zhao; Liu, Huihui; Han, Qunying; Lv, Yi; Liu, Zhengwen

    2016-01-01

    Programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule 3 (TIM-3) are involved in hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study examined the associations of PD1 and TIM3 polymorphisms with the overall survival (OS) of a prospective cohort of 258 HBV-related HCC patients. Results showed that PD1 +8669 G allele-containing genotypes or TIM3 −1516 genotype GG were significantly associated with longer OS (P < 0.001 and P = 0.001, respectively). In multivariate analysis, PD1 +8669 G allele-containing genotypes and TIM3 −1516 genotype GG were independently associated with longer OS (hazard ratio (HR), 1.835; 95% confidence interval (CI), 1.342–2.509; P < 0.001 and HR, 2.070; 95%CI, 1.428–3.002; P < 0.001, respectively). PD1 +8669 G allele-containing genotypes were significantly associated with longer OS in patients receiving surgical (resection or radiofrequency) treatment, transcatheter arterial chemoembolization (TACE) or supportive and symptomatic treatment. TIM3 −1516 genotype GG was significantly associated with longer OS in TACE patients. In multivariate analysis, PD1 +8669 G allele-containing genotypes were independently associated with longer OS in each treatment population. TIM3 −1516 genotype GG was independently associated with longer OS in patients receiving surgical treatment or TACE. These findings suggest that PD1 +8669 A/G and TIM3 −1516 G/T polymorphisms may affect the prognosis of HBV-related HCC and may be new predictors of prognosis for HCC patients. PMID:27034168

  9. 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

  10. Association of Proton Pump Inhibitor Therapy with Hepatic Encephalopathy in Hepatitis B Virus-related Acute-on-Chronic Liver Failure

    PubMed Central

    Lin, Zhao-Ni; Zuo, Yong-Qing; Hu, Peng

    2014-01-01

    Background: Hepatic encephalopathy (HE) is an important neuropsychiatry complication of acute-on-chronic liver failure (ACLF). PPI therapy may increase the intestinal bacterial overgrowth and infections. Objectives: The aim of this study was to assess whether PPI use in ACLF is associated with HE. Patients and Methods: A retrospective case-control study was performed. Fifty five admitted patients with hepatitis B virus (HBV)-related ACLF complicated by Stage II-IV HE developed after admission between January 2008 and December 2012 were matched (by sex, age, and MELD score) with comparable HBV-related ACLF patients (n = 110) who did not develop this complication during hospitalization. We excluded combined HE upon admission and other neurological disorders in patients with ACLF. Univariate and multivariate analyses of 30 variables (laboratory examination, predisposition, treatment, etc.) before the occurrence of HE were carried out to identify the factors predictive of HE. Results: In univariate analysis, patients with HE in ACLF had a significantly higher rate of PPI use (89.1%) compared with non-HE (63.6%, P = 0.001). In addition, clinical and standard laboratory variables were significantly different between the two groups regarding the infection rate, hyponatremia, alpha-fetoprotein (AFP), Arginine Hydrochloride use and Lactulose use. Logistic regression analysis was used to examine the combined effects of the variables with HE as the outcome. HE in ACLF was associated with hyponatremia (odds ratio (OR) = 6. 318, 95% confidence interval (CI) = 2. 803-14.241; P = 0. 000), PPI use was independently associated with HE (OR = 4. 392, CI = 1. 604-12.031; P = 0. 004), and lactulose use was protective (OR = 0. 294, CI = 0. 136-0.675; P = 0. 003). Conclusions: The occurrence of HE is associated with hyponatremia and PPI use in patients with ACLF. PMID:24748895

  11. Impact of Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein in Patients with Hepatitis C Virus-Related Compensated Liver Cirrhosis

    PubMed Central

    Hasegawa, Kunihiro; Takata, Ryo; Nishikawa, Hiroki; Enomoto, Hirayuki; Ishii, Akio; Iwata, Yoshinori; Miyamoto, Yuho; Ishii, Noriko; Yuri, Yukihisa; Nakano, Chikage; Nishimura, Takashi; Yoh, Kazunori; Aizawa, Nobuhiro; Sakai, Yoshiyuki; Ikeda, Naoto; Takashima, Tomoyuki; Iijima, Hiroko; Nishiguchi, Shuhei

    2016-01-01

    We aimed to examine the effect of Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP) level on survival comparing with other laboratory liver fibrosis markers in hepatitis C virus (HCV)-related compensated liver cirrhosis (LC) (n = 165). For assessing prognostic performance of continuous fibrosis markers, we adapted time-dependent receiver operating characteristics (ROC) curves for clinical outcome. In time-dependent ROC analysis, annual area under the ROCs (AUROCs) were plotted. We also calculated the total sum of AUROCs in all time-points (TAAT score) in each fibrosis marker. WFA+-M2BP value ranged from 0.66 cutoff index (COI) to 19.95 COI (median value, 5.29 COI). Using ROC analysis for survival, the optimal cutoff point for WFA+-M2BP was 6.15 COI (AUROC = 0.79348, sensitivity = 80.0%, specificity = 74.78%). The cumulative five-year survival rate in patients with WFA+-M2BP ≥ 6.15 COI (n = 69) was 43.99%, while that in patients with WFA+-M2BP < 6.15 COI (n = 96) was 88.40% (p < 0.0001). In the multivariate analysis, absence of hepatocellular carcinoma (p = 0.0008), WFA+-M2BP < 6.15 COI (p = 0.0132), achievement of sustained virological response (p < 0.0001) and des-γ-carboxy prothrombin < 41 mAU/mL (p = 0.0018) were significant favorable predictors linked to survival. In time-dependent ROC analysis in all cases, WFA+-M2BP had the highest TAAT score among liver fibrosis markers. In conclusion, WFA+-M2BP can be a useful predictor in HCV-related compensated LC. PMID:27626413

  12. 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

  13. 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.

  14. 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

  15. 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

  16. 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

  17. Neonatal leukaemia cutis.

    PubMed

    Handler, M Z; Schwartz, R A

    2015-10-01

    Neonatal leukaemia cutis is a significant neoplasm that may represent a cutaneous manifestation of systemic leukaemia, usually of myeloblastic type. Rarely, it may be or appear to be limited to skin, in which case it is called neonatal aleukaemic leukaemia cutis. By definition, it presents within the first 4 weeks of life and often has a 'blueberry muffin baby' appearance of magenta coloured nodules affecting almost any area of the skin, usually sparing mucous membranes, palms and soles. This clinical pattern is more commonly associated with neonatal infections such rubella and toxoplasmosis, and may be evident with other neonatal neoplasms such as neuroblastoma. Due to the morbidity associated with chemotherapy and reported cases of spontaneous remission without systemic progression in those with neonatal aleukaemic leukaemia cutis without 11q23 translocation, the authors not treating the child with chemotherapy, but to simply monitor for fading of the violaceous nodules, and watch for possible signs of systemic leukaemia.

  18. Interleukin-1 alpha produced by human T-cell leukaemia virus type I-infected T cells induces intercellular adhesion molecule-1 expression on lung epithelial cells.

    PubMed

    Nakayama, Yuko; Ishikawa, Chie; Tamaki, Kazumi; Senba, Masachika; Fujita, Jiro; Mori, Naoki

    2011-12-01

    The pathogenic mechanism of human T-cell leukaemia virus type I (HTLV-I)-related pulmonary disease, which involves overexpression of intercellular adhesion molecule-1 (ICAM-1) in lung epithelial cells, was investigated. The supernatant of HTLV-I-infected Tax(+) MT-2 and C5/MJ cells induced ICAM-1 expression on A549 cells, a human tumour cell line with the properties of alveolar epithelial cells. Neutralization of ICAM-1 partially inhibited HTLV-I-infected T-cell adhesion to A549 cells. Analysis of the ICAM-1 promoter showed that the nuclear factor-kappa B-binding site was important for supernatant-induced ICAM-1 expression. Induction of interleukin (IL)-1 alpha (IL-1α) expression in MT-2 and C5/MJ cells was observed compared with uninfected controls and HTLV-I-infected Tax-negative cell lines. The significance of IL-1α as a soluble messenger was supported by blocking the biological activities of MT-2 supernatant with an IL-1α-neutralizing mAb. Moreover, Tax and IL-1α expression was demonstrated in the bronchoalveolar lavage cells of patients with HTLV-I-related pulmonary disease. Immunohistochemistry confirmed ICAM-1 and IL-1α expression in lung epithelial cells and lymphocytes of patients with HTLV-I-related pulmonary diseases, and in a transgenic mouse model of Tax expression. These results suggest that IL-1α produced by HTLV-I-infected Tax(+) T cells is crucial for ICAM-1 expression in lung epithelial cells and subsequent adhesion of lymphocytes in HTLV-I-related pulmonary diseases.

  19. 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

  20. 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

  1. 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

  2. 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

  3. [Vaccination of chickenpox in children with acute lymphoblastic leukaemia].

    PubMed

    Navajas, A; Astigarraga, I; Fernández-Teijeiro, A; Aga, M; Redondo, M L; Roig, A; Corral, J

    1999-04-01

    Varicella vaccine has shown its efficacy to prevent the disease and complications in healthy and immunodeficient children. In this article the authors evaluate the immunologic status of acute lymphoblastic leukaemia at diagnosis and at follow up and the development of chickenpox and/or herpes zoster. Children with negative serology and continuous complete remission of acute lymphoblastic leukaemia for one year were vaccinated. Of 71 children diagnosed of acute lymphoblastic leukaemia from 1983 to 1996, 25 received the vaccine and seroconversion was obtained in 76% after one dose and 92% after the second dose. Vaccine tolerance was adequate. The incidence of herpes zoster infection was decreased in vaccinated children during chemotherapy compared to the wild-virus infected ones. Nowadays that vaccine for healthy children is recommended, we consider a priority to protect from chickenpox the children affected by leukaemia that are in continuous complete remission of the disease.

  4. No evidence for infection of UK prostate cancer patients with XMRV, BK virus, Trichomonas vaginalis or human papilloma viruses.

    PubMed

    Groom, Harriet C T; Warren, Anne Y; Neal, David E; Bishop, Kate N

    2012-01-01

    The prevalence of specific infections in UK prostate cancer patients was investigated. Serum from 84 patients and 62 controls was tested for neutralisation of xenotropic murine leukaemia virus-related virus (XMRV) Envelope. No reactivity was found in the patient samples. In addition, a further 100 prostate DNA samples were tested for XMRV, BK virus, Trichomonas vaginalis and human papilloma viruses by nucleic acid detection techniques. Despite demonstrating DNA integrity and assay sensitivity, we failed to detect the presence of any of these agents in DNA samples, bar one sample that was weakly positive for HPV16. Therefore we conclude that these infections are absent in this typical cohort of men with prostate cancer.

  5. Bovine leukaemia: facts and hypotheses derived from the study of an infectious cancer.

    PubMed

    Burny, A; Cleuter, Y; Kettmann, R; Mammerickx, M; Marbaix, G; Portetelle, D; van den Broeke, A; Willems, L; Thomas, R

    1988-07-01

    Bovine leukaemia virus (BLV) is the etiological agent of chronic lymphatic leukaemia/lymphoma in cows, sheep and goats. Infection without neoplastic transformation was also obtained in pigs, rhesus monkeys, chimpanzees, rabbits and observed in capybaras and water-buffaloes. Structurally and functionally, BLV is a relative of human T lymphotropic viruses 1 and 2 (HTLV-I and HTLV-II) In humans, HTLV-I induces a T-cell leukaemia and its type 2 counterpart has been found in dermatopathic lymphadenopathy, hairy T-cell leukaemia and prolymphocytic leukaemia cases. At variance with HTLV-I, BLV has not been associated with neurological diseases of the degenerative type. Bovine leukaemia virus, HTLV-I and HTLV-II show clearcut sequence homologies. The pathology of the BLV-induced disease, most notably the absence of chronic viraemia, a long latency period and lack of preferred proviral integration sites in tumours, is similar to that of adult T-cell leukaemia/lymphoma induced by HTLV-I. The most striking feature of these three naturally transmitted leukaemia viruses is the X region located between the env gene and the long terminal repeat (LTR) sequence. The X region contains several overlapping long open reading frames. One of them, designated XBL-I, encodes a trans-activator function capable of increasing the level of gene expression directed by BLV-LTR and most probably is involved in "genetic instability" of BLV-infected cells of the B cell lineage. The "genetic instability" renders the infected cell susceptible to move, along a number of stages, towards full malignancy. Little is known about these events and their causes; we present some theoretical possibilities. Bovine leukaemia virus infection has a worldwide distribution. In temperate climates, the virus spreads mostly via iatrogenic transfer of infected lymphocytes. In warm climates and in areas heavily populated by haematophagous insects, there are indications of insect-borne propagation of the virus.

  6. Aetiology of childhood leukaemia.

    PubMed

    Eden, Tim

    2010-06-01

    The acute leukaemias account for about 30% of all malignancy seen in childhood across the Western world. A peak incidence of precursor B cell ALL has emerged as socio-economic conditions have improved in countries worldwide. From twin studies and the use of neonatal blood spots it has been possible to back track the first initiating genetic events within critical haemopoietic cells to foetal development in utero for most precursor B cell ALL and some cases of AML. These events may occur as part of normal foetal development. Whether other factors (environmental or constitutional) are involved to increase the chance of these first genetic changes happening is unclear. For some leukaemias (e.g. infant MLL positive ALL) the first event appears adequate to create a malignant clone but for the majority of ALL and AML further 'genetic' changes are required, probably postnatal. Many environmental factors have been proposed as causative for leukaemia but only ionising irradiation and certain chemicals, e.g. benzene and cytotoxics (alkylators and topoisomerase II inhibitors) have been confirmed and then principally for acute myeloid leukaemia. It appears increasingly likely that delayed, dysregulated responses to 'common' infectious agents play a major part in the conversion of pre-leukaemic clones into overt precursor B cell ALL, the most common form of childhood leukaemia. Constitutional polymorphic alleleic variants in immune response genes (especially the HLA Class II proteins) and cytokines may play a role in determining the type of immune response. High penetrance germ-line mutations are involved in only about 5% of childhood leukaemias (more in AML than ALL). There is little evidence to support any role of viral transformation in causation, unlike in animals. Other environmental factors for which some evidence exists include non-ionising electromagnetic radiation and electric fields, although their mode of action in leukaemogenesis remains unclear. There is no single

  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.

  8. 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

  9. 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

  10. 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

  11. Subsequent leukaemia in autoimmune disease patients.

    PubMed

    Hemminki, Kari; Liu, Xiangdong; Försti, Asta; Ji, Jianguang; Sundquist, Jan; Sundquist, Kristina

    2013-06-01

    Previous studies have shown that patients diagnosed with some autoimmune (AI) diseases are at an increased risk of leukaemia but limited data are available on survival. We systematically analysed the risks (standardized incidence ratio, SIR) and survival (hazard ratio, HR) in nine types of leukaemia among 402 462 patients hospitalized for any of 33 AI diseases and compared to persons not hospitalized for AI diseases. Risk for all leukaemia was increased after 13 AI diseases and survival was decreased after six AI diseases. SIRs were increased after all AI diseases for seven types of leukaemia, including SIR 1·69 (95% confidence interval (CI): 1·29-2·19) for acute lymphoblastic leukaemia (ALL), 1·85 (95% CI: 1·65-2·07) for acute myeloid leukaemia, 1·68 (95% CI: 1·37-2·04) for chronic myeloid leukaemia, 2·20 (95% CI: 1·69-2·81) for 'other myeloid leukaemia', 2·45 (95% 1·99-2·98) for 'other and unspecified leukaemia', 1·81 (95% CI: 1·11-2·81) for monocytic leukaemia, and 1·36 (95% CI: 1·08-1·69) for myelofibrosis. The HRs were increased for four types of leukaemia, most for myelofibrosis (1·74, 95% CI: 1·33-2·29) and ALL (1·42, 95% CI: 1·03-1·95). Some AI diseases, including rheumatoid arthritis, were associated with increased SIRs and HRs in many types of leukaemia. The present data showed increases in risk and decreases in survival for many types of leukaemia after various AI diseases. Leukaemia is a rare complication in AI disease but findings about this comorbidity at the time of leukaemia diagnosis may help to optimize the treatment and improve survival.

  12. Diagnosis and management of neonatal leukaemia.

    PubMed

    van der Linden, Marieke H; Creemers, Sara; Pieters, Rob

    2012-08-01

    Leukaemia in neonates (infants <1 month) is rare, whereby neonatal acute myeloid leukaemia (AML) is more frequent than neonatal acute lymphoblastic leukaemia (ALL). High mortality rates are observed, though AML has a better prognosis than ALL. Neonatal leukaemia is typically presented with hepatosplenomegaly, leukaemia cutis and/or hyperleucocytosis. Congenital infections should be ruled out before diagnosis. Rearrangement of the MLL gene is the most frequently occurring genetic aberration. Treatment includes intensive multi-agent chemotherapy, usually with age-related dose adjustments next to supportive care. Treatment intensification for ALL could be indicated in the future as the dismal prognosis is subject to high relapse rates in ALL.

  13. Oral verrucous carcinoma arising from lichen planus and esophageal squamous cell carcinoma in a patient with hepatitis C virus-related liver cirrhosis-hyperinsulinemia and malignant transformation: A case report.

    PubMed

    Nagao, Yumiko; Sata, Michio

    2013-01-01

    Oral lichen planus (OLP) is a potentially malignant disorder associated with an increased risk of oral cancer. In Japan, the association of OLP with hepatitis C virus (HCV) infection is well documented. In the present study, a case of oral verrucous carcinoma arising from OLP coexisting vulvo-vaginal-gingival syndrome and esophageal squamous cell carcinoma (SCC) in a patient with HCV-related liver cirrhosis is reported. A 71-year old, non-smoking Japanese woman presented with lesions of OLP affecting the bilateral buccal mucosa, tongue, gingival, palate, oral floor and lower lip. Ten years later, an exophytic mass developed in the mandibular alveolar mucosa, the right buccal mucosa and the right lower lip. Pathological diagnosis confirmed the presence of verrucous carcinoma. However, she developed esophageal rather than oral cancer. The oral cancer was resected surgically three times and the patients underwent radiotherapy. The esophageal cancer was removed by endoscopic submucosal dissection. The risk of carcinogenesis increased as hyperinsulinemia continued. The results suggested that it is necessary to monitor for malignant changes in patients with OLP lesions and HCV infection. In addition, treatment requires the cooperation of various medical specialists, as well as an oral surgeon. PMID:24648893

  14. Possible role of tocopherols in the modulation of host microRNA with potential antiviral activity in patients with hepatitis B virus-related persistent infection: a systematic review.

    PubMed

    Fiorino, S; Bacchi-Reggiani, L; Sabbatani, S; Grizzi, F; di Tommaso, L; Masetti, M; Fornelli, A; Bondi, A; de Biase, D; Visani, M; Cuppini, A; Jovine, E; Pession, A

    2014-12-14

    Hepatitis B virus (HBV) infection represents a serious global health problem and persistent HBV infection is associated with an increased risk of cirrhosis, hepatocellular carcinoma and liver failure. Recently, the study of the role of microRNA (miRNA) in the pathogenesis of HBV has gained considerable interest as well as new treatments against this pathogen have been approved. A few studies have investigated the antiviral activity of vitamin E (VE) in chronic HBV carriers. Herein, we review the possible role of tocopherols in the modulation of host miRNA with potential anti-HBV activity. A systematic research of the scientific literature was performed by searching the MEDLINE, Cochrane Library and EMBASE databases. The keywords used were 'HBV therapy', 'HBV treatment', 'VE antiviral effects', 'tocopherol antiviral activity', 'miRNA antiviral activity' and 'VE microRNA'. Reports describing the role of miRNA in the regulation of HBV life cycle, in vitro and in vivo available studies reporting the effects of VE on miRNA expression profiles and epigenetic networks, and clinical trials reporting the use of VE in patients with HBV-related chronic hepatitis were identified and examined. Based on the clinical results obtained in VE-treated chronic HBV carriers, we provide a reliable hypothesis for the possible role of this vitamin in the modulation of host miRNA profiles perturbed by this viral pathogen and in the regulation of some cellular miRNA with a suggested potential anti-HBV activity. This approach may contribute to the improvement of our understanding of pathogenetic mechanisms involved in HBV infection and increase the possibility of its management and treatment.

  15. 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

  16. Cloning of the Epstein-Barr virus-related rhesus lymphocryptovirus as a bacterial artificial chromosome: a loss-of-function mutation of the rhBARF1 immune evasion gene.

    PubMed

    Ohashi, Makoto; Orlova, Nina; Quink, Carol; Wang, Fred

    2011-02-01

    Rhesus macaques are naturally infected with a gammaherpesvirus which is in the same lymphocryptovirus (LCV) genus as and closely related to Epstein-Barr virus (EBV). The rhesus macaque LCV (rhLCV) contains a repertoire of genes identical to that of EBV, and experimental rhLCV infection of naive rhesus macaques accurately models acute and persistent EBV infection of humans. We cloned the LCL8664 rhLCV strain as a bacterial artificial chromosome to create recombinant rhLCV for investigation in this animal model system. A recombinant rhLCV (clone 16 rhLCV) carrying a mutation in the putative immune evasion gene rhBARF1 was created along with a rescued wild-type (rWT) rhLCV in which the rhBARF1 open reading frame (ORF) was repaired. The rWT rhLCV molecular clone demonstrated viral replication and B-cell immortalization properties comparable to those of the naturally derived LCL8664 rhLCV. Qualitatively, clone 16 rhLCV carrying a mutated rhBARF1 was competent for viral replication and B-cell immortalization, but quantitative assays showed that clone 16 rhLCV immortalized B cells less efficiently than LCL8664 and rWT rhLCV. Functional studies showed that rhBARF1 could block CSF-1 cytokine signaling as well as EBV BARF1, whereas the truncated rhBARF1 from clone 16 rhLCV was a loss-of-function mutant. These recombinant rhLCV can be used in the rhesus macaque animal model system to better understand how a putative viral immune evasion gene contributes to the pathogenesis of acute and persistent EBV infection. The development of a genetic system for making recombinant rhLCV constitutes a major advance in the study of EBV pathogenesis in the rhesus macaque animal model.

  17. 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.

  18. Leukaemias into the 21st century. Part 2: the chronic leukaemias.

    PubMed

    Gibson, J; Iland, H J; Larsen, S R; Brown, C M S; Joshua, D E

    2013-05-01

    Like the acute leukaemias, the chronic leukaemias are broadly classified according to their cell lineage of origin. Chronic myeloid leukaemia and chronic lymphocytic leukaemia are the most common disease entities within the myeloid and lymphoid lineages, although several less common entities are well recognised within each broad subgroup. In common with the dramatic progress in the acute leukaemias, there has been considerable progress in our understanding of the biology and molecular genetics of the chronic leukaemias that is now being translated into significant therapeutic advances.

  19. Potential Interest in Circulating miR-BART17-5p As a Post-Treatment Biomarker for Prediction of Recurrence in Epstein-Barr Virus-Related Nasopharyngeal Carcinoma

    PubMed Central

    Hirai, Nobuyuki; Wakisaka, Naohiro; Kondo, Satoru; Aga, Mitsuharu; Moriyama-Kita, Makiko; Ueno, Takayoshi; Nakanishi, Yosuke; Endo, Kazuhira; Sugimoto, Hisashi; Murono, Shigeyuki; Sato, Hiroshi; Yoshizaki, Tomokazu

    2016-01-01

    Objectives Epstein-Barr virus (EBV)-related micoRNAs (miRNAs), BamHI-A rightward transcripts (BART)-miRNAs, are released in a stable form from viable cells, which are abundant in patients with EBV-positive nasopharyngeal carcinoma (NPC). We estimated copy numbers of circulating miR-BART2-5p, miR-BART17-5p, and miR-BART18-5p as well as BamHI-W DNA as biomarkers. Materials and Methods Serums from 31 EBV-positive (confirmed by in situ hybridization for EBV-encoded small RNAs) NPC patients and 40 non-NPC controls were analyzed. Among the 31 NPC patients, serums at the initial diagnosis and three months after treatment were obtained from 20 patients, and serums only at three months after treatment were obtained from 11 patients. Results The sensitivity/specificity of circulating BamHI-W DNA, miR-BART2-5p, miR-BART17-5p, and miR-BART18-5p for the diagnosis of NPC before treatment were 100 / 100, 85 / 85, 60 / 95, and 25 / 100%, respectively. For BamHI-W DNA, NPC patients with stage IV disease had significantly higher copy numbers than those with I-III. Copy numbers decreased significantly post-treatment. In contrast, copy numbers of the three BART-miRNAs showed no significant correlation with the clinical stage at diagnosis or any significant post-treatment change. After treatment, BamHI-W DNA and miR-BART17-5p were detected in 5 and 6 cases out of 11 patients with recurrent or residual tumors, respectively. However, BamHI-W DNA and miR-BART17-5p were absent in all 20 patients without relapse or residual tumors. Conclusion The copy number of circulating BamHI-W DNA is a more useful biomarker for the initial diagnosis of NPC than the three BART-miRNAs examined. Post-treatment detection of miR-BART17-5p is a potential biomarker of a poor prognosis. PMID:27684719

  20. 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

  1. 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

  2. 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

  3. [Lineage switch - conversion of acute lymphoblastic leukaemia to acute myeloid leukaemia in 4 years old girl].

    PubMed

    Szpecht, Dawid; Derwich, Katarzyna; Wachowiak, Jacek; Konatkowska, Benigna; Dworacki, Grzegorz

    2008-01-01

    We report a case of a 4-year-old girl with diagnosed proB acute lymphoblastic leukaemia with co-expression CD33 antigen, treated according to Acute Lymphoblastic Leukaemia Intercontinental - Berlin Frankfurt Münster 2002 (ALL-IC BFM 2002) protocol for standard risk group. Haematological remission was obtained on day 33 of induction treatment (on time). During induction and consolidation therapy there were no early serious adverse effects. The late isolated bone marrow relapse of acute myeloid leukaemia, type 7 was noted in our patient. We recognized this case as a lineage switch acute lymphoblastic leukaemia to acute myeloid leukaemia. In spite of Ida Flag regimen and following Acute Myeloid Leukaemia - Berlin Frankfurt Münster 2004 (AML-BFM 2004) protocol were administered, the clinical and haematological remission was not achieved and the patient died because of disease progression (circulatory and respiratory insufficiency).

  4. Bovine leukaemia: facts and hypotheses derived from the study of an infectious cancer.

    PubMed

    Burny, A; Cleuter, Y; Kettmann, R; Mammerickx, M; Marbaix, G; Portetelle, D; Van den Broeke, A; Willems, L; Thomas, R

    1987-01-01

    Bovine leukaemia virus (BLV) is the aetiological agent of a chronic lymphatic leukaemia/lymphoma in cows, sheep and goats. Infection without neoplastic transformation has also been demonstrated in pigs, rhesus monkeys, chimpanzees and rabbits and observed in capybaras and water buffaloes. Structurally and functionally, BLV is a relative of human T lymphotropic viruses 1 and 2 (HTLV-I and HTLV-II) since all three viruses show clear-cut sequence homologies. The pathology of the BLV-induced disease, most notably the absence of chronic viraemia, a long latency period and lack of preferred proviral integration sites in tumours, is similar to that of adult T-cell leukaemia/lymphoma induced by HTLV-I. The most striking feature of the three naturally transmitted leukaemia viruses is the X region located between the env gene and the long terminal repeat (LTR) sequence. The X region contains several overlapping long open reading frames, one of which, designated XBL-1, encodes a trans-activator function capable of increasing the level of gene expression directed by BLV-LTR and is most probably involved in genetic instability of BLV-infected cells of the B-cell lineage. The 'genetic instability' may put the cell into a state of fragility, ready to move along a number of stages towards full malignancy. Little is known about these events and their causes and we present some theoretical possibilities. BLV infection has a worldwide distribution. In temperate climates the virus spreads mostly through iatrogenic transfer of infected lymphocytes. In warm climates and in areas heavily populated by haematophagous insects, there are indications of insect-borne propagation of the virus.

  5. Advances in understanding the leukaemia microenvironment.

    PubMed

    Tabe, Yoko; Konopleva, Marina

    2014-03-01

    Dynamic interactions between leukaemic cells and cells of the bone marrow are a feature of haematological malignancies. Two distinct microenvironmental niches in the bone marrow, the 'osteoblastic (endosteal)' and 'vascular' niches, provide a sanctuary for subpopulations of leukaemic cells to evade chemotherapy-induced death and allow acquisition of drug resistance. Key components of the bone marrow microenvironment as a home for normal haematopoietic stem cells and the leukaemia stem cell niches, and the molecular pathways critical for microenvironment/leukaemia interactions via cytokines, chemokines and adhesion molecules as well as hypoxic conditions, are described in this review. Finally, the genetic abnormalities of leukaemia-associated stroma are discussed. Further understanding of the contribution of the bone marrow niche to the process of leukaemogenesis may provide new targets that allow destruction of leukaemia stem cells without adversely affecting normal stem cell self-renewal.

  6. Leukaemias into the 21st century: part 1: the acute leukaemias.

    PubMed

    Brown, C M S; Larsen, S R; Iland, H J; Joshua, D E; Gibson, J

    2012-11-01

    The leukaemias are a biologically and clinically heterogeneous group of malignancies, which manifest as clonal expansions of a single cell at different stages of lympho-haemopoietic development. The transformed cell acquires an unrestrained capacity for self-renewal and, in the case of the acute leukaemias, also fails to differentiate into functional mature cells. Historically leukaemias were classified using a combination of clinical and (presumed) cell lineage criteria. Thus, the four major subgroups of acute and chronic myeloid leukaemia and acute and chronic lymphoid leukaemia were recognised. Up until the last 10-15 years, patients within each major subgroup were treated along broadly similar lines. Genetic abnormalities have been recognised in certain leukaemias for over 50 years; however, the recent explosion in our understanding of the frequency and complexity of molecular abnormalities in the leukaemias has 'opened the door' for the design of more targeted therapies with the expectation that their incorporation into therapeutic regimens will be associated with greater efficacy and less off-target toxicity.

  7. 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

  8. 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 ...

  9. 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

  10. Biochemical enzyme analysis in acute leukaemia.

    PubMed Central

    Drexler, H G; Gaedicke, G; Minowada, J

    1985-01-01

    This report summarises the current knowledge regarding the clinical utility of biochemical enzyme markers for both diagnostic and therapeutic purposes in acute leukaemia. The enzymes studied most extensively in this field are terminal deoxynucleotidyl transferase, adenosine deaminase, 5'-nucleotidase, purine nucleoside phosphorylase, and acid phosphatase, esterase, hexosaminidase isoenzymes. For each enzyme, the quantitative and qualitative characteristics in various immunologically defined subclasses of acute leukaemia are described. The quantitative evaluation of enzyme activities represents an adjunctive classification technique which should be incorporated into the multivariate analysis, the "multiple marker analysis." By qualitative characterisation pronounced heterogeneity of leukaemia subsets is uncovered. The application of 2'-deoxycoformycin, a specific inhibitor of adenosine deaminase, and the potential usefulness of two other enzymes as targets for treatment with selective agents is discussed. The concept that gene products expressed at certain developmental stages of normal cells can similarly be detected in leukaemic cells (which therefore seem to be "frozen" or "arrested" at this particular maturation/differentiation stage) is supported by the results obtained in enzyme studies. Besides their practical clinical importance for classification and treatment of acute leukaemias, biochemical enzyme markers constitute a valuable research tool to disclose biological properties of leukaemic cells. PMID:2981904

  11. Is Having Clonal Cytogenetic Abnormalities the Same as Having Leukaemia.

    PubMed

    Farina, Mirko; Rossi, Giuseppe; Bellotti, Daniella; Marchina, Eleonora; Gale, Robert Peter

    2016-01-01

    A finding of cytogenetic abnormalities, even when these are clonal and even when the abnormalities are typically associated with leukaemia, is not the same as a person having leukaemia. We describe a person who had acute myeloid leukaemia (AML) and achieved a complete haematological remission and who then had persistent and transient clonal cytogenetic abnormalities for 22 years but no recurrence of leukaemia. These data suggest that clones of myeloid cells with mutations and capable of expanding to levels detectable by routine cytogenetic analyses do not all eventuate in leukaemia, even after a prolonged observation interval. The possibility of incorrectly diagnosing a person as having leukaemia becomes even greater when employing more sensitive techniques to detect mutations such as by polymerase chain reaction and whole-exome or whole-genome sequencing. Caution is needed when interpreting clonal abnormalities in AML patients with normal blood and bone marrow parameters.

  12. Human retroviruses in leukaemia and AIDS: reflections on their discovery, biology and epidemiology.

    PubMed

    Karpas, Abraham

    2004-11-01

    The study of retroviruses has had a profound impact by unveiling an unusual form of viral replication: the multiplication of RNA viruses via a proviral DNA, for which Jan Svoboda provided the experimental model over forty years ago. In 1970 Temin, Mizutani and Baltimore discovered that this group of viruses contains a unique enzyme catalysing the synthesis of a DNA copy of the viral RNA: reverse transcriptase (RT). The discovery of RT has itself had an enormous impact on molecular biology in general, but also stimulated many premature claims of its detection in human disease. Claims by Gallo's laboratory that the cytoplasm of human leukaemia cells contained RT proved to be unfounded, as did his report in collaboration with Weiss that myeloid leukaemia contained HL23 virus, this organism proving not to be human but a laboratory contaminant of three monkey viruses. Conclusive demonstration of a retroviral involvement in human leukaemia was first provided in 1981 by Hinuma and his associates, showing that adult T-cell leukaemia (ATL), a rare form of leukaemia endemic to south-west Japan, is caused by a new retrovirus (ATLV). Other publications in December 1980 and through 1981 claimed the discovery of a new human T-cell leukaemia virus involved in mycosis fungoides (MF) and Sézary's syndrome (SS). This virus was termed HTLV by Gallo. The nucleotide sequence of ATLV is strongly conserved, that of my 1983 isolate from a black British ATL patient being practically identical with the Japanese virus isolates. After AIDS was recognised in 1981 by Gottlieb and coworkers as a new human disease, several papers were published by Gallo and his associates during 1983-4, invoking the oncovirus responsible for adult T-cell leukaemia as the cause of AIDS. In 1983 the French scientist Barré-Sinoussi and her colleagues succeeded in isolating a new agent in the disease, a lentivirus, which they named LAV. The French immunologist Klatzmann and his colleagues discovered that LAV killed

  13. Leukaemia 'firsts' in cancer research and treatment.

    PubMed

    Greaves, Mel

    2016-03-01

    Our understanding of cancer biology has been radically transformed over recent years with a more realistic grasp of its multilayered cellular and genetic complexity. These advances are being translated into more selective and effective treatment of cancers and, although there are still considerable challenges, particularly with drug resistance and metastatic disease, many patients with otherwise lethal malignancies now enjoy protracted remissions or cure. One largely unheralded theme of this story is the extent to which new biological insights and novel clinical applications have their origins with leukaemia and related blood cell cancers, including lymphoma. In this Timeline article, I review the remarkable and ground-breaking role that studies in leukaemia have had at the forefront of this progress.

  14. Residential exposures to pesticides and childhood leukaemia

    PubMed Central

    Metayer, Catherine; Buffler, Patricia A.

    2008-01-01

    Like many chemicals, carcinogenicity of pesticides is poorly characterised in humans, especially in children, so that the present knowledge about childhood leukaemia risk derives primarily from epidemiological studies. Overall, case–control studies published in the last decade have reported positive associations with home use of insecticides, mostly before the child's birth, while findings for herbicides are mixed. Previous studies relied solely on self-reports, therefore lacking information on active ingredients and effects of potential recall bias. Few series to date have examined the influence of children's genetic susceptibility related to transport and metabolism of pesticides. To overcome these limitations, investigators of the Northern California Childhood Leukaemia Study (NCCLS) have undertaken, in collaboration with a multidisciplinary team, a comprehensive assessment of residential pesticide exposure, including: (1) quality control of self-reports; (2) home pesticide inventory and linkage to the Environmental Protection Agency to obtain data on active ingredients; (3) collection and laboratory analyses of ∼600 home dust samples for over 60 pesticides and (4) geographic information studies using California environmental databases to assess exposure to agricultural pesticides. The NCCLS is also conducting large-scale genotyping to evaluate the role of genes in xenobiotic pathways relevant to the transport and metabolism of pesticides. A better quantification of children's exposures to pesticides at home is critical to the evaluation of childhood leukaemia risk, especially for future gene–environment interaction studies. PMID:18940823

  15. 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

  16. 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 ...

  17. Increased risk of venous thromboembolism in patients with acute leukaemia

    PubMed Central

    Mohren, M; Markmann, I; Jentsch-Ullrich, K; Koenigsmann, M; Lutze, G; Franke, A

    2006-01-01

    Patients with malignancies have an increased risk for venous thromboembolisms (VTE), but data on patients with acute leukaemia are very limited so far. We found VTE in 12% of 455 patients with acute leukaemia, half of which occurred in association with central venous catheters, with equal risk of ALL and AML. PMID:16421591

  18. Secondary pure erythroid leukaemia in relapsed acute lymphoblastic leukaemia: lineage switch or chemotherapy effect?

    PubMed

    Gupta, Sanjeev Kumar; Kumar, Rajive; Chharchhodawala, Taher; Kumar, Lalit

    2014-05-19

    Pure erythroid leukaemia is a rare subtype of acute myeloid leukaemia (AML) and its occurrence at acute lymphoblastic leukaemia (ALL) relapse has not been reported earlier. A 39-year-old man received chemotherapy for Philadelphia-negative B cell ALL. Subsequently, he developed pure erythroid leukaemia with >80% immature erythroid precursors in bone marrow showing block positivity on periodic acid-Schiff stain, expressing CD71, CD34 but lacking CD235a. The interval between exposure to multidrug chemotherapy including cyclophosphamide and AML diagnosis was 2 years and 9 months. No cytogenetic abnormality was detected at the time of relapse. The patient died 2 weeks after starting AML chemotherapy. The relatively narrow time interval (usually 5-10 years) between chemotherapy and AML development and normal karyotype at relapse raises a possibility of lineage switch besides therapy-related AML as the likely pathogenesis. Further exploration of such cases may unravel the pathways responsible for lineage assignment in pluripotent stem cells.

  19. Review: Aberrant EVI1 expression in acute myeloid leukaemia.

    PubMed

    Hinai, Adil A; Valk, Peter J M

    2016-03-01

    Deregulated expression of the ecotropic virus integration site 1 (EVI1) gene is the molecular hallmark of therapy-resistant myeloid malignancies bearing chromosomal inv(3)(q21q26·2) or t(3;3)(q21;q26·2) [hereafter referred to as inv(3)/t(3;3)] abnormalities. EVI1 is a haematopoietic stemness and transcription factor with chromatin remodelling activity. Interestingly, the EVI1 gene also shows overexpression in 6-11% of adult acute myeloid leukaemia (AML) cases that do not carry any 3q aberrations. Deregulated expression of EVI1 is strongly associated with monosomy 7 and 11q23 abnormalities, which are known to be associated with poor response to treatment. However, EVI1 overexpression has been revealed as an important independent adverse prognostic marker in adult AML and defines distinct risk categories in 11q23-rearranged AML. Recently, important progress has been made in the delineation of the mechanism by which EVI1 becomes deregulated in inv(3)/t(3;3) as well as the cooperating mutations in this specific subset of AML with dismal prognosis.

  20. 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

  1. Leukaemia in Nagasaki atomic bomb survivors from 1945 through 1959.

    PubMed

    TOMONAGA, M

    1962-01-01

    This review of the Nagasaki leukaemia experience during a period of 14 years after the detonation of the atomic bomb, together with comparisons with data from Hiroshima and from other series of post-radiation leukaemia cases, again demonstrates beyond reasonable doubt the leukaemogenic effect on man of ionizing radiation. An increased risk of leukaemia following doses probably as low as 100 rads (air-entry dose) of whole-body radiation is demonstrated on the basis of the available estimates of atomic bomb radiation doses. At doses above this level the increase in leukaemia incidence may be linearly related to the radiation dose. The data are too limited to allow of an evaluation of the risk represented by doses at the lower levels of radiation; but it seems clear that, if a threshold dose for leukaemia induction exists, it is lower than the threshold dose for the clinical expression of acute radiation syndrome.The sex and age distribution of radiation-induced leukaemia and the types of leukaemia observed are also discussed.

  2. A multicentre trial of live attenuated varicella vaccine in children with leukaemia in remission.

    PubMed

    Gershon, A A; Steinberg, S; Gelb, L; Galasso, G; Borkowsky, W; LaRussa, P; Ferrara, A

    1985-01-01

    Two hundred forty children with acute leukaemia in remission for at least 1 year were immunized with live attenuated varicella vaccine. All were susceptible to varicella before immunization. There was a seroconversion to varicella-zoster virus in approximately 85% after 1 dose, and in 97% after 2 doses. The major side effect was mild to moderate rash, seen mainly in children with maintenance chemotherapy suspended for 1 week before and 1 week after vaccination. Vaccinees with rash were at some risk (10%) to transmit vaccine virus to varicella susceptibles with whom they had close contact. Twenty-nine vaccinees were subsequently exposed to varicella in their households. The attack rate of clinical varicella in these vaccinees was 21%, which is significantly lower than the 80%-90% attack rate occurring in varicella susceptibles after household exposure. All these breakthrough cases of varicella were mild, even in leukaemics receiving chemotherapy. Varicella vaccine was approximately 80% effective in preventing clinical varicella in children with leukaemia and completely effective in preventing severe varicella in this high-risk group.

  3. Independent prognostic variables in acute myeloid leukaemia.

    PubMed

    Smith, Matthew L; Hills, Robert K; Grimwade, David

    2011-01-01

    Acute myeloid leukaemia (AML) is one of the most common haematological malignancies and is increasing in frequency due to an ageing population. Whilst remission will be achieved in up to 80% of those receiving intensive chemotherapy, the main variables precluding cure are the treatment-related mortality and relapse rates. Decisions on intensification, de-escalation and allografting rely on the ability to divide an apparently homogeneous group according to risk. A wide range of clinical, cytogenetic and molecular variables may be used to inform this task. Cytogenetic and molecular characterisation has already identified subgroups, such as acute promyelocytic leukaemia (APL) with t(15;17)/PML-RARA and AML with FLT3 mutation for which targeted therapies are available, and further molecularly defined groups who may be potential candidates for this approach are likely to be identified in the future. This review examines the range of established clinical and diagnostic parameters that should be used in assessing prognosis for a patient with AML and looks ahead to an expanding repertoire of potential variables that are currently under evaluation.

  4. Serum enzyme and ferritin concentrations in acute leukaemia.

    PubMed

    Stark, A N; Gailor, K; Langdale, P I; Roberts, B E; Scott, C S

    1987-03-01

    Serum ferritin concentrations were determined in 142 untreated cases of acute leukaemia. No correlation between type of leukaemia as defined by morphology and immunology and the level of serum ferritin was found. Samples were also tested for lactate dehydrogenase (LDH), phosphohexose isomerase (PHI), B-glucuronidase (B-gluc), leucine aminopeptidase (LAP), and C-reactive protein (CRP) levels. Serum ferritin was significantly correlated with serum PHI, LAP, and LDH concentrations but not with leukaemic mass as assessed by total white blood cell count (WBC). Ferritin and CRP levels were also significantly correlated suggesting that ferritin may behave to some extent like an acute phase reactant in acute leukaemia. PMID:3502981

  5. Spontaneous tumour lysis syndrome secondary to the transformation of chronic myelomonocytic leukaemia into acute myeloid leukaemia.

    PubMed

    Langridge, Alexander; Musgrave, Kathryn; Upadhye, Yogesh

    2016-01-01

    A 78-year-old man, with a 6-year history of stable chronic myelomonocytic leukaemia (CMML), presented with general deterioration and worsening pancytopenia. Bone marrow biopsy showed that his disease had transformed into acute myeloid leukaemia (AML). He was started on a supportive transfusion regimen and did not receive any chemotherapy or corticosteroids. Several weeks later, he developed acute renal failure and was admitted to a medical admissions ward. Spontaneous tumour lysis syndrome (sTLS, grade 1) was diagnosed, as per the Cairo and Bishop criteria. He was treated with intravenous fluids, rasburicase and allopurinol. His renal function improved and he recovered from the sTLS. The authors believe that this is the first published case of sTLS occurring as a result of CMML transforming into AML; it highlights the importance of recognising sTLS as a cause of renal failure and electrolyte disturbance before cancer treatment begins. PMID:26961554

  6. Autoimmune antibodies in chronic lymphatic leukaemia.

    PubMed

    Lewis, C M; Pegrum, G D

    1978-01-01

    In chronic lymphocytic leukaemia a factor in patients' serum enhances the in vitro viability of the abnormal cells and this has been identified as an antibody. The activity of this factor can be removed by interaction with anti-immunoglobulin and by ammonium sulphate precipitation with a degree of saturation in excess of 46%. Cohn fractionation and chromatography with A-50 Sephadex show that the factor is not a complex but an immunoglobulin. No activity is removed after reaction of sera with 2-mercapto-ethanol and di-thiothreitol. The evidence therefore suggests that a gamma-G immunoglobulin is involved. Concentrated washings from the leukaemic cells behave in exactly the same way as patients' sera and activity is retained in the same fraction during precipitation and purification procedure. The extensive cross-reactivity of the sera suggests a common chronic lymphatic leukaemic antibody and it is considered that an active autoimmune response may be an integral part of the disease.

  7. 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

  8. Extended diagnostic criteria for plasmacytoid dendritic cell leukaemia.

    PubMed

    Garnache-Ottou, Francine; Feuillard, Jean; Ferrand, Christophe; Biichle, Sabeha; Trimoreau, Franck; Seilles, Estelle; Salaun, Véronique; Garand, Richard; Lepelley, Pascale; Maynadié, Marc; Kuhlein, Emilienne; Deconinck, Eric; Daliphard, Sylvie; Chaperot, Laurence; Beseggio, Lucille; Foisseaud, Vincent; Macintyre, Elizabeth; Bene, Marie-Christine; Saas, Philippe; Jacob, Marie-Christine

    2009-06-01

    The diagnosis of plasmacytoid dendritic cell leukaemia (pDCL) is based on the immunophenotypic profile: CD4(+) CD56(+) lineage(neg) CD45RA(+)/RO(neg) CD11c(neg) CD116(low) CD123(+) CD34(neg) CD36(+) HLA-DR(+). Several studies have reported pDCL cases that do not express this exact profile or expressing some lineage antigens that could thus be misdiagnosed. This study aimed to validate pDCL-specific markers for diagnosis by flow-cytometry or quantitative reverse transcription polymerase chain reaction on bone marrow samples. Expression of markers previously found in normal pDC was analysed in 16 pDCL, four pDCL presenting an atypical phenotype (apDCL) and 113 non-pDC - lymphoid or myeloid - acute leukaemia. CD123 was expressed at significantly higher levels in pDCL and apDCL. BDCA-2 was expressed on 12/16 pDCL and on 2/4 apDCL, but was never detected in the 113 non-pDC acute leukaemia cases. BDCA-4 expression was found on 13/16 pDCL, but also in 12% of non-pDC acute leukaemia. High levels of LILRA4 and TCL1A transcripts distinguished pDCL and apDCL from all other acute leukaemia (except B-cell acute lymphoblastic leukaemia for TCL1A). We thus propose a diagnosis strategy, scoring first the CD4(+) CD56(+/-) MPO(neg) cCD3(neg) cCD79a(neg) CD11c(neg) profile and then the CD123(high), BDCA-2 and BDCA-4 expression. Atypical pDCL can be also identified this way and non-pDC acute leukaemia excluded: this scoring strategy is useful for diagnosing pDCL and apDCL.

  9. The acute promyelocytic leukaemia success story: curing leukaemia through targeted therapies.

    PubMed

    Rice, K L; de Thé, H

    2014-07-01

    The recent finding that almost all patients with acute promyelocytic leukaemia (APL) may be cured using a combination of retinoic acid (RA) and arsenic trioxide (As(2)O(3)) (N Engl J Med, 369, 2013 and 111) highlights the progress made in our understanding of APL pathogenesis and therapeutic approaches over the past 25 years. The study of APL has revealed many important lessons related to transcriptional control, nuclear organization, epigenetics and the role of proteolysis in biological control. Even more important has been the clinical demonstration that molecularly targeted therapy can eradicate disease.

  10. Three additional malignancies occurring within one year in a patient with chronic lymphatic leukaemia.

    PubMed

    Boots, M A; Pegrum, G D

    1978-09-01

    A patient with crhonic lymphatic leukaemia (CLL) is presented who was first seen with a basal cell carcinoma and subsequently developed two further malignant conditions within a year, without receiving any treatment for his leukaemia. It is suggested that this leukaemia was a predisposing factor in the development of his carcinomas.

  11. 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.

  12. Leukaemia and Sellafield: is there a heritable link?

    PubMed Central

    Tawn, E J

    1995-01-01

    The demonstration of a statistical association between paternal preconceptional irradiation and childhood leukaemia appeared to provide a satisfactory explanation for the excess of cases in the village of Seascale, close to the Sellafield nuclear installation, and became the basis of two legal claims for compensation. In the ensuing scientific debate the biological plausibility of a causal interpretation of this association focused on the heritability of leukaemia and a comparison of the genetic risks implied by this finding with current information on the induction of genetic damage by irradiation. After a wide ranging review of the mechanistic issues it is concluded that there is no genetic basis for a causal relationship and this, together with recent appraisals of epidemiological studies, suggests that the association between childhood leukaemia and paternal preconceptional irradiation exposure is most likely to be a chance finding. PMID:7643351

  13. Somatostatin receptors on human lymphocytes and leukaemia cells.

    PubMed Central

    Hiruma, K; Koike, T; Nakamura, H; Sumida, T; Maeda, T; Tomioka, H; Yoshida, S; Fujita, T

    1990-01-01

    Receptors for somatostatin were identified on mitogen-activated human peripheral blood lymphocytes (PBL) and human leukaemic cells in 87.5% of lymphoblastic leukaemia and in 12.5% of non-lymphocytic leukaemia, using a somatostatin radiobinding assay. The specific binding of 125I-somatostatin of these cells increased linearly with the cell numbers and was suppressed by non-iodinated somatostatin. We investigated the distribution of fluorescent somatostatin to mitogen-activated PBL by using a fluorescence-activated cell sorter (FACS). Over 95% of the cell populations bound fluorescent somatostatin and no distinct predilection was found among certain lymphocyte subpopulations and somatostatin receptor-positive cells. Scatchard analysis showed a single class (low affinity) of binding site on mitogen-activated PBL and two classes (high and low affinity) of specific binding sites on lymphoblastic leukaemia cells. PMID:2177723

  14. Changes of Some Hormones Levels in Patients With Hepatitis B Virus-Related Chronic Liver Disease

    PubMed Central

    Serin, Ayfer; Akarsu, Mesut; Akpinar, Hale; Simsek, Ilkay

    2013-01-01

    Background The purpose of the study was to evaluate some of the hormones in patients with chronic liver disease and cirrhosis. Methods The men patients with chronic hepatitis B (Group 1), liver cirrhosis secondary to hepatitis B (Group 2), were included in this study. Additionally, a control group of healthy volunteers (Group 3) was formed. We investigated serum levels of Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), Total testosterone (T. TES), Free-testosterone (F. TES), Estradiol (E2), Androstenedione (ANDR), Dihydroepiandrosterone (DHEA), Progesterone (PPOGES), Prolactin (PRL), Sex hormone binding protein (SHGB) were measured by radioimmunoassay and chemiluminescent immunoassay methods. Result A total of 73 patients with chronic liver disease and cirrhosis were included in the study. Patients were grouped as cirrhosis (n = 28), chronic hepatitis B (n = 41) according to the type of their chronic liver disease. Serum F.TEST level in patient groups (group 1, group 2) was found to be lower than control group (P = 0.045, P = 0.047). Serum LH value was found to be higher in patient group (group 2) than control group (P = 0.048). Serum estradiol was higher in the group 2 compared to the control group (P = 0.046). Conclusions The described disturbances of some of the observed hormones (LH, E2, F. TES) are complex, particularly in their relationship by which the clinical picture of the hepatitis B related cirrhotic patients and chronic liver disease can be explained.

  15. 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

  16. 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

  17. 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

  18. Molecular genetics, natural history and the demise of childhood leukaemia.

    PubMed

    Greaves, M

    1999-12-01

    The patterns of genetic change, clonal evolution, natural history and latency are very different in the paediatric leukaemias compared with adult epithelial cancers but are similar to those in other childhood cancers of mesenchymal stem cell origin. This distinction has a biological logic in the context of the selective pressures for clonal emergence in different developmental and cellular contexts and has a major impact on curability. Most childhood leukaemias and some other mesenchymal stem cell tumours are of fetal origin and can metastasize without corruption of restraints on cell proliferation or bypassing apoptosis. In marked contrast to most invasive or metastatic epithelial carcinomas in adults, these former cancers then retain sensitivity to therapeutic apoptosis. Moreover, their abbreviated and less complex evolutionary status is associated with less genetic diversity and instability, minimising opportunity for clonal selection for resistance. A minority of leukaemias in children and a higher fraction in adults do, however, have genetic alterations that bypass cell cycle controls and apoptosis imposition. These are the 'bad news' genotypes. The cellular and molecular diversity of acute leukaemia impacts also on aetiology. Paediatric acute leukaemias can be initiated prenatally by illegitimate recombination and fusion gene formation in fetal haemopoiesis. For acute lymphoblastic leukaemia (ALL) in children, twin studies suggest that a secondary postnatal molecular event is also required. This may be promoted by an abnormal or delayed response to common infections. Even for a classic case of a cancer that is intrinsically curable by systematic chemotherapy i.e. childhood ALL, prevention may turn out to be the preferred option.

  19. Molecular genetics, natural history and the demise of childhood leukaemia.

    PubMed

    Greaves, M

    1999-02-01

    The patterns of genetic change, clonal evolution, natural history and latency are very different in the paediatric leukaemias compared with adult epithelial cancers but are similar to those in other childhood cancers of mesenchymal stem cell origin. This distinction has a biological logic in the context of the selective pressures for clonal emergence in different developmental and cellular contexts and has a major impact on curability. Most childhood leukaemias and some other mesenchymal stem cell tumours are of fetal origin and can metastasize without corruption of restraints on cell proliferation or bypassing apoptosis. In marked contrast to most invasive or metastatic epithelial carcinomas in adults, these former cancers then retain sensitivity to therapeutic apoptosis. Moreover, their abbreviated and less complex evolutionary status is associated with less genetic diversity and instability, minimising opportunity for clonal selection for resistance. A minority of leukaemias in children and a higher fraction in adults do, however, have genetic alterations that bypass cell cycle controls and apoptosis imposition. These are the 'bad news' genotypes. The cellular and molecular diversity of acute leukaemia impacts also on aetiology. Paediatric acute leukaemias can be initiated prenatally by illegitimate recombination and fusion gene formation in fetal haemopoiesis. For acute lymphoblastic leukaemia (ALL) in children, twin studies suggest that a secondary postnatal molecular event is also required. This may be promoted by an abnormal or delayed response to common infections. Even for a classic case of a cancer that is intrinsically curable by systematic chemotherapy i.e. childhood ALL, prevention may turn out to be the preferred option.

  20. 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

  1. Association of a murine leukaemia stem cell gene signature based on nucleostemin promoter activity with prognosis of acute myeloid leukaemia in patients.

    PubMed

    Ali, Mohamed A E; Naka, Kazuhito; Yoshida, Akiyo; Fuse, Kyoko; Kasada, Atsuo; Hoshii, Takayuki; Tadokoro, Yuko; Ueno, Masaya; Ohta, Kumiko; Kobayashi, Masahiko; Takahashi, Chiaki; Hirao, Atsushi

    2014-07-18

    Acute myeloid leukaemia (AML) is a heterogeneous neoplastic disorder in which a subset of cells function as leukaemia-initiating cells (LICs). In this study, we prospectively evaluated the leukaemia-initiating capacity of AML cells fractionated according to the expression of a nucleolar GTP binding protein, nucleostemin (NS). To monitor NS expression in living AML cells, we generated a mouse AML model in which green fluorescent protein (GFP) is expressed under the control of a region of the NS promoter (NS-GFP). In AML cells, NS-GFP levels were correlated with endogenous NS mRNA. AML cells with the highest expression of NS-GFP were very immature blast-like cells, efficiently formed leukaemia colonies in vitro, and exhibited the highest leukaemia-initiating capacity in vivo. Gene expression profiling analysis revealed that cell cycle regulators and nucleotide metabolism-related genes were highly enriched in a gene set associated with leukaemia-initiating capacity that we termed the 'leukaemia stem cell gene signature'. This gene signature stratified human AML patients into distinct clusters that reflected prognosis, demonstrating that the mouse leukaemia stem cell gene signature is significantly associated with the malignant properties of human AML. Further analyses of gene regulation in leukaemia stem cells could provide novel insights into diagnostic and therapeutic approaches to AML.

  2. Case report: Concomitant Chronic Lymphocytic Leukaemia and Cytogenetically Normal de novo Acute Leukaemia in a Patient.

    PubMed

    Kajtár, Béla; Rajnics, Péter; Egyed, Miklós; Alizadeh, Hussain

    2015-01-01

    The simultaneous occurrence of acute myeloid leukaemia with untreated chronic lymphocytic leukemia is extremely rare. We report a case of a 74-year-old man who was evaluated for macrocytic anaemia. Based on the morphology and immunophenotyping analysis of peripheral blood, a diagnosis of chronic lymphocytic leukemia was established. Subsequently, the bone marrow examination revealed the presence of two distinct, coexisting CLL and AML clones. Cytogenetic and molecular genetic analysis detected deletion 13q14.3 and unmutated immunoglobulin variable heavy-chain in the CLL clone, only. The AML and CLL clones did not share clonality, and the AML did not involve the peripheral blood. A diagnosis of cytogenetically normal de novo AML occurring concurrently with untreated CLL has not been reported previously in English literature.

  3. Oxidative stress responses and NRF2 in human leukaemia.

    PubMed

    Abdul-Aziz, Amina; MacEwan, David J; Bowles, Kristian M; Rushworth, Stuart A

    2015-01-01

    Oxidative stress as a result of elevated levels of reactive oxygen species (ROS) has been observed in almost all cancers, including leukaemia, where they contribute to disease development and progression. However, cancer cells also express increased levels of antioxidant proteins which detoxify ROS. This includes glutathione, the major antioxidant in human cells, which has recently been identified to have dysregulated metabolism in human leukaemia. This suggests that critical balance of intracellular ROS levels is required for cancer cell function, growth, and survival. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor plays a dual role in cancer. Primarily, NRF2 is a transcription factor functioning to protect nonmalignant cells from malignant transformation and oxidative stress through transcriptional activation of detoxifying and antioxidant enzymes. However, once malignant transformation has occurred within a cell, NRF2 functions to protect the tumour from oxidative stress and chemotherapy-induced cytotoxicity. Moreover, inhibition of the NRF2 oxidative stress pathway in leukaemia cells renders them more sensitive to cytotoxic chemotherapy. Our improved understanding of NRF2 biology in human leukaemia may permit mechanisms by which we could potentially improve future cancer therapies. This review highlights the mechanisms by which leukaemic cells exploit the NRF2/ROS response to promote their growth and survival.

  4. [The care pathway of a child with leukaemia].

    PubMed

    Lebot, Anne-Claire; Pastorelli, Céline; Tessier, Emmanuelle; Edelga, Laëtitia; Rialland, Fanny

    2015-01-01

    Each year in France, 500 children and their family are faced with a diagnosis of leukaemia. Their lives then become centred on this disease. From diagnosis to cure, and over the following years, a special relationship is established between the child, their family and the staff of the paediatric haemato-oncology department.

  5. Oxidative Stress Responses and NRF2 in Human Leukaemia

    PubMed Central

    Abdul-Aziz, Amina; MacEwan, David J.; Bowles, Kristian M.; Rushworth, Stuart A.

    2015-01-01

    Oxidative stress as a result of elevated levels of reactive oxygen species (ROS) has been observed in almost all cancers, including leukaemia, where they contribute to disease development and progression. However, cancer cells also express increased levels of antioxidant proteins which detoxify ROS. This includes glutathione, the major antioxidant in human cells, which has recently been identified to have dysregulated metabolism in human leukaemia. This suggests that critical balance of intracellular ROS levels is required for cancer cell function, growth, and survival. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor plays a dual role in cancer. Primarily, NRF2 is a transcription factor functioning to protect nonmalignant cells from malignant transformation and oxidative stress through transcriptional activation of detoxifying and antioxidant enzymes. However, once malignant transformation has occurred within a cell, NRF2 functions to protect the tumour from oxidative stress and chemotherapy-induced cytotoxicity. Moreover, inhibition of the NRF2 oxidative stress pathway in leukaemia cells renders them more sensitive to cytotoxic chemotherapy. Our improved understanding of NRF2 biology in human leukaemia may permit mechanisms by which we could potentially improve future cancer therapies. This review highlights the mechanisms by which leukaemic cells exploit the NRF2/ROS response to promote their growth and survival. PMID:25918581

  6. Expression of low molecular weight proteins in patients with leukaemia.

    PubMed

    Sheikh, N; Abid, R; Qureshi, A W; Basheer, T

    2012-06-01

    The current study is conducted to observe the differences in the level of low molecular weight proteins in the sera of patients with leukaemia in comparison to healthy subjects (control group). The sera of patients with leukaemia showed 15 peaks in the densitometric curve in comparison to the seven peaks of the controls. The peaks in the experimental samples that coincide with those in the control were of 134.14, 113.15, 76.06, 63.25, 48.07, 22.85 and 16.47 kDa molecular weights, respectively. Most of the new peaks appeared between the proteins of molecular weight 36-29 kDa in the experimental groups. Mean density of the 134.14 kDa protein band showed an increase in the protein in experimental groups I and II only whereas 113.15 and 22.85 kDa protein were increased in all experimental groups of patients with leukaemia. The expression of 76.06 and 63.25 kDa protein fraction was downregulated in the patients with leukaemia. A decline in the level of the protein of 48.07 kDa was observed in patients with leukaemia except in group I. Unlike the other protein fractions, the level of the protein of 16.47 kDa was significantly (p < 0.05) increased with a maximum density in group II. Intergroup experimental) comparison revealed an increasing pattern of 95.44 and 89.21 kDa with maximum level in group III sera. However the protein fractions of 38.07 and 34.94 kDa varied in the serum with maximum density in Group IV Protein fractions of 32.92 and 31.24 kDa were expressed in all age groups of patients with leukaemia with a maximum density in group III whereas the percentage densities of 14.42 and 13.56 kDa protein were quite different. This preliminary study will provide a basis to study the role of different proteins in patients with leukaemia.

  7. 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

  8. 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

  9. RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype.

    PubMed

    Estécio, Marcos R H; Maddipoti, Sirisha; Bueso-Ramos, Carlos; DiNardo, Courtney D; Yang, Hui; Wei, Yue; Kondo, Kimie; Fang, Zhihong; Stevenson, William; Chang, Kun-Sang; Pierce, Sherry A; Bohannan, Zachary; Borthakur, Gautam; Kantarjian, Hagop; Garcia-Manero, Guillermo

    2015-05-01

    Correlative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re-expression. Furthermore, relapse-free survival of non-inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias.

  10. Biomimetic nanoparticles for siRNA delivery in the treatment of leukaemia.

    PubMed

    Guo, Jianfeng; Cahill, Mary R; McKenna, Sharon L; O'Driscoll, Caitriona M

    2014-12-01

    Leukaemia is a bone marrow cancer occurring in acute and chronic subtypes. Acute leukaemia is a rapidly fatal cancer potentially causing death within a few weeks, if untreated. Leukaemia arises as a result of disruption to haematopoietic precursors, caused either by acquired gene fusions, gene mutations or inappropriate expression of the relevant oncogenes. Current treatment options have made significant progress, but the 5 year survival for acute leukaemia remains under 10% in elderly patients, and less than 50% for some types of acute leukaemia in younger adults. For chronic leukaemias longer survival is generally expected and for chronic myeloid leukaemia patients on tyrosine kinase inhibitors the median survival is not yet reached and is expected to exceed 10 years. Chemotherapy and haematopoietic stem cell transplantation (HSCT) for acute leukaemia provide the mainstay of therapy for patients under 65 and both carry significant morbidity and mortality. Alternative and superior therapeutic strategies for acute leukaemias are urgently required. Recent molecular-based knowledge of recurring chromosome rearrangements, in particular translocations and inversions, has resulted in significant advances in understanding the molecular pathogenesis of leukaemia. Identification of a number of unique fusion genes has facilitated the development of highly specific small interfering RNAs (siRNA). Although delivery of siRNA using multifunctional nanoparticles has been investigated to treat solid cancers, the application of this approach to blood cancers is at an early stage. This review describes current treatments for leukaemia and highlights the potential of leukaemic fusion genes as therapeutic targets for RNA interference (RNAi). In addition, the design of biomimetic nanoparticles which are capable of responding to the physiological environment of leukaemia and their potential to advance RNAi therapeutics to the clinic will be critically evaluated.

  11. Disseminated fungal infection complicated with pulmonary haemorrhage in a case of acute myeloid leukaemia

    PubMed Central

    Thulkar, S; Sharma, S; Das, P; Kumar, L

    2000-01-01

    Pulmonary haemorrhage is a common necropsy finding in acute leukaemia, however, it is rarely diagnosed during life. A man with acute myeloid leukaemia is reported who presented with disseminated fungal infection, anaemia, thrombocytopenia, and subconjuctival and petechial haemorrhages. During the course of the patient's illness, the chest infection was complicated with bilateral pulmonary haemorrhage. The diagnosis of pulmonary haemorrhage was based on characteristic clinical and radiological findings. The patient improved on treatment.


Keywords: leukaemia; pulmonary infiltrate; haemorrhage PMID:11060145

  12. Oncolytic reovirus enhances rituximab-mediated antibody-dependent cellular cytotoxicity against chronic lymphocytic leukaemia.

    PubMed

    Parrish, C; Scott, G B; Migneco, G; Scott, K J; Steele, L P; Ilett, E; West, E J; Hall, K; Selby, P J; Buchanan, D; Varghese, A; Cragg, M S; Coffey, M; Hillmen, P; Melcher, A A; Errington-Mais, F

    2015-09-01

    The naturally occurring oncolytic virus (OV), reovirus, replicates in cancer cells causing direct cytotoxicity, and can activate innate and adaptive immune responses to facilitate tumour clearance. Reovirus is safe, well tolerated and currently in clinical testing for the treatment of multiple myeloma, in combination with dexamethasone/carfilzomib. Activation of natural killer (NK) cells has been observed after systemic delivery of reovirus to cancer patients; however, the ability of OV to potentiate NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is unexplored. This study elucidates the potential of oncolytic reovirus for the treatment of chronic lymphocytic leukaemia (CLL), both as a direct cytotoxic agent and as an immunomodulator. We demonstrate that reovirus: (i) is directly cytotoxic against CLL, which requires replication-competent virus; (ii) phenotypically and functionally activates patient NK cells via a monocyte-derived interferon-α (IFNα)-dependent mechanism; and (iii) enhances ADCC-mediated killing of CLL in combination with anti-CD20 antibodies. Our data provide strong preclinical evidence to support the use of reovirus in combination with anti-CD20 immunotherapy for the treatment of CLL.

  13. Dermatoglyphics in childhood leukaemia: a guide to prognosis and aetiology?

    PubMed

    Till, M; Larrauri, S; Smith, P G

    1978-06-01

    The results of analysis of the dermatoglyphics of 152 children with acute lymphoblastic leukaemia (ALL) (and the first-degree relatives of 54 of them) contrast with those of 31 children with acute myeloblastic leukaemia (AML) (and the first-degree relatives of 25 of them). In ALL our findings suggest that neither genetic susceptibility nor an environmental factor, effective during the early antenatal period, is of aetiological importance; but the response to treatment, assessed as length of first remission, was found to be related to the amount of fingertip pattern. This may have clinical application. In AML there is evidence of a genetically determined factor carrying a high risk of the development of the disease, in that a member of each of 5 different families of the 25 studied bore a rare hypothenar pattern, compared with none in 75 control families. No dermatoglyphic features were of prognostic significance in AML.

  14. How animal models of leukaemias have already benefited patients.

    PubMed

    Ablain, Julien; Nasr, Rihab; Zhu, Jun; Bazarbachi, Ali; Lallemand-Breittenbach, Valérie; de Thé, Hugues

    2013-04-01

    The relative genetic simplicity of leukaemias, the development of which likely relies on a limited number of initiating events has made them ideal for disease modelling, particularly in the mouse. Animal models provide incomparable insights into the mechanisms of leukaemia development and allow exploration of the molecular pillars of disease maintenance, an aspect often biased in cell lines or ex vivo systems. Several of these models, which faithfully recapitulate the characteristics of the human disease, have been used for pre-clinical purposes and have been instrumental in predicting therapy response in patients. We plea for a wider use of genetically defined animal models in the design of clinical trials, with a particular focus on reassessment of existing cancer or non-cancer drugs, alone or in combination.

  15. 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

  16. Alternative models for early onset of childhood leukaemia.

    PubMed Central

    Wheldon, T. E.; Mairs, R. J.; Barrett, A.; Wheldon, E. G.; Gibson, B. E.

    1992-01-01

    This paper considers theoretical models for early-onset childhood leukaemia. The major focus of attention is the two-hit mutational model. A simple mathematical representation is used to explore mechanisms which might lead to onset of leukaemia at an unusually early age. Two such mechanisms are considered. The first of these, a germinal or very early embryonic first mutation is shown to imply that multiple independent leukaemic clones are likely to arise sequentially in very young patients. Clonal multiplicity could underlie the poor prognosis which has been associated with early onset childhood acute lymphoblastic leukaemia. It implies that curative therapy might require intensive treatment followed by bone marrow rescue to ensure eradication of all single-hit predisposed target cells. The prediction of multiple leukaemic clones might be tested in female patients by means of X-linked restriction fragment length polymorphisms and in patients with B-lineage neoplasms by determination of immunoglobin gene rearrangements. A second mechanism for early onset leukaemogenesis is the occurrence of a high cellular mutation rate in some patients. This is shown to result in leukaemia at significantly earlier age if the mutation rate is sufficiently high to influence target cell loss rate. This mechanism would enable more rapid clonal evolution of leukaemic cells and the early emergence of drug resistant variants. The prediction might be tested experimentally by sequential observation of genetic markers (e.g. Karyotypes, DNA fingerprint patterns) and the rate of emergence of drug resistant phenotypes. Other models, considered more briefly, include one-hit mutational 'dominants' in the developing embryo and faster growth kinetics in neoplasms of younger patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1503920

  17. BET inhibitor resistance emerges from leukaemia stem cells.

    PubMed

    Fong, Chun Yew; Gilan, Omer; Lam, Enid Y N; Rubin, Alan F; Ftouni, Sarah; Tyler, Dean; Stanley, Kym; Sinha, Devbarna; Yeh, Paul; Morison, Jessica; Giotopoulos, George; Lugo, Dave; Jeffrey, Philip; Lee, Stanley Chun-Wei; Carpenter, Christopher; Gregory, Richard; Ramsay, Robert G; Lane, Steven W; Abdel-Wahab, Omar; Kouzarides, Tony; Johnstone, Ricky W; Dawson, Sarah-Jane; Huntly, Brian J P; Prinjha, Rab K; Papenfuss, Anthony T; Dawson, Mark A

    2015-09-24

    Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/β-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.

  18. First-line treatment of chronic myeloid leukaemia

    PubMed Central

    O'Dwyer, Michael

    2010-01-01

    Since the introduction of imatinib just over a decade ago, there has been a dramatic change in the treatment and prognosis of early chronic phase chronic myeloid Leukaemia (CML). This review article focuses on recent advances, culminating in the approval of nilotinib by the US Food and Drug Administration for the treatment of adult patients with newly diagnosed CML in the chronic phase. PMID:23556068

  19. 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.

  20. 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

  1. Acute basophilic leukaemia in a three-month-old calf.

    PubMed

    Laabs, Eva-Maria; Mischke, Reinhard; Dziallas, Peter; Maiolini, Arianna; Tipold, Andrea; Raddatz, Barbara; Puff, Christina; Rehage, Jürgen

    2015-09-03

    A three-month-old female Holstein-Friesian calf was presented with acute tetraparesis. After neurological examination a multifocal lesion in the central nervous system was suspected with the most pronounced lesions between the third thoracic and the third lumbar vertebrae. Haematological examination revealed moderate anaemia as well as severe thrombocytopenia, neutropenia and leucocytosis. A blood smear and bone marrow aspirate exhibited predominantly blasts with basophilic granulation leading to a diagnosis of acute (myeloid) leukaemia with involvement of the basophilic lineage or an acute basophilic leukaemia. Magnetic resonance imaging revealed spinal cord compression; at necropsy, extensive localised haemorrhages extending into the thoracic vertebral canal were found. Histopathology revealed a large population of blast cells in several tissues including the meninges. Due to multifocal detection of neoplastic cells in the vascular system, neoplasia of the haematopoietic system was assumed in agreement with haematological findings. Signs of paresis could be explained by intramedullary spinal cord haemorrhage and myeloid infiltrations of meningeal vessels. In conclusion, despite its rarity, acute myeloid leukaemia with involvement of the basophilic lineage may be considered in diagnosing calves with progressive deteriorating general condition, paresis, leucocytosis with moderate basophilic differentiation or haemorrhagic disorders.

  2. Inotuzumab ozogamicin in the management of acute lymphoblastic leukaemia.

    PubMed

    Morley, N J; Marks, D I

    2016-01-01

    Whilst most adult patients with acute lymphoblastic leukaemia will go into remission with standard induction chemotherapy, many will relapse. Response rates to standard salvage chemotherapy regimens are low and the outlook on relapse is very poor and associated with significant morbidity and mortality hence the need for newer targeted approaches. Inotuzumab ozogamicin (previously known as CMC-544) is an antibody-drug conjugate and consists of a monoclonal anti-CD22 antibody bound to calicheamicin. The target, CD22, is widely expressed on acute lymphoblastic leukaemia cells making it a potential therapeutic target. The calicheamicin is delivered intracellularly and causes leukaemia cell apoptosis. Overall response rates of 57% were observed in a Phase II study and the final results of a Phase III randomised controlled trial comparing this drug to the investigator choice 'standard of care' chemotherapy are eagerly awaited. Whilst initial results are promising, there have been concerns regarding liver toxicity and the incidence of veno-occlusive disease of the liver especially in patients who have previously received or go on to allogeneic stem cell transplant.

  3. 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

  4. Bone marrow necrosis at transformation of chronic granulocytic leukaemia treated with interferon.

    PubMed Central

    Kendra, J R; Pickens, S; Singh, A K; Singh, K

    1992-01-01

    A patient with chronic myeloid leukaemia was treated with interferon without using conventional cytotoxic agents. Bone marrow necrosis developed at the onset of blast transformation. It is suggested that cytotoxic drugs should be given before treatment with interferon for chronic myeloid leukaemia. Cytotoxic drugs may also be needed to prevent rapid bone marrow growth once interferon has been withdrawn. PMID:1401221

  5. 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

  6. Oral manifestations as an early clinical sign of acute myeloid leukaemia: a case report.

    PubMed

    Guan, G; Firth, N

    2015-03-01

    Leukaemia is the most common malignancy in children and one of the most common malignancies in young adults. Acute myeloid leukaemia is often associated with early oral manifestations. The purpose of this study is to report the case of a 49-year-old male with spontaneous gingival bleeding for over two years with undiagnosed leukaemia. Haematological investigation was instigated and on referral to the Haematology Department at Dunedin Public Hospital, the diagnosis of an acute myeloid leukaemia was confirmed. Since oral lesions can be one of the early events of acute myeloid leukaemia, they may be considered as an important diagnostic indicator for oral health practitioners, and their roles in diagnosing and treating such patients.

  7. Vincristine and Prednisone for the Induction of Remissions in Acute Childhood Leukaemia

    PubMed Central

    Hardisty, R. M.; McElwain, T. J.; Darby, Caryl W.

    1969-01-01

    A total of 65 children with acute lymphoblastic leukaemia and seven with other types of acute leukaemia received treatment with a combination of vincristine and prednisone. In all 122 courses of treatment were given. Of 22 patients with acute lymphoblastic leukaemia who received this as their first treatment, all achieved complete remission. The complete remission rates were 82% for patients with acute lymphoblastic leukaemia in their first relapse, 63% in the second relapse, and much lower in subsequent relapses and in the patients with other types of acute leukaemia. Alopecia and gastrointestinal and neuromuscular toxicity occurred respectively in 51%, 29%, and 21% of instances, only the last of these side-effects of vincristine being dose-related. Most of the complete remissions were obtained with a total dose of vincristine which carried only a low risk of neurotoxicity. PMID:5254045

  8. In vitro stimulation of cell-mediated cytotoxicity by acute leukaemias.

    PubMed Central

    Taylor, G. M.

    1981-01-01

    Acute leukaemias stimulated proliferative and cell-mediated cytotoxic (CMC) responses in vitro in normal (unprimed) lymphocytes. Proliferation was detected by increases in viable cell counts and [3H]dT incorporation in mixed lymphocyte-leukaemia-cell cultures. CMC detected on cultured cell-line targets (CCL) including K562 was generally much stronger than on fresh leukaemia cells, and correlated with stimulation of [3H]dT uptake in the responding lymphocytes. Leukaemias which were resistant as targets to CMC were able competitively to inhibit CMC on K562, though not as efficiently as blocking by K562 itself. With one leukaemia, blocking of CMC increased as the level of CMC on K562 was amplified by greater numbers of stimulating cells in the sensitization phase. This suggests that in certain cases blocking of effector cells by acute-leukaemia cells may depend upon the state of activation of the effector cells. Lymphocytes from a leukaemia patient in remission, treated with allogeneic leukaemia-cell immunotherapy and stimulated in vitro with immunizing leukaemia cells, developed strong anti-leukaemic CMC. A non-immunized patient's lymphocytes did not respond in this way, despite comparable levels of CMC on K562 in both patients. Dual stimulation of unprimed normal lymphocytes and remission lymphocytes with allogeneic or autologous leukaemias and various cell lines, amplified anti-leukaemic CMC, but did not markedly alter CMC or CCL. These data do not formally exclude the mediation of in vitro-stimulated anti-leukaemic CMC by NK-like cells, but suggest that such effector cells differ qualitatively from NK-like cells detected in the absence of anti-leukaemic CMC. PMID:6451236

  9. 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

  10. Uveitis and Systemic Inflammatory Markers in Convalescent Phase of Ebola Virus Disease.

    PubMed

    Chancellor, John R; Padmanabhan, Sriranjani P; Greenough, Thomas C; Sacra, Richard; Ellison, Richard T; Madoff, Lawrence C; Droms, Rebecca J; Hinkle, David M; Asdourian, George K; Finberg, Robert W; Stroher, Ute; Uyeki, Timothy M; Cerón, Olga M

    2016-02-01

    We report a case of probable Zaire Ebola virus-related ophthalmologic complications in a physician from the United States who contracted Ebola virus disease in Liberia. Uveitis, immune activation, and nonspecific increase in antibody titers developed during convalescence. This case highlights immune phenomena that could complicate management of Ebola virus disease-related uveitis during convalescence.

  11. 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.

  12. [Characteristic of the yeast isolated from patients with leukaemia].

    PubMed

    Fedorovskaia, E A; Rybal'skaia, A P; Skachkova, N K; Mel'nik, E A; Nemirovskaia, L N; Nagornaia, S S; Babich, T V; Polishchuk, L V

    2008-01-01

    It has been shown that biotopes of upper respiratory system and intestine were contaminated with yeast in 44.6% of patients with leukaemia (of 112 examined ones). Their quantity exceeds the boundary value for practically healthy people and is > or = 10(2) KOE/ml in the nasal activity and fauces and < or = 10(4) KOE/g in the intestine. It was established that in patients with leucemia the mycotic complications are mainly caused by anamorphous yeast of ascomycetic affinity. Candida albicans, as well as C. glabrata, C. rugosa and Candida sp. play the leading role. The Candida genus species are mainly sensitive to amphotericine B, clotrisamol and nistatin.

  13. 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

  14. Incomplete Reiter's syndrome following chemotherapy of acute myeloid leukaemia.

    PubMed Central

    Dharmasena, F.; Englert, H.; Catovsky, D.; Galton, D. A.; Drysdale, H. C.

    1986-01-01

    Reiter's syndrome and other reactive arthritides have been described following infection with various organisms although they can occur in unusual circumstances without an obvious infectious precipitant. We have recently witnessed two attacks of reactive arthritis and keratoderma blenorrhagica occurring in an HLA B27 adult male following chemotherapy on two separate occasions with the same drugs for acute myeloid leukaemia. No attacks occurred before or following the cessation of these drugs. This supports the view that in Reiter's syndrome a common pathogenic pathway is triggered by an 'arthritogenic factor' which in this case appears to have been chemical. PMID:3476917

  15. Anti-lymphocyte antibody levels in chronic lymphocytic leukaemia.

    PubMed

    Lewis, C M; Pegrum, G D

    1979-01-01

    A radioimmunoassay for measuring levels of lymphocyte autoantibody in chronic lymphocytic leukaemia (CLL) has been developed. Antibody in the form of crude IgG was extracted from patients' sera and iodinated. The assay utilizes its cross-reactivity with other CLL cells. Levels were measured in 23 patients. The results show that an inverse relationship exists between the quantity of circulating CLL autoantibodies and the number of mouse red blood cell rosetting lymphocytes (M cells). The preliminary findings do not correlate with disease activity although it is our impression that patients who are maintaining higher levels of autoantibody and fewer M-rosetting cells have nonprogressive disease.

  16. Hypercalcaemia associated with chronic lymphocytic leukaemia in a Giant Schnauzer.

    PubMed

    Kleiter, M; Hirt, R; Kirtz, G; Day, M J

    2001-05-01

    A 7-year-old male Giant Schnauzer was referred with a history of severe vomiting, lethargy, weight loss, polydipsia and polyuria. Detailed investigations revealed leucocytosis with a marked lymphocytosis, mild non-regenerative anaemia, thrombocytopenia, hypercalcaemia and azotaemia. Circulating lymphocytes were small and well-differentiated, and the same lymphoid population was present in bone marrow. Chronic lymphocyctic leukaemia with associated paraneoplastic hypercalcaemia was diagnosed. Immunohistochemical staining of a bone marrow biopsy revealed a neoplastic B-cell line expressing CD79. The dog responded to therapy with prednisolone and chlorambucil for a period of 8 months.

  17. 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.

  18. Peripheral ulcerative keratitis as a complication of acute myeloid leukaemia

    PubMed Central

    Morjaria, Rupal; Barge, Tom; Mordant, David; Elston, John

    2014-01-01

    We report a rare presentation of acute bilateral peripheral ulcerative keratitis (PUK) in a patient with a new diagnosis of untreated acute myeloid leukaemia (AML). To the best of our knowledge, this is the first report of PUK associated with untreated AML and we stress the importance of a rapid and thorough testing to exclude other diagnoses. The patient lost his vision within 10 days to counting fingers. Rapid diagnosis allowed a good visual recovery following prompt treatment with oral steroids and systemic chemotherapy treatment for the AML. PMID:25362188

  19. Acquired factor XI inhibitor in chronic lymphocytic leukaemia.

    PubMed Central

    Goodrick, M. J.; Prentice, A. G.; Copplestone, J. A.; Pamphilon, D. H.; Boon, R. J.

    1992-01-01

    A 71 year old man with chronic lymphocytic leukaemia (CLL) experienced excessive bleeding following transurethral resection of the prostate. Investigations showed a prolonged kaolin cephalin clotting time (KCCT) with low concentrations of factor XI. The prolonged KCCT was largely corrected by mixing with normal plasma but this correction was lost on incubation, confirming the presence of an inhibitor. He was treated with pulsed methylprednisolone and chlorambucil which resulted in the resolution of the bleeding problem and the loss of detectable circulating inhibitor. PMID:1577975

  20. Abnormalities in the erythrocyte membrane in acute lymphoid leukaemia.

    PubMed Central

    Kundu, M; Basu, J; Chakrabarti, P; Rakshit, M M

    1989-01-01

    Erythrocytes from patients suffering from acute lymphoid leukaemia (ALL) show decreased proportions of spectrin tetrameters and altered spatial distribution of band 4.1 and ankyrins. These abnormalities of the cytoskeleton are probably responsible for altered membrane fluidity and transbilayer distribution of phosphatidylethanolamine in ALL. ALL is associated with severe anaemia and usually, but not always, with overproduction of lymphocytes. To our knowledge, this is the first report of abnormalities in the erythrocyte membrane in ALL which may, in part, be responsible for the observed anaemia. PMID:2730573

  1. Current status of gene expression profiling in the diagnosis and management of acute leukaemia.

    PubMed

    Bacher, Ulrike; Kohlmann, Alexander; Haferlach, Torsten

    2009-06-01

    Gene expression profiling (GEP) enables the simultaneous investigation of the expression of tens of thousands of genes and was successfully introduced in leukaemia research a decade ago. Aiming to better understand the diversity of genetic aberrations in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), pioneer studies investigated and confirmed the predictability of many cytogenetic and molecular subclasses in AML and ALL. In addition, GEP can define new prognostic subclasses within distinct leukaemia subgroups, as illustrated in AML with normal karyotype. Another approach is the development of treatment-specific sensitivity assays, which might contribute to targeted therapy studies. Finally, GEP might enable the detection of new molecular targets for therapy in patients with acute leukaemia. Meanwhile, large multicentre studies, e.g. the Microarray Innovations in LEukaemia (MILE) study, prepare for a standardised introduction of GEP in leukaemia diagnostic algorithms, aiming to translate this novel methodology into clinical routine for the benefit of patients with the complex disorders of AML and ALL.

  2. 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.

  3. Concepts of remission, curability and lineage involvement in relationship to the problems of minimal residual leukaemia.

    PubMed

    Jasmin, C; Charpentier, A; Marion, S; Proctor, S J

    1991-07-01

    Minimal residual leukaemia (MRL) is due to chemotherapeutic failure. Chemoincurability in chronic myeloid leukaemia and in myelodysplastic syndrome is the norm and is the result of tumour defect arising within the marrow stem cell compartment. We propose that this is indeed the state of affairs in the majority of adult acute leukaemias and such tumours derived from stem cells are chemoincurable. The proportion of acute leukaemias which belong to this category can only be cured by allogeneic bone marrow transplantation though conventional chemotherapy and autotransplant may result in prolonged periods of remission and a return to a preleukaemic state in some patients. A proportion of the acute leukaemias occurring predominantly in children are presently curable by chemotherapy. It is hypothesized that these chemocurable leukaemias derive from the compartment of haemopoietic progenitors already irreversibly committed to a single lineage. Some recent studies using markers of the leukaemic clone to determine the origin of in vitro myeloid colony forming cells support this concept. Intrinsic and/or acquired genetic chemoresistance represents a supplementary restriction to the chemocurability of acute leukaemias. New methods of detecting MRL are sensitive enough to detect up to one leukaemic cell in 10(6) bone marrow mononuclear cells. However, it is possible that even such sensitive techniques will not be sufficient to determine whether patients in complete remission continue to harbour leukaemic cells in the stem cell compartment when the marker of interest might not be expressed.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Vaccination and the risk of childhood acute leukaemia: the ESCALE study (SFCE)

    PubMed Central

    Mallol-Mesnard, Nathalie; Menegaux, Florence; Auvrignon, Anne; Auclerc, Marie-Françoise; Bertrand, Yves; Nelken, Brigitte; Robert, Alain; Michel, Gérard; Margueritte, Geneviève; Perel, Yves; Méchinaud, Françoise; Bordigoni, Pierre; Leverger, Guy; Baruchel, André; Hémon, Denis; Clavel, Jacqueline

    2007-01-01

    Background In 2002, a poster alerted the French health authorities to the possibility that the risk of childhood leukaemia might be increased by hepatitis B vaccination. Elucidating the role of vaccination in the etiology of childhood acute leukaemia was therefore included in the objectives of an ongoing national study. Methods The ESCALE study was a French national population-based case-control study conducted in France in 2003 and 2004 in order to investigate the role of infectious, environmental and genetic factors in 4 childhood neoplastic diseases (leukaemia, lymphoma, neuroblastoma, and brain tumor). The controls were randomly selected from the French population and age and gender frequency matched with the cases. A total of 776 cases of acute leukaemia (91% of the eligible cases) and 1681 controls (69% of the eligible controls) were included. In a specific standardized telephone interview, which was the same for both the cases and controls, each mother was asked to read out her child’s complete vaccination record. Results No association between vaccination and the risk of childhood acute leukaemia (ALL or AML) was observed. No relationship between the risk of leukaemia and the type of vaccine, number of doses of each vaccine, total number of injections, total number of vaccine doses or number of early vaccinations was evidenced. No confounding factor was observed. Conclusion The study did not show any evidence of a role of vaccination in the etiology of childhood leukaemia. PMID:17227780

  5. Feline leukaemia provirus load during the course of experimental infection and in naturally infected cats.

    PubMed

    Hofmann-Lehmann, R; Huder, J B; Gruber, S; Boretti, F; Sigrist, B; Lutz, H

    2001-07-01

    Feline leukaemia virus (FeLV) infection in domestic cats can vary in its outcome (persistent, transient, no infection) for reasons that are not entirely known. It was hypothesized that the initial virus and provirus load could significantly influence the course of retrovirus infection. To determine the role of provirus loads, two methods of PCR, a nested PCR and a fluorogenic probe-based (TaqMan) real-time quantitative PCR, which were specific to the U3 region of FeLV-A were established. FeLV provirus in naturally and experimentally infected cats was then measured. Only 3 weeks after experimental FeLV-A infection, persistently infected cats demonstrated higher provirus loads and lower humoral immune responses than cats that had overcome antigenaemia. Lower initial provirus loads were associated with successful humoral immune responses. Unexpectedly, provirus in the buffy-coat cells of two cats that tested negative for the p27 antigen (a marker for viraemia) was also detected. In 597 Swiss cats, comparison of p27 antigen levels with PCR results revealed broad agreement. However, similar to the experimental situation, a significant number of animals (10%) was negative for the p27 antigen and FeLV-positive by PCR. These cats had a mean provirus load 300-fold lower than that of animals testing positive for the p27 antigen. In conclusion, an association between the provirus load and the outcome of FeLV infection was found. Detection of provirus carriers should contribute to further the control of FeLV. In addition, quantification of provirus loads will lead to a better understanding of FeLV pathogenesis and anti-retrovirus protective mechanisms.

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. t(1:14) and trisomy 4 in a patient with concomitant leukaemias.

    PubMed

    Zahir, Muhammad Nauman; Masood, Nehal; Shabbir-Moosajee, Munira

    2014-05-01

    Cytogenetic abnormalities have long been recognized as the genetic basis of the occurrence of various malignancies. Specific cytogenetic abnormalities have shown to occur recurrently in particular subtypes of leukaemias and lymphomas. t(1;14) is an infrequently occurring recurrent chromosomal translocation that has been described in literature to be associated with haematological malignancies. Trisomy 4 is another rare genetic abnormality which has been reported in association with both acute myeloid and lymphoid leukaemias. The concomitant occurrence of a myeloid malignancy in association with a lymphoproliferative disorder is a distinctly unusual phenomenon. We report the case of a young patient with concomitant T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia with a novel cytogenetic abnormality i.e. t(1;14) with trisomy 4. We believe this is the first reported case where a patient with two concomitant haematological malignancies, harboured this karyotype.

  13. Oral complications and dental care in children with acute lymphoblastic leukaemia.

    PubMed

    Valéra, Marie-Cécile; Noirrit-Esclassan, Emmanuelle; Pasquet, Marléne; Vaysse, Fréderic

    2015-08-01

    Acute leukaemia is the most common type of childhood cancer, the acute lymphoblastic type accounting for the majority of cases. Children affected by leukaemia receive various forms of treatments including chemotherapeutic agents and stem cell transplants. Leukaemia and its treatment can directly or indirectly affect oral health and further dental treatments. The oral complications include mucositis, opportunistic infections, gingival inflammation and bleeding, xerostomia and carious lesions. An additional consideration in children is the impact of the treatments on the developing dentition and on orofacial growth. The aim of this review is to describe the oral complications in children with acute lymphoblastic leukaemia and the methods of prevention and management before, during and after the cancer treatment.

  14. Role of mesenchymal stem cells in leukaemia: Dr. Jekyll or Mr. Hyde?

    PubMed

    Wong, Rebecca S Y; Cheong, Soon-Keng

    2014-08-01

    Mesenchymal stem cells (MSCs) have captured the attention of researchers today due to their multipotent differentiation capacity. Also, they have been successfully applied clinically, in the treatment of various diseases of the heart and musculoskeletal systems, with encouraging results. Their supportive role in haematopoiesis and their anti-inflammatory and immunomodulatory properties have enhanced their contribution towards the improvement of engraftment and the treatment of graft-versus-host disease in patients receiving haematopoietic stem cell transplantation. However, there is a growing body of research that supports the involvement of MSCs in leukaemogenesis with several genetic and functional abnormalities having been detected in the MSCs of leukaemia patients. MSCs also exert leukaemia-enhancing effects and induce chemotherapy resistance in leukaemia cells. This paper addresses the key issues in the therapeutic value as well as the harmful effects of the MSCs in leukaemia with a sharp focus on the recent updates in the published literature. PMID:23794030

  15. 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

  16. Antisera against leukaemia-associated antigens on human lymphocytes.

    PubMed Central

    Hsu, C C; Marti, G E; Mittal, K K

    1977-01-01

    Antisera were raised in rabbits against leukaemic lymphosarcoma (LSL) cells which carried surface markers of both thymus-derived T lymphocytes (T cells) and bone marrow-derived B lymphocytes (B cells). After absorption with leucocytes, erythrocytes and serum proteins from normal individuals, the antisera demonstrated significant complement-dependent cytotoxicity against leukaemic cells from patients with acute lymphoblastic leukaemia (ALL) (9/11), LSL (7/9) and chronic lymphocytic leukaemia (CLL) (9/12), with an antibody titre of 1:64 or greater. The antisera did not react with: (a) blood lymphocytes from clinically healthy individuals (0/23), patients with ono-lymphoproliferative disorders (0/8) and normal umbilical cords (0/3), (b) normal lymphocytes stimulated by pokeweed mitogen (0/7), allogeneic lymphocytes (0/3), fetuin (0/1), purified protein derivative (PPD) (0/2), and candida antigen (0/1); (C) normal marrow cells (0/3), (D) normal thymocytes (0/2) and (E) leukaemic cells from patients with acute myeloblastic (AML) (0/10) and chronic granulocytic leukaemia (CGL) (0/3). However, the antisera did react with lymphoblastoid cells from continuous B-cell lines derived from an AML patient and from a non-leukaemic individual and, to a lesser extent, with lymphocytes from patients with infectious mononucleosis. The antisera also reacted with lymphocytes from chronically infected tonsils. Cytotoxicity of the antisera against lymphoblastoid and tonsillar cells was inhibited by ALL and CLL cell-lysates; and, conversely, cytotoxicity against ALL cells was inhibited by the lymphoblastoid cell extract. In contrast, a cell lysate or extract from normal inhibited by the lymphoblastoid cell extract. In contrast, a cell lysate or extract from normal lymphocytes did not inhibit cytotoxicity toward lymphoblastoid, tonsillar or ALL cells. Cytotoxicity of the antisera was neutralized by a goat anti-rabbit IgG (GAR IgG). These results suggest that the antisera contained

  17. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.

    PubMed

    Dawson, Mark A; Prinjha, Rab K; Dittmann, Antje; Giotopoulos, George; Bantscheff, Marcus; Chan, Wai-In; Robson, Samuel C; Chung, Chun-wa; Hopf, Carsten; Savitski, Mikhail M; Huthmacher, Carola; Gudgin, Emma; Lugo, Dave; Beinke, Soren; Chapman, Trevor D; Roberts, Emma J; Soden, Peter E; Auger, Kurt R; Mirguet, Olivier; Doehner, Konstanze; Delwel, Ruud; Burnett, Alan K; Jeffrey, Phillip; Drewes, Gerard; Lee, Kevin; Huntly, Brian J P; Kouzarides, Tony

    2011-10-02

    Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.

  18. [Necrotizing tonsillitis and renal vein thrombosis due to acute myeloid leukaemia].

    PubMed

    Akram, Javed; Josefsson, Pernilla; Rømeling, Frans

    2012-09-01

    A 37-year-old woman was admitted to hospital with severe tonsillitis with unilateral necrotizing tonsillitis. She suddenly got fever, malaise, difficulties swallowing, pain in the throat and deterioration despite four days of penicillin treatment. During hospitalisation, she experienced abdominal pain, and blood tests showed pancytopenia. She was transferred to a haematological department, where a bone marrow biopsy showed acute myeloid leukaemia. Subsequently, an abdominal computed tomography with intravenous contrast revealed bilateral renal vein thrombosis, probably because of coagulopathy due to leukaemia.

  19. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia

    PubMed Central

    Dawson, Mark A.; Prinjha, Rab K.; Dittman, Antje; Giotopoulos, George; Bantscheff, Marcus; Chan, Wai-In; Robson, Samuel C; Chung, Chun-wa; Hopf, Carsten; Savitski, Mikhail M.; Huthmacher, Carola; Gudgin, Emma; Lugo, Dave; Beinke, Soren; Chapman, Trevor D.; Roberts, Emma J.; Soden, Peter E; Auger, Kurt R.; Mirguet, Olivier; Doehner, Konstanze; Delwel, Ruud; Burnett, Alan K.; Jeffrey, Phillip; Drewes, Gerard; Lee, Kevin; Huntly, Brian J.P; Kouzarides, Tony

    2013-01-01

    Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies1. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process plays an important role in leukaemia induction2,3. Here we use a global proteomic strategy to demonstrate that MLL-fusions, as part of SEC2,3 and the polymerase associated factor (PAFc) complex4,5 are associated with the BET family of acetyl-lysine recognising, chromatin “adaptor” proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family GSK1210151A (I-BET151) has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL-fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells (LSC) is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias. PMID:21964340

  20. 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

  1. 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

  2. Nuclear power plants and childhood leukaemia: lessons from the past and future directions.

    PubMed

    Kuehni, C; Spycher, B D

    2014-01-01

    In the 1980s, leukaemia clusters were discovered around nuclear fuel reprocessing plants in Sellafield and Dounreay in the United Kingdom. This raised public concern about the risk of childhood leukaemia near nuclear power plants (NPPs). Since then, the topic has been well-studied, but methodological limitations make results difficult to interpret. Our review aims to: (1.) summarise current evidence on the relationship between NPPs and risk of childhood leukaemia, with a focus on the Swiss CANUPIS (Childhood cancer and nuclear power plants in Switzerland) study; (2.) discuss the limitations of previous research; and (3.) suggest directions for future research. There are various reasons that previous studies produced inconclusive results. These include: inadequate study designs and limited statistical power due to the low prevalence of exposure (living near a NPP) and outcome (leukaemia); lack of accurate exposure estimates; limited knowledge of the aetiology of childhood leukaemia, particularly of vulnerable time windows and latent periods; use of residential location at time of diagnosis only and lack of data on address histories; and inability to adjust for potential confounders. We conclude that risk of childhood leukaemia around NPPs should continue to be monitored and that study designs should be improved and standardised. Data should be pooled internationally to increase the statistical power. More research needs to be done on other putative risk factors for childhood cancer such as low-dose ionizing radiation, exposure to certain chemicals and exposure to infections. Studies should be designed to allow examining multiple exposures.

  3. 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

  4. Organising pneumonia mimicking invasive fungal disease in patients with leukaemia.

    PubMed

    Forghieri, Fabio; Potenza, Leonardo; Morselli, Monica; Maccaferri, Monica; Pedrazzi, Letizia; Barozzi, Patrizia; Vallerini, Daniela; Riva, Giovanni; Zanetti, Eleonora; Quadrelli, Chiara; Rossi, Giulio; Rivasi, Francesco; Messino', Massimino; Rumpianesi, Fabio; Grottola, Antonella; Venturelli, Claudia; Pecorari, Monica; Codeluppi, Mauro; Torelli, Giuseppe; Luppi, Mario

    2010-07-01

    Clinical charts from 63 consecutive highly immunocompromised haematologic patients presenting with pulmonary nodular lesions on CT scan, classified as either probable or possible invasive fungal disease (IFD) according to the revised EORTC/MSG classification, were retrospectively studied. Histopathological analysis of lung tissues, available for 23 patients, demonstrated proven IFD in 17 cases (14 invasive aspergillosis and 3 invasive zygomycosis), diffuse alveolar damage in one and organising pneumonia (OP) in five cases. In the OP cases, three of which have been defined as probable IFD according to EORTC/MSG classification, extensive immunohistochemical, molecular and immunological analyses for fungi were negative. Our case descriptions extend the notion that OP may be encountered as a distinct histopathological entity in pulmonary nodular lesions in patients with leukaemia with probable/possible IFD.

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

    PubMed

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

    2016-05-01

    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

  6. 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

  7. 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.

  8. 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.

  9. Investigation of human parvovirus B19 occurrence and genetic variability in different leukaemia entities.

    PubMed

    da Costa, A C; Bendit, I; de Oliveira, A C S; Kallas, E G; Sabino, E C; Sanabani, S S

    2013-01-01

    Human parvovirus B19V (B19V) has been associated with various haematological disorders, but data on its prevalence in leukaemia are scarce. In this cross-sectional study, we investigated patients in Sao Paulo, Brazil with leukaemia to determine the molecular frequency of B19 variants and characterize the viral genetic variability by partial and complete sequencing of the coding of non-structural protein 1 (NS1)/viral capsid proteins 1 and 2 (VP1/VP2). The presence of B19V infections was investigated by PCR amplification of the viral NS1 gene fragment and confirmed by sequencing analysis. The NS1/VP1/VP2 and partially larger gene fragments of the NS1-positive samples were determined by overlapping nested PCR and direct sequencing results. The B19V NS1 was detected in 40 (16%) of 249 bone marrow samples including 12/78 (15.4%) acute lymphoblastic leukaemia, 25/155 (16.1%) acute myeloid leukaemia and 3/16 (18.7%) chronic myeloid leukaemia samples. Of the 40 participants, 25 (62.5%) were infected with genotype 1a and 15 (37.5%) with genotype 3b. The phylogenetic analysis of other regions revealed that 12/40 (30%) of the patients with leukaemia were co-infected with genotypes 1a and 3b. In addition, a new B19V intergenotypic recombinant (1a/3b) and an NS1 non-recombinant genotype 1a were detected in one patient. Our findings demonstrated a relatively high prevalence of B19V monoinfections and dual infections and provide, for the first time, evidence of inter-genotypic recombination in adults with leukaemia that may contribute to the genetic diversity of B19V and may also be a source of new emerging viral strains with future implications for diagnosis, therapy and efficient vaccine development.

  10. Epigenetic dysregulation of leukaemic HOX code in MLL-rearranged leukaemia mouse model.

    PubMed

    Ng, Ray Kit; Kong, Cheuk Ting; So, Chi Chiu; Lui, Wing Chi; Chan, Yuen Fan; Leung, Ka Chun; So, Kam Chung; Tsang, Ho Man; Chan, Li Chong; Sham, Mai Har

    2014-01-01

    HOX genes are frequently dysregulated in human leukaemia with the gene rearrangement between mixed lineage leukaemia (MLL) and partner genes. The resultant MLL fusion proteins are known to mediate leukaemia through disruption of the normal epigenetic regulation at the target gene loci. To elucidate the pathogenic role of MLL fusion proteins in HOX dysregulation in leukaemia, we generated a novel haematopoietic lineage-specific Mll-Een knock-in mouse model using a Cre-mediated inversion strategy. The Mll(Een) (/+) invertor mice developed acute myeloid leukaemia, with organomegaly of the spleen, liver and mesenteric lymph nodes caused by infiltration of blast cells. Using Mll-Een-expressing leukaemic cell lines derived from bone marrow of Mll(Een) (/+) mutant mice, we showed that induction of Hox genes in leukaemic cells was associated with hypomethylated promoter regions and an aberrant active chromatin state at the Hox loci. Knock-down of Prmt1 was insufficient to reverse the active chromatin status and the hypomethylated Hox loci, suggesting that Prmt1-mediated histone arginine methylation was only partially involved in the maintenance of Hox expression in leukaemic cells. Furthermore, in vivo analysis of bone marrow cells of Mll(Een) (/+) mice revealed a Hox expression profile similar to that of wild-type haematopoietic stem cells. The leukaemic Hox profile was highly correlated with aberrant hypomethylation of Hox promoters in the mutant mice, which highlights the importance of DNA methylation in leukaemogenic mechanisms induced by MLL fusion proteins. Our results point to the involvement of dynamic epigenetic regulations in the maintenance of the stem cell-like HOX code that initiates leukaemic stem cells in MLL-rearranged leukaemia. This provides insights for the development of alternative strategies for leukaemia treatment.

  11. 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

  12. 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

  13. 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

  14. The Florey lecture, 1986. Vaccine prevention of virus-induced human cancers.

    PubMed

    Epstein, M A

    1987-03-23

    Carcinogenic viruses have been discovered in numerous animal species over the last 80 years but their role in human cancer has only recently become an important issue. With EB virus involved with endemic Burkitt's lymphoma and undifferentiated nasopharyngeal carcinoma, hepatitis B virus with primary liver cancer, papilloma viruses with carcinoma of the cervix, and T-cell leukaemia virus with adult T leukaemia, 20-25% of all human cancer appears to have a virus component in its causation. By analogy with certain virus-induced animal cancers, vaccine prevention of infection should greatly reduce subsequent tumour development; vaccines against hepatitis B virus are already on trial for this purpose in populations at risk. Experiments are described in which an EB virus subunit vaccine consisting of the virus-determined membrane antigen glycoprotein molecule of molecular mass 340 kDa (MA gp340) has been prepared by two purification methods. Material from one of these has successfully protected cotton-top tamarins against a 100% lymphomagenic dose of challenge virus and investigations are under way to identify an immunogen, based on MA gp340, suitable for use in man. Genetically engineered bacterial, yeast, and mammalian cells expressing the gp340 gene are already available; this gene has also been inserted into vaccinia and varicella virus vectors. Powerful new adjuvants are also considered, together with future strategies for human vaccine studies. PMID:2884667

  15. Maternal prenatal cigarette, alcohol and illicit drug use and risk of infant leukaemia: a report from the Children's Oncology Group.

    PubMed

    Slater, Megan E; Linabery, Amy M; Blair, Cindy K; Spector, Logan G; Heerema, Nyla A; Robison, Leslie L; Ross, Julie A

    2011-11-01

    Several case-control studies have evaluated associations between maternal smoking, alcohol consumption and illicit drug use during pregnancy and risk of childhood leukaemia. Few studies have specifically focused on infants (<1 year) with leukaemia, a group that is biologically and clinically distinct from older children. We present data from a Children's Oncology Group case-control study of 443 infants diagnosed with acute leukaemia [including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)] between 1996 and 2006 and 324 population controls. Mothers were queried about their cigarette, alcohol and illicit drug use 1 year before and throughout pregnancy. Odds ratios (ORs) and 95% confidence intervals [CI] were calculated using adjusted unconditional logistic regression models. Maternal smoking (>1 cigarette/day) and illicit drug use (any amount) before and/or during pregnancy were not significantly associated with infant leukaemia. Alcohol use (>1 drink/week) during pregnancy was inversely associated with infant leukaemia overall [OR = 0.64; 95% CI 0.43, 0.94], AML [OR = 0.49; 95% CI 0.28, 0.87], and leukaemia with mixed lineage leukaemia gene rearrangements ('MLL+') [OR = 0.59; 95% CI 0.36, 0.97]. While our results agree with the fairly consistent evidence that maternal cigarette smoking is not associated with childhood leukaemia, the data regarding alcohol and illicit drug use are not consistent with prior reports and are difficult to interpret. It is possible that unhealthy maternal behaviours during pregnancy, some of which carry potential legal consequences, may not be adequately measured using only self-report. Future case-control studies of childhood leukaemia that pursue these exposures may benefit from incorporation of validated instruments and/or biomarkers when feasible.

  16. Living with cancer: a qualitative report of the experiences of leukaemia patients in Lagos, Nigeria.

    PubMed

    Adejoh, Samuel Ojima; Temilola, Olusegun Moses; Olayiwola, Bolutife

    2013-12-01

    The study examined the qualitative, cognitive and psychosocial experiences of those living with leukaemia undergoing treatment at a teaching hospital. Twenty respondents who consented to participate were purposively selected from the cancer patients with leukaemia receiving treatment in the said teaching hospital. The in-depth interview method was used to collect data. The data was analysed using manual content analysis. Data showed that patients lack basic knowledge about leukaemia and had no beliefs regarding leukaemia. Some patients believed in God and a medical breakthrough for a cure, while for some, the hope of living was not certain. The ill-health condition had brought about financial predicament to both patients and family members and has limited their productivity in terms of income-generating activities. Good interpersonal relationships and support from their care providers aided their compliance to treatment regime and provided hope for living positively with their condition. The study concludes that there is a need to educate the patients on the causes of their condition. Financial supports should be rendered to those living with leukaemia, while health care providers should be encouraged to continue to maintain good interpersonal relationships with their patients.

  17. Suberoylanilide hydroxamic acid (SAHA) and cladribine synergistically induce apoptosis in NK-LGL leukaemia.

    PubMed

    Sun, Xiaoshen; Hasanali, Zainul S; Chen, Allshine; Zhang, Dianzheng; Liu, Xin; Wang, Hong-Gang; Feith, David J; Loughran, Thomas P; Xu, Kailin

    2015-02-01

    Natural killer (NK) large granular lymphocyte (LGL) leukaemia features a clonal proliferation of CD3(-) NK cells that can be classified into either aggressive or chronic categories. The NKL cell line, derived from an aggressive Asian NK cell leukaemia, and patient samples from chronic NK-LGL leukaemia were used in our study to probe for synergistic efficacy of the epigenetic drugs vorinostat (SAHA) and cladribine in this disease. We demonstrate that histone deacetylases (HDACs) are over-expressed in both aggressive and chronic NK leukaemia. Administration of the HDAC inhibitor SAHA reduces class I and II HDAC expression and enhances histone acetylation in leukaemic NK cells. In vitro combination treatment with SAHA and cladribine dose-dependently exerts synergistic cytotoxic and apoptotic effects on leukaemic NK cells. Expression profiling of apoptotic regulatory genes suggests that both compounds led to caspase-dependent apoptosis through activation of intrinsic mitochondrial and extrinsic death receptor pathways. Collectively, these data show that combined epigenetic therapy, using HDAC and DNA methyltransferase inhibitors, may be a promising therapeutic approach for NK-LGL leukaemia.

  18. The role of multiparametric flow cytometry in the detection of minimal residual disease in acute leukaemia.

    PubMed

    Lee, Denise; Grigoriadis, George; Westerman, David

    2015-12-01

    Flow cytometry is the most accessible method for minimal residual disease (MRD) detection due to its availability in most haematological centres. Using a precise combination of different antibodies, immunophenotypic detection of MRD in acute leukaemia can be performed by identifying abnormal combinations or expressions of antigens on malignant cells at diagnosis, during and post treatment. These abnormal phenotypes, referred to as leukaemia-associated immunophenotypes (LAIPs) are either absent or expressed at low frequency in normal bone marrow (BM) cells and are used to monitor the behaviour and quantitate the amount of residual disease following treatment. In paediatric acute lymphoblastic leukaemia (ALL), the level of MRD by multiparametric flow cytometry (MPFC) during therapy is recognised as an important predictor of outcome. Although less extensively studied, adult ALL and adult and paediatric acute myeloid leukaemia (AML) have also demonstrated similar findings. The challenge now is incorporating this information for risk-stratification so that therapy can be tailored individually and ultimately improve outcome while also limiting treatment-related toxicity. In this review we will elaborate on the current and future role of MPFC in MRD in acute leukaemia while also addressing its limitations.

  19. The distribution of MLL breakpoints correlates with outcome in infant acute leukaemia.

    PubMed

    Emerenciano, Mariana; Meyer, Claus; Mansur, Marcela B; Marschalek, Rolf; Pombo-de-Oliveira, Maria S

    2013-04-01

    Acute leukaemia in early childhood - and mainly infant leukaemia (IL) - is characterized by acquired genetic alterations, most commonly by the presence of distinct MLL rearrangements (MLL-r). The aim of this study was to investigate possible correlations between clinical features and molecular analyses of a series of 545 childhood leukaemia (≤24 months of age) cases: 385 acute lymphoblastic leukaemia (ALL) and 160 acute myeloid leukaemia (AML). The location of the genomic breakpoints was determined in a subset of 30 MLL-r cases. The overall survival of the investigated cohort was 60·5%, as determined by the Kaplan-Meier method. Worse outcomes were associated with age at diagnosis ≤6 months (P < 0·001), high white blood cell count (P = 0·001), and MLL-r (P = 0·002) in ALL, while children with AML displayed a poorer outcome (P = 0·009) regardless of their age strata. Moreover, we present first evidence that MLL-r patients with poor outcome preferentially displayed chromosomal breakpoints within MLL intron 11. Based on the literature, most MLL-r IL display a breakpoint localization towards intron 11, which in turn may explain their worse clinical course. In summary, the MLL breakpoint localization is of clinical importance and should be considered as a novel outcome predictor for MLL-r patients.

  20. Higher risk for acute childhood lymphoblastic leukaemia in Swedish population centres 1973-94

    PubMed Central

    Hjalmars, U; Gustafsson, G

    1999-01-01

    A population-based sample of acute childhood leukaemia cases in Sweden 1973–94 was analysed by a geographical information system (GIS) for spatial leukaemia distribution in relation to population density. The annual incidence rate for acute lymphoblastic leukaemia (ALL) was 3.6, and for acute non-lymphoblastic leukaemia (ANLL) 0.7, cases per 100 000 children. Incidence rates in population centres, constituting 1.3% of Sweden's land area and approximately 80% of the population, compared with the rest of Sweden showed a statistically significant excess of ALL [odds ratio (OR) 1.68; 95% confidence interval (CI) 1.44–1.95], but not ANLL (OR 1.13; 95% CI 0.98–1.32). An increasing trend, however not statistically significant, was found for ALL incidence with both increasing population density in parishes and increasing degree of urbanity in municipalities. These findings support the theories that some environmental factors associated with high population density, such as infectious agents, may be of aetiological importance for childhood acute lymphoblastic leukaemia. © 1999 Cancer Research Campaign PMID:10408689

  1. 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

  2. Is this acute lymphoblastic leukaemia or juvenile rheumatoid arthritis.

    PubMed

    Kirubakaran, Chellam; Scott, Julius Xavier; Ebenezer, Sam

    2011-08-01

    Arthritis could be a presenting feature of acute lymphoblastic leukaemia (ALL) and could be wrongly diagnosed as juvenile rheumatoid arthritis (JRA). Clinical and laboratory parameters might differentiate ALL and JRA in children who present with arthritis. Out of a total of 250 children of ALL, 10 were referred to the department of child health and paediatric haemato-oncology of Christian Medical College, Vellore during 1990-2002. They were compared with 10 age-matched children who had systematic onset of JRA. The age groups in ALL and JRA were 6.05 +/- 2.45 years and 5.47 +/- 4.4 years respectively. Severe pain as evidenced by inability to walk was found in children but one child with JRA was unable to walk (p < 0.05). Lymphocytosis was noticed in 7 children (70%) with ALL whereas none had in JRA group. ESR was elevated in all cases in both the groups. One case in each group had antinuclear antibody positivity. It can be concluded that ALL can masquerade as systematic onset of JRA. So paediatricians should be careful enough while diagnosing the disease process.

  3. 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

  4. Unusual intracytoplasmic immunoglobulin inclusions in chronic lymphocytic leukaemia.

    PubMed

    Guglielmi, P; Preud'Homme, J L; Gourdin, M F; Reyes, F; Daniel, M T

    1982-01-01

    Unusual intracytoplasmic immunoglobulin inclusions were found by immunofluorescence in three patients with chronic lymphocytic leukaemia. The inclusions contained the same immunoglobulin chains as those detected on the plasma membrane, except for delta chains which were expressed on the cell surface and not in the cytoplasmic inclusions. The cytoplasmic staining persisted throughout culture for 8 or more days. An initial study of patients 1's cells showed that the inclusions contained only mu chains, and kappa chains gradually became apparent after in vitro culture. In a second study, the fresh lymphocytes contained both mu and and kappa chains. Initially, biosynthetic experiments showed production of mu chains which polymerized in the cytoplasm and were not secreted. Subsequently there was synthesis of heavy and light chains which assembled into monomeric subunits that were retained and secretion of free light chains. The apparent molecular weight of these immunoglobulin chains was larger than that of their secretory counterparts. Immunoelectronmicroscopy revealed cytoplasmic mu chains in strands of endoplasmic reticulum. In the two other patients, immunofluorescence displayed unusual staining patterns of bright networks in perinuclear areas. PMID:6275878

  5. 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

  6. 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.

  7. Somatic PTPN11 mutations in childhood acute myeloid leukaemia.

    PubMed

    Tartaglia, Marco; Martinelli, Simone; Iavarone, Ivano; Cazzaniga, Giovanni; Spinelli, Monica; Giarin, Emanuela; Petrangeli, Valentina; Carta, Claudio; Masetti, Riccardo; Aricò, Maurizio; Locatelli, Franco; Basso, Giuseppe; Sorcini, Mariella; Pession, Andrea; Biondi, Andrea

    2005-05-01

    Somatic mutations in PTPN11, the gene encoding the transducer SHP-2, have emerged as a novel class of lesions that upregulate RAS signalling and contribute to leukaemogenesis. In a recent study of 69 children and adolescents with de novo acute myeloid leukaemia (AML), we documented a non-random distribution of PTPN11 mutations among French-American-British (FAB) subtypes. Lesions were restricted to FAB-M5 cases, where they were relatively common (four of 12 cases). Here, we report on the results of a molecular screening performed on 181 additional unselected patients, enrolled in participating institutions of the Associazione Italiana Ematologia Oncologia Pediatrica-AML Study Group, to provide a more accurate picture of the prevalence, spectrum and distribution of PTPN11 mutations in childhood AML and to investigate their clinical relevance. We concluded that PTPN11 defects do not represent a frequent event in this heterogeneous group of malignancies (4.4%), although they recur in a considerable percentage of patients with FAB-M5 (18%). PTPN11 lesions rarely occur in other subtypes. Within the FAB-M5 group no clear association of PTPN11 mutations with any clinical variable was evident. Nearly two third of the patients with this subtype were found to harbour an activating mutation in PTPN11, NRAS, KRAS2 or FLT3.

  8. Acute myeloid leukaemia: optimal management and recent developments.

    PubMed

    Villela, Luis; Bolaños-Meade, Javier

    2011-08-20

    The current treatment of patients with acute myeloid leukaemia yields poor results, with expected cure rates in the order of 30-40% depending on the biological characteristics of the leukaemic clone. Therefore, new agents and schemas are intensively studied in order to improve patients' outcomes. This review summarizes some of these new paradigms, including new questions such as which anthracycline is most effective and at what dose. High doses of daunorubicin have shown better responses in young patients and are well tolerated in elderly patients. Monoclonal antibodies are promising agents in good risk patients. Drugs blocking signalling pathways could be used in combination with chemotherapy or in maintenance with promising results. Epigenetic therapies, particularly after stem cell transplantation, are also discussed. New drugs such as clofarabine and flavopiridol are reviewed and the results of their use discussed. It is clear that many new approaches are under study and hopefully will be able to improve on the outcomes of the commonly used '7+3' regimen of an anthracycline plus cytarabine with daunorubicin, which is clearly an ineffective therapy in the majority of patients.

  9. 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

  10. 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.

  11. A case of chronic myeloid leukaemia presenting as megakaryocytic blast crisis (AML M7)

    PubMed Central

    Karkuzhali, Ponnuswamy; Shanthi, Velusamy; Usha, Thiruvengadam

    2013-01-01

    Acute megakaryocytic leukaemia (AMeL) is a rare subtype of acute myeloid leukaemia, which can be frequently misdiagnosed as acute myelofibrosis or myelosclerosis [1]. Chronic myeloid leukaemia (CML) presenting primarily as megakaryocytic blast crisis is very rare, with very few case reports published to date [2, 3]. This case report describes a 36-year-old woman who presented with anaemia and massive splenomegaly with peripheral blood and bone marrow showing features of AMeL. Reverse transcriptase polymerase chain reaction and gel-electrophoretic study of peripheral blood leucocytes demonstrated breakpoint cluster region–Abelson oncogene translocation encoding for p210 fusion protein. Megakaryocytic blast crisis as the primary presentation of CML is very rare and requires clinical correlation and additional cytogenetic studies to determine the diagnosis. PMID:24282446

  12. 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

  13. 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

  14. Towards an understanding of the biology and targeted treatment of paediatric relapsed acute lymphoblastic leukaemia.

    PubMed

    Irving, Julie A E

    2016-03-01

    Acute lymphoblastic leukaemia is the most common childhood cancer and for those children who relapse, prognosis is poor and new therapeutic strategies are needed. Recurrent pathways implicated in relapse include RAS, JAK STAT, cell cycle, epigenetic regulation, B cell development, glucocorticoid response, nucleotide metabolism and DNA repair. Targeting these pathways is a rational therapeutic strategy and may deliver novel, targeted therapies into the clinic. Relapse often stems from a minor clone present at diagnosis and thus analysis of persisting leukaemia during upfront therapy may allow targeted drug intervention to prevent relapse.

  15. Diagnostic and prognostic significance of peripheral blood cultural characteristics in adult acute leukaemia.

    PubMed Central

    Balkwill, F. R.; Oliver, R. T.

    1976-01-01

    A simple liquid culture technique has been used to study peripheral blood from patients with acute myelogenous leukaemia. Evidence is presented that cells from morphologically identical types of leukaemia have differing capacity for "differentiation" from free floating blast cells into plastic-adherent phagocytic, trypsin-resistant macrophage-like cells with Fc and C3 receptors. Preliminary analysis suggests that patients whose cells have the greatest capacity for "differentiation" have a better chance of achieving complete remission. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:1063591

  16. Ajoene (natural garlic compound): a new anti-leukaemia agent for AML therapy.

    PubMed

    Hassan, H T

    2004-07-01

    The reputation of garlic (Allium sativum) as an effective remedy for tumours extends back to the Egyptian Codex Ebers of 1550 b.c. Several garlic compounds including allicin and its corresponding sulfide inhibit the proliferation and induce apoptosis of several human non-leukaemia malignant cells including breast, bladder, colorectal, hepatic, prostate cancer, lymphoma and skin tumour cell lines. Ajoene (4,5,9-trithiadodeca-1,6,11-triene-9-oxide) is a garlic-derived compound produced most efficiently from pure allicin and has the advantage of a greater chemical stability than allicin. Several clinical trials and in vitro studies of ajoene have demonstrated its best-known anti-thrombosis, anti-microbial and cholesterol lowering activities. Recently, topic application of ajoene has produced significant clinical response in patients with skin basal cell carcinoma. Ajoene was shown to inhibit proliferation and induce apoptosis of several human leukaemia CD34-negative cells including HL-60, U937, HEL and OCIM-1. Also, ajoene induces 30% apoptosis in myeloblasts from chronic myeloid leukaemia patient in blast crisis. More significantly, ajoene profoundly enhanced the apoptotic effect of the two chemotherapeutic drugs: cytarabine and fludarabine in human CD34-positive resistant myeloid leukaemia cells through enhancing their bcl-2 inhibitory and caspase-3 activation activities. The two key anti-leukaemia biological actions of ajoene were the inhibition of proliferation and the induction of apoptosis. Studies have shown the anti-proliferation activity of ajoene to be associated with a block in the G2/M phase of cell cycle in human myeloid leukaemia cells. The apoptosis inducing activity of ajoene is via the mitochondria-dependent caspase cascade through a significant reduction of the anti-apoptotic bcl-2 that results in release of cytochrome c and the activation of caspase-3. Since acute myeloid leukaemia (AML) is a heterogeneous malignant disease in which disease

  17. Progressive trichodysplasia spinulosa in a patient with chronic lymphocytic leukaemia in remission.

    PubMed

    Lee, Joyce S-S; Frederiksen, Peter; Kossard, Steven

    2008-02-01

    A 70-year old Caucasian man with chronic lymphocytic leukaemia developed trichodysplasia spinulosa 2 months after ceasing chemotherapy. Histological features characteristic to this condition include dilated and enlarged hair follicles, hyperplastic hair bulbs, hyperplasia of inner root sheath cells with numerous large, eosinophilic, trichohyaline granules, and hypercornification. Although he was in remission for chronic lymphocytic leukaemia, lesions were slowly progressive 15 months after cessation of chemotherapy. We also describe a painless pull-test where spicules can be easily plucked and assessed microscopically for inner root sheath keratinization, or observed with surface microscopy in a clinic setting.

  18. 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

  19. Epigenetic regulation of cathepsin L expression in chronic myeloid leukaemia

    PubMed Central

    Samaiya, Misti; Bakhshi, Sameer; Shukla, Abhay A; Kumar, Lalit; Chauhan, Shyam S

    2011-01-01

    The expression and significance of cathepsin L (CTSL) has been extensively studied in solid tumours. However no such information in chronic myeloid leukaemia (CML) was available. We investigated the activity and expression of this protease in peripheral blood mononuclear cells (PBMCs) of 47 adult CML patients. Thirty adults suffering from systemic diseases and 50 healthy volunteers served as controls. The mRNA levels of CTSL, its specific endogenous inhibitor cystatin C and transcriptional up-regulator vascular endothelial growth factor (VEGF) were quantitated by real-time qPCR. CTSL protease activity and its mRNA expression were significantly higher in CML chronic phase (CP) patients compared to CML accelerated phase/blast crisis (AP/BC) patients and controls (P≤ 0.001). VEGF whose expression was most pronounced in CP and declined (P≤ 0.001) in the advanced phases of the malignancy exhibited a strong positive correlation with CTSL expression (r= 0.97; P≤ 0.001). Cystatin C expression was significantly lower (P≤ 0.001) in CML and displayed inverse correlation with CTSL (r=−0.713; P≤ 0.001) activity. CTSL promoter was significantly hypomethylated in CML CP compared to CML AP/BC patients as well as controls. K562, a BC CML cell line displayed CTSL activity, expression and methylation status of CTSL promoter that was comparable to CML AP/BC patients. Treatment of these cells or PBMCs isolated from CML AP/BC patients with 5′-aza-cytidine resulted in a dramatic increase in CSTL activity and/or expression thereby demonstrating the role of promoter methylation in the stage specific expression of CTSL in CML. Differential expression of CTSL in CML at various stages of malignancy may prove useful in identification of the high-risk patients thereby facilitating better management of disease. PMID:21496199

  20. Acute childhood leukaemia and environmental exposure to potential sources of benzene and other hydrocarbons; a case-control study

    PubMed Central

    Steffen, C; Auclerc, M; Auvrignon, A; Baruchel, A; Kebaili, K; Lambilliotte, A; Leverger, G; Sommelet, D; Vilmer, E; Hemon, D; Clavel, J

    2004-01-01

    Aim: To analyse the association between potential environmental exposure to hydrocarbons and the risk of acute childhood leukaemia. Methods: A hospital based multicentre case control study, stratified on centre, age, and sex, with 280 leukaemia cases and 285 controls was carried out. Data were collected by a standardised interview of the mothers. Results: No clear association was seen between maternal occupational exposure to hydrocarbons during pregnancy and leukaemia, or between residential traffic density and leukaemia. There was an association between dwellings neighbouring a petrol station or a repair garage during childhood and the risk of childhood leukaemia (OR 4.0, 95% CI 1.5 to 10.3), with a duration trend. The association, which appeared particularly strong for acute non-lymphocytic leukaemia (OR 7.7, 95% CI 1.7 to 34.3), was not altered by adjustment for potential confounding factors. Conclusions: Results showed an association between acute childhood leukaemia and dwellings neighbouring auto repair garages and petrol stations, which are benzene emitting sources. These findings could be due to chance, although the strength of the association and the duration trend are arguments for a causal association. PMID:15317919

  1. CD45RA, a specific marker for leukaemia stem cell sub-populations in acute myeloid leukaemia.

    PubMed

    Kersten, Bas; Valkering, Matthijs; Wouters, Rolf; van Amerongen, Rosa; Hanekamp, Diana; Kwidama, Zinia; Valk, Peter; Ossenkoppele, Gert; Zeijlemaker, Wendelien; Kaspers, Gertjan; Cloos, Jacqueline; Schuurhuis, Gerrit J

    2016-04-01

    Chemotherapy resistant leukaemic stem cells (LSC) are thought to be responsible for relapses after therapy in acute myeloid leukaemia (AML). Flow cytometry can discriminate CD34(+) CD38(-) LSC and normal haematopoietic stem cells (HSC) by using aberrant expression of markers and scatter properties. However, not all LSC can be identified using currently available markers, so new markers are needed. CD45RA is expressed on leukaemic cells in the majority of AML patients. We investigated the potency of CD45RA to specifically identify LSC and HSC and improve LSC quantification. Compared to our best other markers (CLL-1, also termed CLEC12A, CD33 and CD123), CD45RA was the most reliable marker. Patients with high percentages (>90%) of CD45RA on CD34(+) CD38(-) LSC have 1·69-fold higher scatter values compared to HSC (P < 0·001), indicating a more mature CD34(+) CD38(-) phenotype. Patients with low (<10%) or intermediate (10-90%) CD45RA expression on LSC showed no significant differences to HSC (1·12- and 1·15-fold higher, P = 0·31 and P = 0·44, respectively). CD45RA-positive LSC tended to represent more favourable cytogenetic/molecular markers. In conclusion, CD45RA contributes to more accurate LSC detection and is recommended for inclusion in stem cell tracking panels. CD45RA may contribute to define new LSC-specific therapies and to monitor effects of anti-LSC treatment.

  2. 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.

  3. FLT3 inhibition: a moving and evolving target in acute myeloid leukaemia.

    PubMed

    Leung, A Y H; Man, C-H; Kwong, Y-L

    2013-02-01

    Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene is a gain-of-function mutation common in acute myeloid leukaemia (AML). It is associated with inferior prognosis and response to chemotherapy. Single base mutations at the FLT3 tyrosine kinase domain (TKD) also leads to a gain of function, although its prognostic significance is less well defined because of its rarity. The clinical benefits of FLT3 inhibition are generally limited to AML with FLT3-ITD. However, responses are transient and leukaemia progression invariably occurs. There is compelling evidence that leukaemia clones carrying both ITD and TKD mutations appear when resistance to FLT3 inhibitors occurs. Interestingly, the emergence of double ITD and TKD mutants can be recapitulated in vitro when FLT3-ITD+ leukaemia cell lines are treated with mutagens and FLT3 inhibitors. Furthermore, murine xenotransplantation models also suggest that, in some cases, the FTL3-ITD and TKD double mutants actually exist in minute amounts before treatment with FLT3 inhibitors, expand under the selection pressure of FLT3 inhibition and become the predominant resistant clone(s) during the drug-refractory phase. On the basis of this model of clonal evolution, a multipronged strategy using more potent FLT3 inhibitors, and a combinatorial approach targeting both FLT3-dependent and FLT3-independent pathways, will be needed to improve outcome.

  4. The inherent metastasis of leukaemia and its exploitation by sonodynamic therapy.

    PubMed

    Trendowski, Matthew

    2015-05-01

    Nearly all cancers are linked by the inexorable phenotype of metastasis as malignant growths have the capability to spread from their place of origin to distant sites throughout the body. While different cancers may have various propensities to migrate towards specific locations, they are all linked by this unifying principal. Unlike most neoplasms, leukaemia has inherent cell motility as leukocytes are required to move throughout the vascular system, suggesting that no mutations are required for anchorage independent growth. As such, it seems likely that leukaemias are inherently metastatic, endowed with the deadliest phenotype of cancer simply due to cell of origin. This article presents the biology of metastasis development and how leukaemia cells are inherently provided these phenotypic characteristics. It is then proposed how clinicians may be able to exploit the motility of leukaemia and metastatic emboli of other cancer types through an approach known as sonodynamic therapy (SDT), a treatment modality that combines chemotherapeutic agents with ultrasound to preferentially damage malignant cells. As experimental evidence has indicated, SDT is a promising therapeutic approach in need of clinical testing for further validation.

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

    PubMed

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

    1981-03-01

    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.

  6. Geographical and ecological analyses of childhood acute leukaemias and lymphomas in north-west England.

    PubMed

    McNally, Richard J Q; Alston, Robert D; Cairns, Donal P; Eden, Osborn B; Birch, Jillian M

    2003-10-01

    Childhood leukaemias and lymphomas have been associated with exposure to environmental factors, including infections, which show geographical variation. This study examined the geographical distribution of the incidence of acute leukaemia and lymphoma using Manchester Children's Tumour Registry (MCTR) data 1976-2000. A total of 910 children were included, all of whom had histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses, all the children were aged 0-14 years and were resident in the counties of Greater Manchester or Lancashire. Standardized morbidity ratios were calculated. Poisson regression was used to examine the relationship between incidence rates and small-area (census ward) population density, ethnic composition and deprivation index. There was a monotonic relationship between acute lymphoblastic leukaemia (ALL) incidence and population density (P = 0.05). Higher rates were seen in more densely populated areas. There was evidence for a monotonic relationship between the incidence of the mixed cellularity subtype of Hodgkin's disease (HD) and the Townsend deprivation score (P = 0.001). Markedly higher incidence was associated with greater levels of unemployment and household overcrowding. The results for ALL and mixed cellularity HD support the involvement of environmental factors, such as infections, in disease aetiology.

  7. T-cell prolymphocytic leukaemia (T-PLL): a rare disease with a grave prognosis.

    PubMed

    Vivekanandarajah, Abhirami; Atallah, Jean Paul; Gupta, Shilpi

    2013-05-02

    T-cell prolymphocytic leukaemia (T-PLL) is an extremely uncommon haematological malignancy that has an aggressive course and a grave prognosis. We describe a patient who presented with lymphocytosis, scalp erythema, ascites and splenomegaly and was diagnosed with T-PLL. He was treated with alemtuzumab with a good response and was referred for allogeneic stem cell transplantation.

  8. Multiple major cerebral artery thromboses with profound thrombocytopenia in acute leukaemia.

    PubMed

    Sims, D G; Scott, D J; Noble, T C

    1976-01-01

    A child with acute lymphoblastic leukaemia complicated by prolonged gastrointestinal and skin haemorrhages due to profound thrombocytopenia finally died of thrombotic occlusions of major cerebral arteries due to mucormycosis. Biopsy of any suspect lesion is needed urgently before prolonged therapy with amphotericin B is started. So far there have been no cures in childhood.

  9. Langerhans cells increase in the dermal lesions of adult T cell leukaemia in Japan

    PubMed Central

    Shamoto, M

    1983-01-01

    In cases of adult T cell leukaemia neoplastic T cell infiltration in the skin was accompanied by an increase in Langerhans cells. This is in keeping with the view that Langerhans cells may induce antigen-specific and allogenic T cell activation. Images PMID:6600750

  10. Refractory Bartonella quintana bacillary angiomatosis following chemotherapy for chronic lymphocytic leukaemia.

    PubMed

    Holmes, Natasha E; Opat, Stephen; Kelman, Anthony; Korman, Tony M

    2011-01-01

    Bacillary angiomatosis is a well-recognized infection with cutaneous and systemic manifestations caused by Bartonella henselae or Bartonella quintana and occurs in immunocompromised patients. We report a case of B. quintana bacillary angiomatosis following fludarabine-based chemotherapy for chronic lymphocytic leukaemia that was refractory to standard treatment and was complicated by lymphadenopathy and osteomyelitis.

  11. 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

  12. High-dose gallium-67 therapy in patients with relapsed acute leukaemia: a feasibility study.

    PubMed Central

    Jonkhoff, A. R.; Plaizier, M. A.; Ossenkoppele, G. J.; Teule, G. J.; Huijgens, P. C.

    1995-01-01

    Gallium-67 (67Ga) accumulates in malignant tissues via the transferrin receptor without need for a monoclonal antibody and emits cytotoxic low-energy electrons. In this study we investigated the feasibility, pharmacokinetics, toxicity and preliminary efficiency of high-dose 67Ga injected intravenously (i.v.) in patients with acute leukaemia not responding to conventional therapy. Twelve doses of 36-105 mCi of Gallium67 citrate were administered as a push injection to eight patients with resistant leukaemia in a pilot study. All five patients with acute myeloid leukaemia (AML) and three patients with acute lymphoblastic leukaemia (ALL) had resistant disease or resistant relapse. No (sub)acute toxicity was observed. Independent of the administered dose, whole-blood radioactivity levels 10 min after administration measured only 1.25 +/- 1.39 microCi ml-1, indicating a large volume of distribution. Urine excretion in the first 24 h ranged from 18% to 51.5% (median 29.5%) of the administered dose. Cellular uptake of 67Ga was less than in previous in vitro studies. Whole-body radiation dose was estimated to be 0.25 +/- 0.03 cGy mCi-1. Red marrow dose was estimated to be between 0.18 +/- 0.02 and 0.97 +/- 0.12 cGy mCi-1. One definite response was observed in an ALL patient with disappearance of skin lesions, normalisation of the enlarged spleen and profound leucopenia. Three other patients showed transient reductions in white blood cell counts without disappearance of blasts from the peripheral blood. We conclude that high-dose i.v. 67Ga can be safely administered but that the uptake of 67Ga in blast cells must increase to make 67Ga therapeutically useful in patients with relapsed leukaemia. Images Figure 2 PMID:8519674

  13. Risk of acute myeloid leukaemia and multiple myeloma in workers exposed to benzene.

    PubMed Central

    Wong, O

    1995-01-01

    OBJECTIVE--To determine the risk of developing acute myeloid leukaemia (AML) and multiple myeloma in a cohort of workers exposed to benzene. The results were used to show the importance of taking specificity of disease into consideration in causation analysis. METHODS--Data were derived from a cohort of workers employed at two Goodyear plants in Ohio in the manufacture of Pliofilm. Based on data in the Pliofilm study, several papers that examined the relation between exposure to benzene and leukaemia (all cell types combined) have been published. In the current analyses based on updated data in the study, standardised mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were calculated for AML and multiple myeloma by cumulative exposure to benzene. The results based on AML were compared with those for leukaemia (all cell types combined) published previously. RESULTS--An exposure response relation was shown between cumulative exposure to benzene and AML. No increased risk of AML was detected for cumulative exposure to benzene below 200 ppm-years (SMR 0.91). Above 200 ppm-years, risk of AML rose drastically; reaching a significant SMR of 98.37 for > 400 ppm-years. For multiple myeloma, no relation with exposure to benzene was detected. CONCLUSION--Analysis specific to AML shows the importance of taking specificity of disease into consideration in causation analysis. This investigation shows that previous analyses based on all leukaemia cell types combined have incorrectly set the estimated threshold too low, and have underestimated risk above the threshold. Current regulatory policies that rely on previous analyses based on all leukaemia cell types combined should be re-examined. PMID:7627314

  14. Magic angle spinning NMR of viruses.

    PubMed

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

    2015-04-01

    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

  15. 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

  16. Association between the MDR1 gene variant C3435T and risk of leukaemia: a meta-analysis.

    PubMed

    Zhang, B-B; Xuan, C; Deng, K-F; Wu, N; Lun, L-M

    2013-09-01

    Although a number of genetic studies have attempted to link the multidrug resistance (MDR1) C3435T polymorphism to risk of leukaemia, the results were often inconsistent. The present study aimed at investigating the pooled association using a meta-analysis on the published studies. 1933 cases and 2215 controls of 11 published studies in English before June 2012 were involved in the updated meta-analysis. Furthermore, subgroup analysis was performed in different ethnic and leukaemia subtype groups. This meta-analysis suggests that the MDR1 C3435T polymorphism associate with risk of leukaemia. The effect of the variant on the expression levels and the possible functional role of the variant in leukaemia should be addressed in further studies.

  17. [Prognostic value of absolute monocyte count in chronic lymphocytic leukaemia].

    PubMed

    Szerafin, László; Jakó, János; Riskó, Ferenc

    2015-04-01

    Bevezetés: Az alacsony perifériás lymphocyta- és magas monocytaszám kedvezőtlen prognózisra utal különböző típusú lymphomákban és egyéb daganatos megbetegedésekben. Krónikus lymphoid leukaemiában azonban az abszolút monocytaszám prognosztikus értékéről csak kevés adat ismert. Célkitűzés: A szerzők krónikus lymphoid leukaemiás betegeik diagnóziskor mért abszolút monocytaszámának hatását vizsgálták a kezelésig eltelt időre és a túlélésre. Módszer: 2005. január 1. és 2012. december 31. között diagnosztizált 223 krónikus lymphoid leukaemiás beteg adatait rögzítették. Értékelték a kezelést igénylő betegek arányát, a kezelésig eltelt idő és a túlélés relatív kockázatát, valamint a halálokokat a Rai-stádiumtól függően, a CD38-, ZAP-70-pozitivitásnak és az abszolút monocytaszámnak megfelelően. Eredmények: Rai 0, I., II., III. és IV. stádiumban a betegek 21,1%-a, 57,4%-a, 88,9%-a, 88,9%-a és 100%-a, CD38-, illetve ZAP-70-pozitivitás esetén a betegek 61,9%-a, illetve 60,8%-a, továbbá, ha az abszolút monocytaszámuk <0,25 G/l, 0,25–0,75 G/l és >0,75 G/l volt, akkor a betegek 76,9%-a, 21,2%-a és 66,2%-a szorult kezelésre. A kezelés elkezdéséig tartó medián idő, illetve a túlélés medián ideje a monocytaszámtól függően 19,5, 65 és 35,5 hónap, illetve 41,5, 65 és 49,5 hónap volt. A kezelésmegkezdés szükségességének relatív kockázata, RR = 1,62 (p<0,01) volt a 0,25 G/l alatti vagy 0,75 G/l feletti és a 0,25–0,75 G/l abszolút monocytaszámú betegek összehasonlításakor, míg a túlélésé RR = 2,41 (p<0,01) volt, ha a 0,25 G/l alatti és feletti abszolút monocytaszámú betegeket hasonlították össze. A relatív kockázatok Rai 0 stádiumú betegekben vizsgálva is szignifikánsak maradtak. A fő halálokok alacsony abszolút monocytaszám esetén fertőzések (41,7%) és a krónikus lymphoid leukaemia (58,3%), míg közepes és magas monocytasz

  18. 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

  19. UPPER AIRWAYS CANCER, MYELOID LEUKAEMIA AND OTHER CANCERS IN A COHORT OF BRITISH CHEMICAL WORKERS EXPOSED TO FORMALDEHYDE

    PubMed Central

    Coggon, David; Ntani, Georgia; Harris, E Clare; Palmer, Keith T

    2014-01-01

    The International Agency for Research on Cancer controversially has classified formaldehyde as causing nasopharyngeal carcinoma and myeloid leukaemia. To provide further information on this question, we extended follow-up of 14,008 chemical workers at six factories in England and Wales, covering the period 1941-2012. Mortality was compared with national death rates, and associations with incident upper airways cancer and leukaemia were explored in nested case-control analyses. Excess deaths were observed from cancers of the oesophagus (100 v 93.1 expected), stomach (182 v 141.4), rectum (107 v 86.8), liver (35 v 26.9) and lung (813 v 645.8), but none of these tumours exhibited a clear exposure-response relationship. Nested case-control analyses of 115 men with upper airways cancer (including one nasopharyngeal cancer), 92 with leukaemia, and 45 with myeloid leukaemia indicated no elevations of risk in the highest exposure category (high exposure for ≥1 year). When the two highest exposure categories were combined the odds ratio for myeloid leukaemia was 1.26 (95%confidence interval: 0.39, 4.08). Our results provide no support for a hazard of myeloid leukaemia, nasopharyngeal carcinoma or other upper airways tumours from formaldehyde, and indicate that any excess risk of these cancers, even from relatively high exposures, is at most small. PMID:24714728

  20. Mesenchymal stromal cells primed with Paclitaxel attract and kill leukaemia cells, inhibit angiogenesis and improve survival of leukaemia-bearing mice.

    PubMed

    Pessina, Augusto; Coccè, Valentina; Pascucci, Luisa; Bonomi, Arianna; Cavicchini, Loredana; Sisto, Francesca; Ferrari, Maura; Ciusani, Emilio; Crovace, Antonio; Falchetti, Maria Laura; Zicari, Sonia; Caruso, Arnaldo; Navone, Stefania; Marfia, Giovanni; Benetti, Anna; Ceccarelli, Piero; Parati, Eugenio; Alessandri, Giulio

    2013-03-01

    Current leukaemia therapy focuses on increasing chemotherapy efficacy. Mesenchymal stromal cells (MSCs) have been proposed for carrying and delivery drugs to improve killing of cancer cells. We have shown that MSCs loaded with Paclitaxel (PTX) acquire a potent anti-tumour activity. We investigated the effect of human MSCs (hMSCs) and mouse SR4987 loaded with PTX (hMSCsPTX and SR4987PTX) on MOLT-4 and L1210, two leukaemia cell (LCs) lines of human and mouse origin, respectively. SR4987PTX and hMSCsPTX showed strong anti-LC activity. hMSCsPTX, co-injected with MOLT-4 cells or intra-tumour injected into established subcutaneous MOLT-4 nodules, strongly inhibited growth and angiogenesis. In BDF1-mice-bearing L1210, the intraperitoneal administration of SR4987PTX doubled mouse survival time. In vitro, both hMSCs and hMSCsPTX released chemotactic factors, bound and formed rosettes with LCs. In ultrastructural analysis of rosettes, hMSCsPTX showed no morphological alterations while the attached LCs were apoptotic and necrotic. hMSCs and hMSCsPTX released molecules that reduced LC adhesion to microvascular endothelium (hMECs) and down-modulated ICAM1 and VCAM1 on hMECs. Priming hMSCs with PTX is a simple procedure that does not require any genetic cell manipulation. Once the effectiveness of hMSCsPTX on established cancers in mice is proven, this procedure could be proposed for leukaemia therapy in humans.

  1. Unusual fungal sepsis of Alternaria alternata in acute lymphoblastic leukaemia in an adult patient.

    PubMed

    Jain, S; Tarai, B; Tuli, P; Das, P

    2015-01-01

    We report a case of unusual fungal sepsis of Alternaria alternata in a patient of acute lymphoblastic leukaemia in 62-year-old male who presented with complaints of 'off and on' fever with decreased oral intake. On evaluation, haemogram showed low platelet count and 68% blast cells in peripheral blood. On flow cytometry of peripheral blood, the gated blasts (approximately 55%) highly express CD45, CD10, CD19, CD22 and condition was diagnosed as acute lymphoblastic leukaemia. He was started on standard induction treatment along with supportive therapies. During the course of treatment, two sets of paired blood cultures were sent 48 h apart. All of blood cultures were done on Bac-T alert 3D system. All of them yielded fungus. The fungus was then grown on Sabouraud's Dextrose agar media. It was identified as A. alternata. The patient condition worsened and later had cardiac arrest in ICU and could not be revived.

  2. DNMT3A: the DioNysian MonsTer of acute myeloid leukaemia

    PubMed Central

    O’Brien, Emma Conway; Brewin, John

    2014-01-01

    In the mythology of Ancient Greece, there was often a creative tension between the opposing forces of the gods Apollo and Dionysius, the two sons of Zeus. The Apollonian force was considered to be rational and lifegiving, whilst Dionysian forces were chaotic and elemental. Acute myeloid leukaemia is characterised by the clash of these forces: the chaotic proliferation of immature myeloid cells in the bone marrow overcomes the normal, orderly production of healthy blood cells. DNMT3A mutations occur early in the leukaemogenic process and may even act as “founder” mutations – the first step in a pathway towards malignant transformation. As such, these mutations may represent a Dionysian agent of disorder, inciting the chaotic myeloid proliferation and arrest of differentiation which are hallmarks of AML. This review will focus on the role of DNMT3A mutations in leukaemia pathogenesis, their influence on prognosis, and the potential for therapeutic targeting. PMID:25469209

  3. Advances in therapy for Philadelphia-positive acute lymphoblastic leukaemia of childhood and adolescence.

    PubMed

    Bleckmann, Kirsten; Schrappe, Martin

    2016-03-01

    The presence of the BCR/ABL1 fusion gene in childhood acute lymphoblastic leukaemia (ALL) is a rare finding and has been an adverse prognostic factor associated with a high risk of therapeutic failure. The current key components of treatment are intensive polychemotherapy and a BCR/ABL1 kinase domain inhibitor. This treatment approach has been applied in a few clinical trials by paediatric leukaemia study groups. Thus, this subtype of ALL serves as the first model system for truly targeted treatment. The role of haematopoietic stem cell transplantation (HSCT) is increasingly called into question, at least in a favourable, though not yet clearly defined, subset of patients. Currently, the choice of the most effective tyrosine kinase inhibitor is not yet settled, in particular, in view of potential reduction of overall treatment intensity.

  4. Intracytoplasmic inclusions in B prolymphocytic leukaemia: ultrastructural, cytochemical, and immunological studies.

    PubMed Central

    Robinson, D S; Melo, J V; Andrews, C; Schey, S A; Catovsky, D

    1985-01-01

    The intracytoplasmic inclusions seen in most cells from a patient with B prolymphocytic leukaemia were analysed using both light and electron microscopy. They consisted of a dense homogeneous structure and were surrounded by a membrane, which had no continuity with the Golgi cisternae or the endoplasmic reticulum; some inclusions had a clear association with small lysosomal granules. Immunofluorescence and immunoperoxidase studies using light microscopy failed to elucidate completely the nature of the inclusions, but immunocytochemical reactions performed using electron microscopy suggested an immunoglobulin nature. All inclusions were negative for acid phosphatase and periodic acid Schiff. The nature of the inclusions described in the prolymphocytes of this patient were compared with those previously recorded in B prolymphocytic leukaemia. Images PMID:2993372

  5. Acute sinusitis and blindness as the first presentation of chronic lymphocytic leukaemia.

    PubMed

    Lim, K H; Thomas, G; van Beers, E J; Hosman, A E; Mourits, M P; van Noesel, C J M; Kater, A P; Reinartz, S M

    2014-12-01

    Chronic lymphocytic leukaemia (CLL) is the most frequent form of leukaemia among adults in the Western world, presenting at a median age of 65 years. The diagnosis is usually made incidentally during routine blood examination while the disease is still in its early phase. We report a case of blindness of 24 hours due to acute sinusitis based on CLL localisation in a patient with undiagnosed CLL. Emergency endoscopic sinus surgery and intra- and extra-ocular orbital decompression were performed. The sinusitis resolved after surgery and intravenous antibiotics. Her vision improved within 24 hours and eventually recovered completely after six months. Her CLL remained in an indolent state, needing no active treatment. This case illustrates that blindness from a lymphoproliferative disorder may be treated with emergency endoscopic sinus surgery instead of conventional chemotherapy in order to salvage the vision first, even if the vision is lost for more than 24 hours.

  6. Incidence of leukaemia in young people in the vicinity of Hinkley Point nuclear power station, 1959-86.

    PubMed Central

    Ewings, P. D.; Bowie, C.; Phillips, M. J.; Johnson, S. A.

    1989-01-01

    The incidence of leukaemia and non-Hodgkin's lymphoma in young people (aged under 25) living in a predefined area around the nuclear power station at Hinkley Point, Somerset, was examined for the period 1959-86 by using cancer registry data. During the period since Hinley Point began operations--that is, 1964-86--there were 19 cases in the area compared with 10.4 expected from national rates, giving a standardised registration ratio of 1.82 (95% confidence interval 1.10 to 2.85). The incidence in the rest of Somerset was also high, however (standardised registration ratio 1.18; 95% confidence interval 0.98 to 1.41), and the high rate around Hinkley Point may simply have been reflecting the high local incidence (ratio of the two standardised registration ratio's 1.54; 95% confidence interval 0.90 to 2.52). Analysis of predetermined five year periods showed that the excess cases in the Hinkley Point area were concentrated in the 10 years 1964-73 after commissioning of the station, at a time when rates in the rest of Somerset were close to the national average. In particular the nine cases occurring in the five years 1969-73 were about four times the number expected from national rates (standardised registration ratio 3.96; 95% confidence interval 1.81 to 7.52). Rates in the Hinkley Point area after 1973 were fairly low, especially as compared with the rest of Somerset. In the five years 1959-63 (that is, before Hinkley Point was commissioned) rates throughout Somerset (including the Hinkley Point area) were higher than the national rate. These findings should be interpreted with caution, and further studies are required to test the plausibility of theories relating to radiation and viruses. PMID:2504406

  7. Specific aquaporins facilitate Nox-produced hydrogen peroxide transport through plasma membrane in leukaemia cells.

    PubMed

    Vieceli Dalla Sega, Francesco; Zambonin, Laura; Fiorentini, Diana; Rizzo, Benedetta; Caliceti, Cristiana; Landi, Laura; Hrelia, Silvana; Prata, Cecilia

    2014-04-01

    In the last decade, the generation and the role of reactive oxygen species (ROS), particularly hydrogen peroxide, in cell signalling transduction pathways have been intensively studied, and it is now clear that an increase of ROS level affects cellular growth and proliferation pathways related to cancer development. Hydrogen peroxide (H2O2) has been long thought to permeate biological membranes by simple diffusion since recent evidence challenged this notion disclosing the role of aquaporin water channels (AQP) in mediating H2O2 transport across plasma membranes. We previously demonstrated that NAD(P)H oxidase (Nox)-generated ROS sustain glucose uptake and cellular proliferation in leukaemia cells. The aim of this study was to assess whether specific AQP isoforms can channel Nox-produced H2O2 across the plasma membrane of leukaemia cells affecting downstream pathways linked to cell proliferation. In this work, we demonstrate that AQP inhibition caused a decrease in intracellular ROS accumulation in leukaemia cells both when H2O2 was produced by Nox enzymes and when it was exogenously added. Furthermore, AQP8 overexpression or silencing resulted to modulate VEGF capacity of triggering an H2O2 intracellular level increase or decrease, respectively. Finally, we report that AQP8 is capable of increasing H2O2-induced phosphorylation of both PI3K and p38 MAPK and that AQP8 expression affected positively cell proliferation. Taken together, the results here reported indicate that AQP8 is able to modulate H2O2 transport through the plasma membrane affecting redox signalling linked to leukaemia cell proliferation.

  8. Childhood infectious diseases and risk of leukaemia in an adult population.

    PubMed

    Parodi, Stefano; Crosignani, Paolo; Miligi, Lucia; Nanni, Oriana; Ramazzotti, Valerio; Rodella, Stefania; Costantini, Adele Seniori; Tumino, Rosario; Vindigni, Carla; Vineis, Paolo; Stagnaro, Emanuele

    2013-10-15

    Our study is aimed at investigating the association between common childhood infectious diseases (measles, chickenpox, rubella, mumps and pertussis) and the risk of developing leukaemia in an adult population. A reanalysis of a large population-based case-control study was carried out. Original data included 1,771 controls and 649 leukaemia cases from 11 Italian areas. To contain recall bias, the analysis was restricted to subjects directly interviewed and with a good quality interview (1,165 controls and 312 cases). Odds ratios (ORs) and their related 95% confidence intervals (95% CIs) were estimated by unconditional polychotomous logistic regression model adjusting for age, gender and occupational and lifestyle exposures. A protective effect of at least one infection (OR = 0.66, 95% CI: 0.45-0.97), measles (OR = 0.57, 95% CI: 0.39-0.82) and pertussis (OR = 0.66, 95% CI: 0.45-0.98) was observed for chronic lymphoid leukaemia (CLL). The number of infections was strongly inversely associated with the risk of CLL (p = 0.002, test for trend). With regard to the other types of leukaemia, only a protective effect of pertussis was observed for AML (OR = 0.52, 95% CI: 0.32-0.87). Our results pointed out a protective role of childhood infectious diseases on the risk of CLL in adults. Although a specific antioncogenic effect of some infectious disease, especially measles, cannot be ruled out, the observed decrease of risk with increasing number of infections suggests that a more general "hygiene hypothesis" could be the most likely explanation of the detected association. The protective role of pertussis remains to be elucidated.

  9. Identification of cellular immunoglobulins in chronic lymphocytic leukaemia by immunoperoxidase staining.

    PubMed Central

    Markey, G M; McConnell, R E; Alexander, H D; Morris, T C; Robertson, J H

    1983-01-01

    An indirect immunoperoxidase technique has been used for visualisation of cellular immunoglobulins in chronic lymphocytic leukaemia. Baker's formol calcium was used as fixative. Monoclonal light and heavy chain patterns were demonstrated in 24 out of 27 cases. Only one case did not have any demonstrable immunoglobulins. The presence of alpha or gamma heavy chain immunoglobulin isotypes in leukaemic lymphocytes was found to be related to low mouse rosetting capacity (p less than 0.05). Images PMID:6418770

  10. Tumour lysis syndrome after treatment of chronic lymphocytic leukaemia with fludarabine.

    PubMed Central

    Montalban, C.; Liaño, F.; Aguilera, A.

    1994-01-01

    Fludarabine is one of the most recent and promising therapeutic agents for chronic lymphocytic leukaemia. We describe a patient who developed tumour lysis syndrome after the first course of treatment with fludarabine and call attention to this uncommon but potentially lethal complication that has not been previously taken into account in this neoplasia. It should always be anticipated when patients are treated with new and effective drugs. PMID:7971632

  11. Paternal radiation exposure and leukaemia in offspring: the Ontario case-control study.

    PubMed Central

    McLaughlin, J R; King, W D; Anderson, T W; Clarke, E A; Ashmore, J P

    1993-01-01

    OBJECTIVES--To test the hypothesis that there is an association between childhood leukaemia and the occupational exposure of fathers to ionising radiation before a child's conception. DESIGN--Case-control study with eight matched controls per case. SETTING--Regions of Ontario, Canada, with an operating nuclear facility. SUBJECTS--Cases were children (age 0-14) who died from or were diagnosed as having leukaemia from 1950 to 1988 and were born to mothers living in the vicinity of an operating nuclear facility. Controls were identified from birth certificates, matched by date of birth and residence at birth. There were 112 cases and 890 controls. MAIN OUTCOME MEASURES--Paternal radiation exposure was determined by a record linkage to the Canadian National Dose Registry. RESULTS--Six fathers of cases and 53 fathers of controls had had a total whole body dose > 0.0 mSv before the child's conception, resulting in an odds ratio of 0.87 (95% confidence interval 0.32 to 2.34). There was no evidence of an increased leukaemia risk in relation to any exposure period (lifetime or six months or three months before conception) or exposure type (total whole body dose, external whole body dose, or tritium dose), except for radon exposure to uranium miners, which had a large odds ratio that was not significantly different from the null value. CONCLUSIONS--The findings of this study in Ontario did not support the hypothesis that childhood leukaemia is associated with the occupational exposure of fathers to ionising radiation before the child's conception. PMID:8241906

  12. BCR-ABL fusion peptides and cytotoxic T cells in chronic myeloid leukaemia.

    PubMed

    Clark, R E; Christmas, S E

    2001-01-01

    The BCR-ABL gene that arises in chronic myeloid leukaemia (CML) is a neoantigen. Peptides derived from the BCR-ABL fusion junction may therefore be immunogenic, if appropriately presented to the immune system. This article reviews data demonstrating that certain junctional peptides will bind to HLA molecules, and that these peptides will elicit specific T-lymphocyte responses in vitro, in both normal subjects and in CML patients. The clinical relevance of these observations is discussed.

  13. Influenza virus A (H1N1) in giant anteaters (Myrmecophaga tridactyla).

    PubMed

    Nofs, Sally; Abd-Eldaim, Mohamed; Thomas, Kathy V; Toplon, David; Rouse, Dawn; Kennedy, Melissa

    2009-07-01

    In February 2007, an outbreak of respiratory disease occurred in a group of giant anteaters (Myrmecophaga tridactyla) at the Nashville Zoo. Isolates from 2 affected animals were identified in March 2007 as a type A influenza virus related to human influenza subtype H1N1.

  14. 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

  15. Quercus Suber L. Cork Extracts Induce Apoptosis in Human Myeloid Leukaemia HL-60 Cells.

    PubMed

    Bejarano, Ignacio; Godoy-Cancho, Belén; Franco, Lourdes; Martínez-Cañas, Manuel A; Tormo, María A

    2015-08-01

    Quercus suber L. cork contains a diversity of phenolic compounds, mostly low molecular weight phenols. A rising number of reports support with convergent findings that polyphenols evoke pro-apoptotic events in cancerous cells. However, the literature related to the anti-cancer bioactivity of Q. suber L. cork extractives (QSE) is still limited. Herein, we aim to describe the antitumor potential displayed by cork extractives obtained by different extraction methods in the human promyelocytic leukaemia cells. In order to quantify the effects of QSE on cancer cells viability, phosphatidylserine exposure, caspase-3 activity, mitochondrial membrane potential and cell cycle were evaluated. The results indicated that the QSE present a time-dependent and dose-dependent cytotoxicity in the human promyelocytic leukaemia cells. Such a noxious effect leads these leukaemia cells to their death through apoptotic processes by altering the mitochondrial outer membrane potential, activating caspase-3 and externalizing phosphatidylserine. However, cells cycle progression was not affected by the treatments. This study contributes to open a new way to use this natural resource by exploiting its anti-cancer properties. Moreover, it opens new possibilities of application of cork by-products, being more efficient in the sector of cork-based agriculture. Copyright © 2015 John Wiley & Sons, Ltd.

  16. Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia.

    PubMed

    Mitchell, Richard; Wagner, John E; Hirsch, Betsy; DeFor, Todd E; Zierhut, Heather; MacMillan, Margaret L

    2014-02-01

    Acute leukaemia or advanced myelodysplastic syndrome (MDS ≥ 5% blasts) in Fanconi anaemia (FA) patients is associated with a poor prognosis. We report 21 FA patients with acute leukaemia or advanced MDS who underwent haematopoietic cell transplantation (HCT) at the University of Minnesota between 1988 and 2011. Six patients had biallelic BRCA2 mutations. Eight patients received pre-transplant cytoreduction, with 3 achieving complete remission. HCT donor source included human leucocyte antigen-matched sibling (n = 2) or alternative donors (n = 19). Neutrophil engraftment was 95% for the entire cohort, and the incidence of acute graft-versus-host disease was 19%. 5-year overall survival (OS) was 33%, with a relapse rate of 24%, with similar OS in patients with biallelic BRCA2 mutations. Our study supports the use of HCT in the treatment of FA patients with acute leukaemia or advanced MDS, however, the role of chemotherapy prior to HCT remains unclear for this population. FA patients with biallelic BRCA2 are unique and may benefit from higher dose chemotherapy relative to other complementation groups.

  17. Acute Myeloid Leukaemia Diagnosed by Intra-Oral Myeloid Sarcoma. A Case Report

    PubMed Central

    Papamanthos, Mattheos K.; Skulakis, Haralampos E.; Fericean, Angela-Monika A.; Zorba, Matina T.; Matiakis, Apostolos T.

    2010-01-01

    Myeloid sarcoma (MS) is a rare extramedullary malignant tumor composed of immature myeloid cells. It is strongly associated with a well known or covert acute myeloid leukaemia, chronic myeloproliferative diseases or myelodysplastic syndromes. Intraoral MS scarcely occurs. An unusual case of acute myeloid leukaemia, which was diagnosed by mandibular MS that was developed in the alveolar socket after a dental extraction, is reported. The histological examination (including immunohistochemical analysis) of a subsequent biopsy showed infiltration of the oral mucosa by neoplastic cells. This lesion was therefore classified as acute myeloid leukaemia. The patient was referred to oncologists that confirmed the initial diagnosis. The patient underwent chemotherapy and the mandibular tumor disappeared. Forty days later, a relapse of the disease, which appeared as a great-ulcerated lesion, was developed in the hard palate. Thirty days after the second chemotherapy had finished, a new intraoral tumor was developed in the vestibular maxillary gingiva. Review of the literature shows no report of intraoral relapse and particularly multiple relapse of a MS that involves the oral cavity. Even though MS is encountered infrequently in the oral cavity, it should be considered in the differential diagnosis of conditions (especially tumors) with a similar clinical appearance. PMID:20512638

  18. 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.

  19. Treatment of acute myeloblastic leukaemia in a patient with Bombay blood type: a case report.

    PubMed

    Okamoto, Y; Tsuda, T; Matsunami, M; Hirose, T; Sakaguchi, R; Katayama, N; Ota, K

    2001-01-01

    A 62-year-old female was admitted to our hospital with suspected acute leukaemia and after investigation we diagnosed acute myeloblastic leukaemia (AML-M1). The patient's blood type was found to be the very rare Bombay type and surveillance of her relatives showed the same blood type in her male cousin on her mother's side. Alongside chemotherapy the patient received 4000 ml of frozen Bombay-type red cells, 1400 ml of concentrated red cells in manitol adenine phosphate solutions and 360 units of type O concentrated platelets without marked effects. The anti-H antibody was initially at 128 dilution but for unknown reasons increased to 2048 dilution after remission of AML-M1. About 3 months after hospitalization the patient died of Cryptococcus neoformans pneumonia despite strict precautions against infection. Although AML-M1 is a common adult leukaemia and is chemosensitive to anti-leukaemic drugs, neither AML-M1 in a patient with Bombay-type red cells nor its treatment with chemotherapy and transfusion with type Oh frozen red cells have previously been reported.

  20. A mathematical model of subpopulation kinetics for the deconvolution of leukaemia heterogeneity.

    PubMed

    Fuentes-Garí, María; Misener, Ruth; García-Munzer, David; Velliou, Eirini; Georgiadis, Michael C; Kostoglou, Margaritis; Pistikopoulos, Efstratios N; Panoskaltsis, Nicki; Mantalaris, Athanasios

    2015-07-01

    Acute myeloid leukaemia is characterized by marked inter- and intra-patient heterogeneity, the identification of which is critical for the design of personalized treatments. Heterogeneity of leukaemic cells is determined by mutations which ultimately affect the cell cycle. We have developed and validated a biologically relevant, mathematical model of the cell cycle based on unique cell-cycle signatures, defined by duration of cell-cycle phases and cyclin profiles as determined by flow cytometry, for three leukaemia cell lines. The model was discretized for the different phases in their respective progress variables (cyclins and DNA), resulting in a set of time-dependent ordinary differential equations. Cell-cycle phase distribution and cyclin concentration profiles were validated against population chase experiments. Heterogeneity was simulated in culture by combining the three cell lines in a blinded experimental set-up. Based on individual kinetics, the model was capable of identifying and quantifying cellular heterogeneity. When supplying the initial conditions only, the model predicted future cell population dynamics and estimated the previous heterogeneous composition of cells. Identification of heterogeneous leukaemia clones at diagnosis and post-treatment using such a mathematical platform has the potential to predict multiple future outcomes in response to induction and consolidation chemotherapy as well as relapse kinetics.

  1. Crystal structure of Auer rods in acute myeloblastic leukaemia (AMyL).

    PubMed Central

    Pearson, E C

    1986-01-01

    Ultrathin sections containing Auer rods from cases of acute myeloblastic leukaemia (AMyL) were tilted in the goniometer stage of the electron microscope and the resulting series of electronmicrographs analysed in an optical diffractometer illuminated by laser. The results showed that Auer rods of AMyL show a truly three dimensional crystal structure. Measurements from the optical diffraction patterns were consistent with a monoclinic unit cell, the unit cell edge lengths a, b, and c being 6.6 [SD) 0.5) nm, 8.6 (0.2) nm, and 9.6 (1.0) nm, respectively; the angle between a and c being 120 (7) degrees. This structure was quite distinct from the "tubular" substructure reported by others in the Auer rods of acute promyelocytic leukaemia (APL), although it was consistent with periodicities measured by others in Auer rods of AMyL. A complete understanding of the three dimensional structures of Auer rods in the different types of acute myeloid leukaemia (AML) could well prove to be of considerable diagnostic importance. Images PMID:3013944

  2. The CD68 protein as a potential target for leukaemia-reactive CTL.

    PubMed

    Sadovnikova, E; Parovichnikova, E N; Savchenko, V G; Zabotina, T; Stauss, H J

    2002-10-01

    CD68, a haematopoietic differentiation marker of the monocyte-macrophage lineage, is expressed in various human malignancies including chronic and acute myeloid leukaemia (AML). While the majority of normal CD34(+) cells are negative for CD68 expression, CD34(+) cells from AML patients produce elevated amounts of this protein. The purpose of this study was to identify CTL epitopes in the human CD68 protein. Mouse CD68 was also analysed to search for epitopes that could be used in murine tumor model. Peptides binding to murine H2(b) class I molecules were identified and used to stimulate CTL responses from allogeneic donor mice to avoid immunological tolerance. High avidity CTL clones specific for three different peptide epitopes did not kill CD68-expressing murine target cells, indicating that endogenous antigen processing failed to produce sufficient amounts of these peptides. In contrast, allo-restricted human CTL specific for an HLA-A2-binding peptide of CD68 recognised not only picomolar concentrations of peptide, but also displayed low levels of killing against HLA-A2-positive K562 and THP-1 leukemia cell lines and blast cells from AML patients. These data suggest that human leukaemia cells express limited amounts of CD68-derived peptides, and that high avidity CTL capable of recognising sub-picomolar concentrations of peptides are required for efficient killing of leukaemia cells.

  3. Iowa radon leukaemia study: a hierarchical population risk model for spatially correlated exposure measured with error.

    PubMed

    Smith, Brian J; Zhang, Lixun; Field, R William

    2007-11-10

    This paper presents a Bayesian model that allows for the joint prediction of county-average radon levels and estimation of the associated leukaemia risk. The methods are motivated by radon data from an epidemiologic study of residential radon in Iowa that include 2726 outdoor and indoor measurements. Prediction of county-average radon is based on a geostatistical model for the radon data which assumes an underlying continuous spatial process. In the radon model, we account for uncertainties due to incomplete spatial coverage, spatial variability, characteristic differences between homes, and detector measurement error. The predicted radon averages are, in turn, included as a covariate in Poisson models for incident cases of acute lymphocytic (ALL), acute myelogenous (AML), chronic lymphocytic (CLL), and chronic myelogenous (CML) leukaemias reported to the Iowa cancer registry from 1973 to 2002. Since radon and leukaemia risk are modelled simultaneously in our approach, the resulting risk estimates accurately reflect uncertainties in the predicted radon exposure covariate. Posterior mean (95 per cent Bayesian credible interval) estimates of the relative risk associated with a 1 pCi/L increase in radon for ALL, AML, CLL, and CML are 0.91 (0.78-1.03), 1.01 (0.92-1.12), 1.06 (0.96-1.16), and 1.12 (0.98-1.27), respectively. PMID:17373673

  4. Cell viability of acute myeloid leukaemia blasts in culture correlates with treatment outcome.

    PubMed

    Maha, Abdullah; Cheong, Soon-Keng; Leong, Chooi-Fun; Seow, Heng-Fong

    2008-02-01

    Despite the advances in understanding the pathophysiology of acute myeloid leukaemia (AML), the cure rate for acute myeloid leukaemia patients remains low. Cytogenetic abnormalities and age are the prognostic factors that guide treatment decisions. However, many AML patients still die. The biological factors that influence treatment outcome are largely unknown. Thus, the objective of our study was to use the in vitro viability test to correlate with treatment outcome. Acute myeloid leukaemia blasts demonstrated differing ability to survive in culture. Our examination of blast phenotype at various days in culture showed two possible growth directions. First, cells underwent maturation by increased expression of CD16 and down-regulated CD34 (a haemopoietic stem cell marker). These cells also appeared to have undergone apoptosis. Alternatively, cells continued to survive in culture and maintained high expression of CD34. An MTT assay was carried out to determine viability after three days of culture. Lower optical density values were obtained for samples that underwent apoptosis and higher values were obtained for samples that survived in culture. Apoptosis was measured by Annexin V/propidium iodide staining. A comparison between results of MTT assay and duration of disease free survival revealed that a higher viability in vitro correlated significantly with shorter survival duration in the patient (R -0.761, p=0.002, n=13). Thus, this study further supports the hypothesis that AML patients with poor survival may be related to having blasts with a biologically more immature or stem cell-like nature.

  5. Risk of leukaemia mortality from exposure to ionising radiation in US nuclear workers: a pooled case-control study

    PubMed Central

    Daniels, Robert D; Bertke, Stephen; Waters, Kathleen M; Schubauer-Berigan, Mary K

    2015-01-01

    Objective To follow-up on earlier studies of the leukaemogenicity of occupational ionising radiation exposure. Methods We conducted a nested case-control analysis of leukaemia mortality in a pooled cohort of US nuclear workers followed through 2005. Each case was matched to four controls on attained age. Exposures were estimated from available records. General relative risk models were used to estimate the excess relative risk (ERR) of leukaemia, excluding chronic lymphocytic (CLL), acute myeloid leukaemia, chronic myeloid leukaemia and CLL while controlling for potential confounders. Preferred exposure lags and time-windows of risks were calculated using joint maximum likelihood. Dose-response was also examined using linear, linear-quadratic, categorical and restricted cubic spline models. Results There were 369 leukaemia deaths in 105 245 US nuclear workers. The adjusted ERR for non-CLL leukaemia was 0.09 (95% CI −0.17 to 0.65) per 100 mGy. Elevated non-CLL risks were observed from exposures occurring 6–14 years prior to attained age of cases (ERR per 100 mGy=1.9; 95% CI <0 to 8.0). Lagged models indicated non-linearity of risk at very low (<10 mGy) and high (>100 mGy) doses, which contributed to the imprecision of results in linear models. Similar risk attenuation was not evident in time-windows-based models. Conclusions Risk estimates were in reasonable agreement with previous estimates, with the temporality of non-CLL leukaemia risk as a dominant factor in dose-response analyses. Future research should focus on methods that improve evaluations of the dose-response, particularly in the low-dose range. PMID:23000827

  6. Out come of induction of remission in undernourished children with acute lymphoblastic leukaemia.

    PubMed

    Begum, M; Jahan, S; Tawfique, M; Mannan, M A

    2012-10-01

    Acute lymphoblastic leukaemia (ALL) is the most common childhood leukaemia. On the other hand under-nutrition is a common problem in our country. This prospective study was conducted to see the outcome of induction of remission in undernourished children with acute lymphoblastic leukaemia. This study was carried out in the department of Paediatric hematology and oncology of Bangabandhu Sheikh Mujib Medical University (BSMMU) during the period from November 2002 to October 2004. A total of sixty (60) children who were diagnosed as acute lymphoblastic leukaemia in 1 to 15 years of age were included in this study. But the children with previous history of congenital disease and that of chemotherapy or steroid were excluded from this study. Patients were divided into two groups on the basis of Z score of weight for age. Thirty (30) children those with Z score- 2 or less were classified as undernourished and was labeled as Group A and another thirty (30) patient those Z score above-2 were classified as well nourished and was placed in Group B, After inclusion into the study, completion of induction of remission was monitored by physical examination and laboratory investigations. The result showed that mean age in Group A was 77.16 ± 7.07 months and that in Group B was 74.13 ± 5.09 months with male preponderance in both the groups. Mean body weight in Group A was 14.55 ± 0.76 Kg and that in Group B was 21.40 ± 1.05 kg (p<0.001). Children in Group A required 39.06 ± 0.72 days to complete induction but in Group B it required 31.63 ± 0.17 days (p<0.04). Hospital stay in Group A children was 52.10 ± 1.08 days and in Group B 42.37 ± 0.50 (p<0.002). The result suggested that under nutrition has an influence on the out come of induction of remission in undernourished children with acute lymphoblastic leukaemia. So appropriate measures are essential to improve nutritional status of children for successful management of ALL in children.

  7. Day-care, early common infections and childhood acute leukaemia: a multicentre French case–control study

    PubMed Central

    Perrillat, F; Clavel, J; Auclerc, M F; Baruchel, A; Leverger, G; Nelken, B; Philippe, N; Schaison, G; Sommelet, D; Vilmer, E; Hémon, D

    2002-01-01

    We conducted a case–control study to investigate the role of early infections in the aetiology of childhood acute leukaemias. The study included 280 incident cases (240 acute lymphoblastic leukaemia and 40 acute non-lymphoblastic leukaemia) and 288 hospital controls, frequency matched by age, gender, hospital, catchment area of the hospital and ethnic origin. Data were obtained from standardised face-to-face interviews of the mothers. The interviews included questions on early common infections, day-care attendance, breast-feeding, birth order and infantile diseases. Odds ratios were estimated using an unconditional regression model including the stratification variables, parental socio-economic status and perinatal characteristics. Birth order was not associated with childhood leukaemia (acute lymphoblastic or acute non-lymphoblastic). A statistically-significant inverse association was observed between childhood leukaemia and day-care attendance (odds ratio=0.6, 95% Confidence Interval=(0.4–1.0)), repeated early common infections (⩾4 per year before age two, odds ratio=0.6 (0.4–1.0)), surgical procedures for ear–nose–throat infections before age two (odds ratio=0.5 (0.2–1.0)) and prolonged breast-feeding (⩾6 months, odds ratio=0.5 (0.2–1.0)). In the multivariate model including day-care attendance, early common infections and breast-feeding, results concerning breast-feeding remained unchanged. A statistically significant interaction between day-care attendance and repeated early common infections was observed. When the interaction was taken into account, the simple effects of day-care and early common infections disappeared (odds ratio=1.1 (0.5–2.3) and odds ratio=0.8 (0.5–1.3), respectively) while the joint effect of day-care attendance and early common infections was negatively associated with childhood leukaemia (odds ratio=0.3 (0.1–0.8)). All the above associations were observed both for acute lymphoblastic leukaemia and acute non

  8. Evidence that continued remission in patients treated for acute leukaemia is dependent upon autologous natural killer cells.

    PubMed

    Lowdell, Mark W; Craston, Rose; Samuel, David; Wood, Marion E; O'Neill, Elena; Saha, Vaskar; Prentice, H Grant

    2002-06-01

    Although it has been known for more than 40 years that allogeneic immune responses cure leukaemias after bone marrow transplantation, autologous leukaemia-specific immunity remains controversial and its impact upon survival has not been established. Here we have tested 25 patients with de novo acute leukaemias, while in remission at completion of their anti-leukaemia therapy, for evidence of autologous cytolytic immunity to their leukaemic cells taken and cryopreserved at disease presentation. We have measured this degree of cell-mediated cytotoxicity in vitro and termed it "leukaemia cytolytic activity" (LCA). Patients whose disease ultimately relapsed had significantly lower LCA than those who remained in remission beyond 2 years (P < 0.001); the absence of LCA when in remission predicted subsequent relapse within 2 years with a sensitivity of 100% and specificity of 77%. LCA was mediated in vitro by CD56+/CD8alpha+/CD3- natural killer cells. We propose that it is this immune response, rather than the chemotherapy per se, which is responsible for continued remission and that measurement of LCA in patients at completion of therapy may be used as an indicator of risk of subsequent relapse. Patients lacking this response will require further treatment, either with an allogeneic donor transplant or an alternative immunotherapeutic strategy. PMID:12060116

  9. The use of rituximab and bendamustine in treating chronic lymphocytic leukaemia (CLL) in end-stage renal disease (ESRD).

    PubMed

    Shoji, Jun; Lew, Susie Q

    2013-05-02

    A patient with a history of type 2 diabetes mellitus and chronic lymphocytic leukaemia has renal failure with large kidneys. The patient refused kidney biopsy to determine the aetiology of her renal failure. She uses peritoneal dialysis to treat renal failure. She received rituximab and bendamustine to treat chronic lymphocytic leukaemia. Adenopathy resolves with treatment and she does not experience any electrolyte disturbances or decrease in urine output as a result of chemotherapy in the setting of renal failure. Renal function did not recover with chemotherapy.

  10. 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

  11. 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

  12. 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

  13. A novel zinc finger gene, ZNF465, is inappropriately expressed in acute myeloid leukaemia cells.

    PubMed

    Collin, Joseph F; Wells, James W; Czepulkowski, Barbara; Lyne, Linden; Duriez, Patrick J; Banham, Alison H; Mufti, Ghulam J; Guinn, Barbara-Ann

    2015-05-01

    To increase our knowledge of leukaemia-associated antigens, especially in acute myeloid leukaemia (AML) M4, we prepared a phage display cDNA library using mRNA from the bone marrow cells of a patient with AML M4 at diagnosis. We immunoscreened 10(6) pfu with autologous sera and identified an antigen which we named GKT-AML8. The cDNA showed more than 99% similarity to a sequence on 2q21.2 and 95% sequence similarity to a sequence on 19q13.3. These genes were named ZNF465 and ZNF466, respectively, following HUGO Gene Nomenclature Committee (HGNC) guidelines. Expressed sequence tag data suggests that both genes are transcriptionally active. ZNF465 and ZNF466 encode a 5' krüppel associated box domain typical of negative regulators of gene transcription. We have confirmed the translational start site in the +1 frame in a near-Kozak sequence that produces a 102 amino acid polypeptide from ZNF465. The high level of sequence similarity between ZNF465 and ZNF466 makes their transcripts almost indistinguishable by real-time polymerase chain reaction (RT-PCR). However, GKT-AML8 showed most sequence similarity to ZNF465 and no transcript matching the 3' ZNF466 sequence could be detected in patient samples or healthy volunteers. ZNF465/466 expression was detectable in 12/13 AML and 10/14 chronic myeloid leukaemia patients' samples but not in normal donor peripheral blood (0/8) or 0/3 bone marrow samples which had been separated into CD34(+) and CD34(-) samples. The altered expression of ZNF465/466 in patients' samples and its absence in healthy donor haematopoietic samples indicate that ZNF465 is overexpressed in early myeloid disease and as such may represent a promising target for immunotherapy.

  14. Population mixing and leukaemia in young people around the La Hague nuclear waste reprocessing plant

    PubMed Central

    Boutou, O; Guizard, A-V; Slama, R; Pottier, D; Spira, A

    2002-01-01

    In order to investigate for an association between population mixing and the occurrence of leukaemia in young people (less than 25 years), a geographical study was conducted, for the years 1979 to 1998, in Nord Cotentin (France). This area experienced between the years 1978 and 1992 a major influx of workers for the construction of a nuclear power station and a new nuclear waste reprocessing unit. A population mixing index was defined on the basis of the number of workers born outside the French department of ‘La Manche’ and living in each ‘commune’, the basic geographical unit under study. The analyses were done with indirect standardisation and Poisson regression model allowing or not for extra-Poisson variation. Urban ‘communes’ were considered as the reference population. The Incidence Rate Ratio was 2.7 in rural ‘communes’ belonging to the highest tertile of population mixing (95% Bayesian credible interval, 95%BCI=1.2–5.9). A positive trend was observed among rural strata with increasing population mixing index (IRR for trend=1.4, 95%BCI=1.1–1.8). The risk became stronger for Acute Lymphoblastic Leukaemia in children 1–6 years old in the highest tertile of population mixing (IRR=5.5, 95%BCI=1.4–23.3). These findings provide further support for a possible infective basis of childhood leukaemia. British Journal of Cancer (2002) 87, 740–745. doi:10.1038/sj.bjc.6600529 www.bjcancer.com © 2002 Cancer Research UK PMID:12232757

  15. Treatment of acute myeloid leukaemia with a triple cytotoxic regime: DAT.

    PubMed Central

    Rees, J. K.; Sandler, R. M.; Challener, J.; Hayhoe, F. G.

    1977-01-01

    Twenty patients with acute myeloid leukaemia (AML) were treated with a combination of chemotherapy which included daunorubicin, cytosine arabino-side and 6-thioguanine (DAT). The complete remission rate was 85% and was achieved, in responsive cases, after an average of 2 courses of therapy. Patients remained in hospital for an average of 37.5 days during remission-induction therapy and 3.7 days per month thereafter. The median remission period was 48 weeks and median survival was 70 weeks. A disappointing feature was the high relapse rate. This feature of the results re-affirms the need for a more effective form of remission therapy. PMID:271512

  16. Influence of radiation quality on mouse chromosome 2 deletions in radiation-induced acute myeloid leukaemia.

    PubMed

    Brown, Natalie; Finnon, Rosemary; Manning, Grainne; Bouffler, Simon; Badie, Christophe

    2015-11-01

    Leukaemia is the prevailing neoplastic disorder of the hematopoietic system. Epidemiological analyses of the survivors of the Japanese atomic bombings show that exposure to ionising radiation (IR) can cause leukaemia. Although a clear association between radiation exposure and leukaemia development is acknowledged, the underlying mechanisms remain incompletely understood. A hemizygous deletion on mouse chromosome 2 (del2) is a common feature in several mouse strains susceptible to radiation-induced acute myeloid leukaemia (rAML). The deletion is an early event detectable 24h after exposure in bone marrow cells. Ultimately, 15-25% of exposed animals develop AML with 80-90% of cases carrying del2. Molecular mapping of leukaemic cell genomes identified a minimal deleted region (MDR) on chromosome 2 (chr2) in which a tumour suppressor gene, Sfpi1 is located, encoding the transcription factor PU.1, essential in haematopoiesis. The remaining copy of Sfpi1 has a point mutation in the coding sequence for the DNA-binding domain of the protein in 70% of rAML, which alters a single CpG sequence in the codon for arginine residue R235. In order to identify chr2 deletions and Sfpi.1/PU.1 loss, we performed array comparative genomic hybridization (aCGH) on a unique panel of 79rAMLs. Using a custom made CGH array specifically designed for mouse chr2, we analysed at unprecedentedly high resolution (1.4M array- 148bp resolution) the size of the MDR in low LET and high-LET induced rAMLs (32 X-ray- and 47 neutron-induced). Sequencing of Sfpi1/PU.1DNA binding domain identified the presence of R235 point mutations, showing no influence of radiation quality on R235 type or frequency. We identified for the first time rAML cases with complex del2 in a subset of neutron-induced AMLs. This study allowed us to re-define the MDR to a much smaller 5.5Mb region (still including Sfpi1/PU.1), identical regardless of radiation quality.

  17. 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

  18. 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.

  19. Chronic lymphatic leukaemia and engine exhausts, fresh wood, and DDT: a case-referent study.

    PubMed Central

    Flodin, U; Fredriksson, M; Persson, B; Axelson, O

    1988-01-01

    The effect of potential risk factors for chronic lymphatic leukaemia was evaluated in a case-referent study encompassing 111 cases and 431 randomised referents, all alive. Information on exposure was obtained by questionnaires posted to the subjects. Crude rate ratios were increased for occupational exposure to solvents. DDT, engine exhausts, fresh wood (lumberjacks, paper pulp workers, and sawmill workers, for example) and also in farming. Further analysis of the material by means of the Miettinen confounder score technique reduced the number of rate ratios significantly exceeding unity to encompass only occupational exposure to engine exhaust, fresh wood, DDT, and contact with horses. PMID:2449239

  20. Fludarabine phosphate for the first-line treatment of chronic lymphocytic leukaemia.

    PubMed

    Walker, S; Palmer, S; Erhorn, S; Brent, S; Dyker, A; Ferrie, L; Horsley, W; Macfarlane, K; White, S; Thomas, S

    2009-06-01

    This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of fludarabine phosphate or fludarabine plus cyclophosphamide for the first-line treatment of chronic lymphocytic leukaemia,based upon the evidence submission from Schering Health Care (SHC) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process.The submission was of good quality with no major errors or omissions in the clinical evidence.Two published studies and seven abstracts were included in the company submission, which showed improvements in overall response and progression-free survival (PFS) and a higher complete response rate in the fludarabine containing arms; however, until the complete data are made available for evaluation these results must be interpreted with caution. The manufacturer's decision-analytic Markov model to estimate the cost-effectiveness of treatment with fludarabine monotherapy, fludarabine plus cyclophosphamide and chlorambucil was considered to be the most relevant source for informing this STA;it was appropriate for the decision problem and the data sources used to inform the model were appropriate from a UK NHS perspective.The incremental cost-effectiveness ratio of fludarabine plus cyclophosphamide compared with chlorambucil from the revised model presented in the manufacturer's addendum was pounds 3244 per additional quality-adjusted life-year.The results were robust to a range of subgroup and sensitivity analyses. Additional sensitivity and survival analyses were carried by the ERG to investigate possible bias in the results. This brought into question the validity of the assumptions underpinning the extrapolation of data over a lifetime time horizon and showed that the ICER estimates submitted by the manufacturer were notcalculated correctly and uncertainty surrounding the decision problems was not expressed fully.Based on these analyses the ERG

  1. Visuomotor function in children treated for acute lymphoblastic leukaemia with chemotherapy only.

    PubMed

    Knight, Sarah; McCarthy, Maria; Anderson, Vicki; Hutchinson, Esther; De Luca, Cinzia

    2014-01-01

    This study aimed to evaluate visuomotor function in children treated for acute lymphoblastic leukaemia (ALL). The performance of 64 children, 1-7 years post-chemotherapy for ALL, was compared to that of their healthy peers (n = 56) on visuomotor integration (VMI) and motor coordination (MC) tasks. Children posttreatment for ALL displayed significantly reduced VMI, but not MC, performances as compared to controls. Children treated on chemotherapy-only ALL regimes are at heightened risk for visuomotor integration deficits. Monitoring of visuomotor skills and implementation of appropriate interventions targeting higher level visuomotor integration skills should form an important component of any ALL long-term effects program. PMID:24571929

  2. A case of acute myelogenous leukaemia characterised by the BCR-FGFR1 translocation

    PubMed Central

    Matikas, Alexios; Tzannou, Ifigeneia; Oikonomopoulou, Dimitra; Bakiri, Maria

    2013-01-01

    The 8p11 myeloproliferative syndrome is a rare atypical disorder defined by the presence of rearrangements between the fibroblast growth factor receptor 1 (FGFR1) and 1 of 13 partner genes described to date, including the BCR gene on chromosome 22. The disease characterised by the BCR-FGFR1 fusion gene has distinct biological and clinical features, with significant diversity among the published cases. We report a case of BCR-FGFR1 disease which was presented as acute myeloid leukaemia with an aggressive clinical course and we review all the adult cases published in the literature. PMID:23519513

  3. Development of psoriasis in a patient with chronic myelogenous leukaemia during nilotinib treatment.

    PubMed

    Nagai, Tadashi; Karakawa, Masaru; Komine, Mayumi; Muroi, Kazuo; Ohtsuki, Mamitaro; Ozawa, Keiya

    2013-09-01

    The tyrosine kinase inhibitor (TKI) imatinib has been shown to promote psoriasis in some patients with chronic myelogenous leukaemia (CML), but it remained unclear whether second-generation TKIs such as nilotinib and dasatinib had a similar potential. Here, we present a patient in whom psoriatic erythema appeared at 26 months after initiation of nilotinib treatment. Topical ointments of activated vitamin D3 derivative and corticosteroid were applied; whereupon, the erythema gradually improved. During the clinical course, nilotinib administration continued without reduction in its dose. This is the first report of psoriasis that developed during nilotinib treatment. We also discuss the mechanisms of nilotinib-mediated progression of psoriasis.

  4. 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

  5. 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

  6. 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

  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. 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

  9. Precocious and premature puberty associated with treatment of acute lymphoblastic leukaemia.

    PubMed

    Leiper, A D; Stanhope, R; Kitching, P; Chessells, J M

    1987-11-01

    Early puberty in 28 children (23 girls, five boys) treated for acute lymphoblastic leukaemia (ALL) at a mean age of 4.0 years (range 1.4-7.8) is described. All but one had received prophylactic cranial irradiation (1800-2400 cGy) and three children had received additional cranial or craniospinal irradiation as treatment for relapse of their leukaemia. Mean age for the onset of puberty was 8.8 (SD 0.8) years in the girls and 9.3 (0.8) years in the boys; this is greater than two standard deviations from the mean for normal girls and boys. Five children (three girls, two boys) had precocious puberty. The onset of puberty occurred at greater than two standard deviations from the mean for normal girls and boys in 14(13%) girls and 4(3%) boys treated at less than eight years of age between 1970 and 1985. In a group of 55 girls treated for ALL who had survived in first remission for six years or more from diagnosis, there was a relation between young age at onset of treatment and early menarche. We suggest that premature activation of the hypothalamic-pituitary-gonadal axis occurs as a consequence of hypothalamic dysfunction due to cranial irradiation. Precocious and premature puberty in children treated for ALL may be an important factor in contributing to short stature.

  10. Greek parents' reactions, difficulties and resources in childhood leukaemia at the time of diagnosis.

    PubMed

    Patistea, E; Makrodimitri, P; Panteli, V

    2000-06-01

    Open-ended interviews were used to examine parental psychological reactions, difficulties and resources during the period following the diagnosis of childhood leukaemia. Data were obtained from 71 randomly selected mothers and fathers of children diagnosed with leukaemia at least 3 months prior to the study. The content analysis revealed a wide diversity of parental responses including many of the defensive mechanisms described in the literature such as shock, denial, anxiety and guilt. The most difficult factors for the parents to deal with during the initial period were the psychological upset and the financial burden. Problems associated with relating to others and to the health care system were also identified. Hope, social support and the marital relationship were the most helpful resources in managing the multifaceted problems caused by the diagnosis. Forty-five per cent of the participants felt that the quality of their marital relationship was improved, whereas fewer reported that the diagnosis seriously disturbed their marriage. Spouses were found to adopt symmetrical rather than complementary ways of responding to and coping with the event. Nurses have a key role in assessing the individual parent, the marital unit and the entire family system and planning appropriate interventions. PMID:11261016

  11. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia

    PubMed Central

    Ma, Xiaotu; Edmonson, Michael; Yergeau, Donald; Muzny, Donna M.; Hampton, Oliver A.; Rusch, Michael; Song, Guangchun; Easton, John; Harvey, Richard C.; Wheeler, David A.; Ma, Jing; Doddapaneni, HarshaVardhan; Vadodaria, Bhavin; Wu, Gang; Nagahawatte, Panduka; Carroll, William L.; Chen, I-Ming; Gastier-Foster, Julie M.; Relling, Mary V.; Smith, Malcolm A.; Devidas, Meenakshi; Auvil, Jaime M. Guidry; Downing, James R.; Loh, Mignon L.; Willman, Cheryl L.; Gerhard, Daniela S.; Mullighan, Charles G.; Hunger, Stephen P.; Zhang, Jinghui

    2015-01-01

    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. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse. PMID:25790293

  12. 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

  13. Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia

    PubMed Central

    Hoelbl, Andrea; Schuster, Christian; Kovacic, Boris; Zhu, Bingmei; Wickre, Mark; Hoelzl, Maria A; Fajmann, Sabine; Grebien, Florian; Warsch, Wolfgang; Stengl, Gabriele; Hennighausen, Lothar; Poli, Valeria; Beug, Hartmut; Moriggl, Richard; Sexl, Veronika

    2010-01-01

    Tumourigenesis caused by the Bcr/Abl oncoprotein is a multi-step process proceeding from initial to tumour-maintaining events and finally results in a complex tumour-supporting network. A key to successful cancer therapy is the identification of critical functional nodes in an oncogenic network required for disease maintenance. So far, the transcription factors Stat3 and Stat5a/b have been implicated in bcr/abl-induced initial transformation. However, to qualify as a potential drug target, a signalling pathway must be required for the maintenance of the leukaemic state. Data on the roles of Stat3 or Stat5a/b in leukaemia maintenance are elusive. Here, we show that both, Stat3 and Stat5 are necessary for initial transformation. However, Stat5- but not Stat3-deletion induces G0/G1 cell cycle arrest and apoptosis of imatinib-sensitive and imatinib-resistant stable leukaemic cells in vitro. Accordingly, Stat5-abrogation led to effective elimination of myeloid and lymphoid leukaemia maintenance in vivo. Hence, we identified Stat5 as a vulnerable point in the oncogenic network downstream of Bcr/Abl representing a case of non-oncogene addiction (NOA). PMID:20201032

  14. French American British (FAB) morphological classification of childhood lymphoblastic leukaemia and its clinical importance.

    PubMed

    Lilleyman, J S; Hann, I M; Stevens, R F; Eden, O B; Richards, S M

    1986-09-01

    As part of the Medical Research Council Leukaemia Trial UKALL VIII, 738 unselected children with acute lymphoblastic leukaemia (ALL) had the morphology of their marrow blast cells reviewed by a panel of three haematologists. Ninety four (13%) showed appearances classifiable as type L2 by the French American and British (FAB) cooperative group's criteria, five (0.7%) were typed L3, and the remaining 639 (86%) as L1. Disregarding the patients classified as L3, those with the L2 variant showed an inferior disease free survival to that of the remainder (p less than 0.01), and more of them failed to remit after receiving "standard" remission induction treatment (p less than 0.01). They included an excess of older children (p less than 0.01) with less profound marrow failure at diagnosis, and fewer of them expressed the common ALL antigen (p = 0.05). There was no association between L2 morphology and the diagnostic white cell count, sex, or the presence of a mediastinal mass. These findings confirm earlier reports that FAB L2 ALL is associated with a poor prognosis and that it occurs more commonly in older children. The high remission failure rate is a recent observation and indicates that alternative early treatment may be appropriate for such patients.

  15. 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

  16. The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia.

    PubMed

    Suresh, Sukanya; McCallum, Lynn; Crawford, Lisa J; Lu, Wan Hua; Sharpe, Daniel J; Irvine, Alexandra E

    2013-11-01

    Deregulated NOTCH1 has been reported in lymphoid leukaemia, although its role in chronic myeloid leukaemia (CML) is not well established. We previously reported BCR-ABL down-regulation of a novel haematopoietic regulator, CCN3, in CML; CCN3 is a non-canonical NOTCH1 ligand. This study characterizes the NOTCH1–CCN3 signalling axis in CML. In K562 cells, BCR-ABL silencing reduced full-length NOTCH1 (NOTCH1-FL) and inhibited the cleavage of NOTCH1 intracellular domain (NOTCH1-ICD), resulting in decreased expression of the NOTCH1 targets c-MYC and HES1. K562 cells stably overexpressing CCN3 (K562/CCN3) or treated with recombinant CCN3(rCCN3) showed a significant reduction in NOTCH1 signalling (> 50% reduction in NOTCH1-ICD, p < 0.05).Gamma secretase inhibitor (GSI), which blocks NOTCH1 signalling, reduced K562/CCN3 colony formation but increased that of K562/control cells. GSI combined with either rCCN3 or imatinib reduced K562 colony formation with enhanced reduction of NOTCH1 signalling observed with combination treatments. We demonstrate an oncogenic role for NOTCH1 in CML and suggest that BCR-ABL disruption of NOTCH1–CCN3 signalling contributes to the pathogenesis of CML.

  17. High-mobility group A1 proteins are overexpressed in human leukaemias.

    PubMed Central

    Pierantoni, Giovanna Maria; Agosti, Valter; Fedele, Monica; Bond, Heather; Caliendo, Irene; Chiappetta, Gennaro; Lo Coco, Francesco; Pane, Fabrizio; Turco, Maria Caterina; Morrone, Giovanni; Venuta, Salvatore; Fusco, Alfredo

    2003-01-01

    High-mobility group A (HMGA) proteins are non-histone nuclear proteins that bind DNA and several transcription factors. They are involved in the regulation of chromatin structure and function. HMGA protein expression is low in normal adult tissues, but abundant during embryonic development and in several human tumours. Rearrangements of the HMGA genes have been frequently detected in human benign tumours of mesenchymal origin, e.g. lipomas, lung hamartomas and uterine leiomiomas. HMGA proteins have been implicated in the control of cell growth and differentiation of the pre-adipocytic cell line 3T3-L1. In an attempt to better understand the role of HMGA1 proteins in haematological neoplasias and in the differentiation of haematopietic cells, we have investigated their expression in human leukaemias and in leukaemic cell lines induced to terminal differentiation. Here we report HMGA1 overexpression in most fresh human leukaemias of different origin and in several leukaemic cell lines. Moreover, differentiation of three cell lines towards the megakaryocytic phenotype was associated with HMGA1 protein induction, whereas induction of erythroid and monocytic differentiation generally resulted in reduced HMGA1 expression. PMID:12573034

  18. SWI/SNF Subunits SMARCA4, SMARCD2 and DPF2 Collaborate in MLL-Rearranged Leukaemia Maintenance.

    PubMed

    Cruickshank, V Adam; Sroczynska, Patrycja; 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.

  19. 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

  20. 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.

  1. Revaccination of children after completion of standard chemotherapy for acute lymphoblastic leukaemia: a pilot study comparing different schedules.

    PubMed

    Lehrnbecher, Thomas; Schubert, Ralf; Allwinn, Regina; Dogan, Kader; Koehl, Ulrike; Grüttner, Hans-Peter

    2011-03-01

    Given that a significant proportion of children with acute lymphoblastic leukaemia (ALL) lose immune protection to tetanus, diphtheria, and poliomyelitis, revaccination is indicated after chemotherapy. Our randomized pilot study comparing different revaccination schedules suggests that children with ALL might be revaccinated with non-live vaccines as early as 3 months after chemotherapy.

  2. 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

  3. 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.

  4. 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

  5. Effects of bioactive compounds from carrots (Daucus carota L.), polyacetylenes, beta-carotene and lutein on human lymphoid leukaemia cells.

    PubMed

    Zaini, Rana G; Brandt, Kirsten; Clench, Malcolm R; Le Maitre, Christine L

    2012-07-01

    New therapies for leukaemia are urgently needed. Carrots have been suggested as a potential treatment for leukaemia in traditional medicine and have previously been studied in other contexts as potential sources of anticancer agents. Indicating that carrots may contain bioactive compounds, which may show potential in leukaemia therapies. This study investigated the effects of five fractions from carrot juice extract (CJE) on human lymphoid leukaemia cell lines, together with five purified bioactive compounds found in Daucus carota L, including: three polyacetylenes (falcarinol, falcarindiol and falcarindiol-3-acetate) and two carotenoids (beta-carotene and lutein). Their effects on induction of apoptosis using Annexin V/PI and Caspase 3 activity assays analysed via flow cytometry and inhibition of cellular proliferation using Cell Titer Glo assay and cell cycle analysis were investigated. Treatment of all three lymphoid leukaemia cell lines with the fraction from carrot extracts which contained polyacetylenes and carotenoids was significantly more cytotoxic than the 4 other fractions. Treatments with purified polyacetylenes also induced apoptosis in a dose and time responsive manner. Moreover, falcarinol and falcarindiol-3-acetate isolated from Daucus carota L were more cytotoxic than falcarindiol. In contrast, the carotenoids showed no significant effect on either apoptosis or cell proliferation in any of the cells investigated. This suggests that polyacetylenes rather than beta-carotene or lutein are the bioactive components found in Daucus carota L and could be useful in the development of new leukemic therapies. Here, for the first time, the cytotoxic effects of polyacetylenes have been shown to be exerted via induction of apoptosis and arrest of cell cycle.

  6. Case-control study on risk factors for leukaemia and brain tumours in children under 5 years in Germany.

    PubMed

    Spix, C; Schulze-Rath, R; Kaatsch, P; Blettner, M

    2009-01-01

    In the context of a case control study on the cancer risk for children under five by distance to the nearest nuclear power plant, we collected information on other risk factors in a subset. We present the interview study as if it had been an independent study. Parents of 471 cases with Leukaemia, Lymphoma or CNS (Central Nervous System)-tumour from the German Childhood Cancer Registry, diagnosed at age under 5 in the years 1993-2003, and 1,457 matched controls were to be interviewed. For Leukaemia, 243 cases/604 controls, and for CNS 102 cases/246 controls participated, lymphoma cases were too few. Questions related to social status, ionizing radiation, pregnancy and birth, immune system, and selected toxins. The analysis is exploratory in nature; variables were selected by backward elimination. For leukaemia we found a significant protective effect of social contacts (OR=0.50, 95% CI [0.29;0.87]) and a risk for high birth weight (OR=1.96 95% CI [1.12;3.41] comparing >4,000 g to "normal"). We could not reproduce other associations reported in the literature such as a negative association with allergies. For CNS tumours we found a significant protective effect of social contacts (OR=0.30 95% CI [0.13;0.72]), of pesticides and herbicides (OR=0.39 95% CI [0.18;0.83]) and an increased risk for low birth weight (p=0.0232). This study on risk factors for childhood leukaemia and brain tumours is relatively small and exploratory. We could reproduce some major associations reported in the literature (leukaemia: social contacts and high birth weight) but not others. Some observations may be reporting artefacts or self selection artefacts. PMID:19890788

  7. 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.

  8. Therapeutic effect of traditional Chinese medicine on coagulation disorder and accompanying intractable jaundice in hepatitis B virus-related liver cirrhosis patients

    PubMed Central

    Li, Yang-Mei; Yang, Hong-Zhi; Guan, Wei-Bing; Ke, Qian-Shan; Dai, Min; Xie, He-Ping; Zhang, Shi-Jun

    2008-01-01

    AIM: To observe the therapeutic effects of new traditional Chinese medicine (TCM) therapy on coagulation disorder and accompanying intractable jaundice in HBV-related liver cirrhosis patients. METHODS: Using stratified random sampling according to fibrinogen (Fib) levels, 145 liver cirrhosis patients due to hepatitis B complicated by coagulation disorder were treated. Of them, 70 in research group were treated with TCM by “nourishing yin, cooling blood and invigorating blood circulation” and Western medicine, 75 in control group were treated with conventional Western medicine. The indexes of liver function, coagulation function and bleeding events were observed and compared. RESULTS: The prothrombin time (PT) was shorter and the fibrinogen (Fib) level was higher in the research group than in the control group (Fib = 1.6-2.0 g/L, 1.1-1.5 g/L, and ≤ 1.0 g/L). The total bilirubin (TBIL) level was significantly lower in the research group than in the control group, except for the subgroup of FIB ≤ 1.0 g/L. CONCLUSION: TCM therapy can improve coagulation function and decrease TBIL. PMID:18932286

  9. Susceptibility of porcine preimplantation embryos to viruses associated with reproductive failure.

    PubMed

    Zhao, Haijing; Zhao, Guangyuan; Wang, Wenjun

    2016-10-15

    In the modern biological area, the applications of pig as a laboratory model have extensive prospects, such as gene transfer, IVF, SCNT, and xenotransplantation. However, the risk of pathogen transmission by porcine embryos is always a topic to be investigated, especially the viruses related to reproductive failure, for instance, pseudorabies virus, porcine reproductive and respiratory syndrome virus, porcine parvovirus, and porcine circovirus type 2. It should be mentioned that the zona pellucida (ZP) of porcine embryos can be a barrier against the viruses, but certain pathogens may stick to or even pass through the ZP. With intact, free, and damaged ZP, porcine preimplantation embryos are susceptible to these viruses in varying degrees, which may be associated with the virus-specific receptor on embryonic cell membrane. These topics are discussed in the present review. PMID:27423729

  10. Leukaemia cell of origin identified by chromatin landscape of bulk tumour cells

    PubMed Central

    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

  11. 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

  12. Significance of mouse red cell rosette-forming lymphocytes in chronic lymphocytic leukaemia.

    PubMed

    Pegrum, G D; Evans, C A

    1978-01-01

    Increased mouse red cell (M) rosetting lymphocytes were demonstrated in the peripheral blood of patients with chronic lymphatic leukaemia. The range was wide, and patients showed considerable variation not only in the number of M cells but also in T and B rosetting lymphocytes. Treatment reduced M rosette lymphocytes proportionately as the total white count fell, and differential removal occurred only when the patients became leucopaenic. If we assume the M rosetting cells are the abnormal 'leukaemic' cells, treatment does not preferentially remove these. The M rosetting capacity appeared to be related to the presence of an immunoglobulin factor previously demonstrated on the cells and in the serum of patients with CLL which enhances in vitro viability of the leukaemic cells.

  13. GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations.

    PubMed

    Green, Claire L; Tawana, Kiran; Hills, Robert K; Bödör, Csaba; Fitzgibbon, Jude; Inglott, Sarah; Ancliff, Phil; Burnett, Alan K; Linch, David C; Gale, Rosemary E

    2013-06-01

    GATA2 mutations have recently been reported in acute myeloid leukaemia (AML) patients with CEBPA-double mutations. To explore their impact on this favourable-risk disease, we determined GATA2 status in 153 sporadic AML patients and three members of a germ-line CEBPA-mutant family at AML presentation. Overall, 27% (15/55) CEBPA-double, 16% (7/43) CEBPA-single and 0% (0/55) normal karyotype/CEBPA-wild-type patients were GATA2-mutant. All familial AML patients acquired both a second CEBPA and a GATA2 mutation. CEBPA and GATA2 mutant levels indicated that both mutations were likely to be early events in leukaemogenesis. GATA2 status did not impact on the favourable outcome of CEBPA-double/FLT3-inernal tandem duplication-negative patients.

  14. Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies?

    PubMed

    Sanchez-Correa, Beatriz; Campos, Carmen; Pera, Alejandra; Bergua, Juan M; Arcos, Maria Jose; Bañas, Helena; Casado, Javier G; Morgado, Sara; Duran, Esther; Solana, Rafael; Tarazona, Raquel

    2016-04-01

    Several age-associated changes in natural killer (NK) cell phenotype have been reported that contribute to the defective NK cell response observed in elderly patients. A remodelling of the NK cell compartment occurs in the elderly with a reduction in the output of immature CD56(bright) cells and an accumulation of highly differentiated CD56(dim) NK cells. Acute myeloid leukaemia (AML) is generally a disease of older adults. NK cells in AML patients show diminished expression of several activating receptors that contribute to impaired NK cell function and, in consequence, to AML blast escape from NK cell immunosurveillance. In AML patients, phenotypic changes in NK cells have been correlated with disease progression and survival. NK cell-based immunotherapy has emerged as a possibility for the treatment of AML patients. The understanding of age-associated alterations in NK cells is therefore necessary to define adequate therapeutic strategies in older AML patients.

  15. 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

  16. 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

  17. 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.

  18. Cytogenetic features of leukaemias diagnosed in residents of areas contaminated after the Chernobyl nuclear accident.

    PubMed

    Domrachev, E V; Aseeva, E A; Obukhova, T N; Kobzev, Y N; Olshanskaya, Y V; D'achenko, L V; Udovichenko, A I; Zakharova, A V; Milyutina, G I; Nechai, V V; Vorobiov, A I

    2000-05-01

    A comparison of chromosomal abnormalities in bone marrow leukaemic cells and of stable and unstable aberrations in lymphocytes of patients with hematological malignancies who live in areas with or without contamination by the Chernobyl nuclear accident has been made using FISH and G-banding. Healthy residents of these areas comprised the control group. No systematic cytogenetic differences of leukaemic cells between patients from contaminated and uncontaminated areas were observed. Lymphocyte aberrations, however, were generally higher in all subjects from contaminated areas. Comparison has been made with specific cytogenetic features of leukaemic cells and a high level of stable aberrations in lymphocytes of patients with secondary leukaemias that had developed after chemo- and/or radio-therapy.

  19. The development of integrated haematopathology laboratories: a new approach to the diagnosis of leukaemia and lymphoma.

    PubMed

    Richards, S J; Jack, A S

    2003-12-01

    The diagnosis and monitoring of leukaemia and lymphoma requires the effective integration of a wide range of diagnostic techniques and expertise. The need to develop this type of service that crosses traditional boundaries of laboratory specialities is being recommended in national guidance. The Haematological Malignancy Diagnostic Service based within the Leeds Teaching Hospitals NHS Trust was established in 1993 to provide specialist laboratory services for the diagnosis of haematological malignancy for Yorkshire and Humberside in the UK. The department uses a wide range of methodologies including morphology, immunocytochemistry, flow cytometry and molecular genetics [fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR)] in a systematic and co-ordinated way. We describe how the department was established, its current working practices and highlight the advantages of an integrated laboratory for diagnosis of tumours of the haematopoietic system.

  20. Involvement of a common progenitor cell in core binding factor acute myeloid leukaemia associated with mastocytosis.

    PubMed

    Cornet, Edouard; Dumézy, Florent; Roumier, Christophe; Lepelley, Pascale; Jouy, Nathalie; Philippe, Nathalie; Renneville, Aline; Berthon, Céline; Nelken, Brigitte; Quesnel, Bruno; Preudhomme, Claude

    2012-11-01

    In core binding factor (CBF) acute myeloid leukaemia (AML), realtime quantitative PCR is useful to quantify the fusion transcript ratio (CBFβ-MYH11 and AML1-ETO, in case of inv(16) and t(8;21) respectively) in peripheral blood and bone marrow during the courses of chemotherapy, in order to monitor minimal residual disease (MRD). In two cases of CBF AML associated with systemic mastocytosis (SM), the persistence of mast cells and the detection of a high ratio of fusion transcript, in bone marrow, during the courses of chemotherapy, led us to determine whether the mast cell component of the disease carried the same molecular alterations as leukaemic blasts. We demonstrate that sorted mast cells carried CBF abnormality. These observations point out the lack of specificity of MRD monitoring by RQ-PCR in these exceptional AML cases with SM. Moreover, this suggests that leukaemic blasts and mast cells derive from a common malignant progenitor.

  1. Correlations between nuclear morphology and bundles of cytoplasmic fibrils in 50 cases of acute myeloid leukaemia.

    PubMed Central

    Pearson, E C

    1986-01-01

    An electron microscopic examination was carried out of peripheral blood or bone marrow samples, or both, from 50 patients entered into the Medical Research Council 9th Acute Myeloid Leukaemia Trial. The results showed a striking correlation between the presence of conspicuous bundles of fibrils within the cytoplasm of the leukaemic cells and the degree of convolution or lobulation of the nuclei. In none of the samples were predominantly convoluted or lobed nuclei observed in the absence of prominent fibrillar bundles and in only two cases were nuclei of a more regular outline seen in association with many conspicuous bundles of cytoplasmic fibrils. No correlation was found between the apparent degree of maturity of the nuclei, as assessed by the degree of chromatin condensation, and the absence or abundance of fibrillar bundles. Images PMID:3456357

  2. 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

  3. Invasive fungal infection of the central nervous system in a patient with acute myeloid leukaemia

    PubMed Central

    Janik-Moszant, Anna; Matyl, Aleksander; Rurańska, Iwona; Machowska-Majchrzak, Agnieszka; Kluczewska, Ewa; Szczepański, Tomasz

    2012-01-01

    Summary Background: Although the new intensive chemotherapeutic programs introduced recently into hematooncological therapies have led to a higher number of recoveries, persistent neutropenia favours the spread of severe infections, frequently fungal infections. Systemic fungal infections in patients treated for proliferative diseases of the hematopoietic system are characterised by a severe, progressing course and high morbidity. Case Reports: We present a case report that demonstrates the diagnostic problem of lesions in the central nervous system which developed following the fourth block of chemotherapy in an eight-year-old boy treated for acute myeloid leukaemia. The risk factors, high values of the inflammatory parameters and imaging results enabled us to diagnose a fungal infection of the central nervous system. Results: A fast improvement in the clinical condition of the patient after the applied antifungal therapy and the regression of lesions in the central nervous system shown in the imaging studies confirmed our final diagnosis. PMID:22802867

  4. A role for growth hormone and prolactin in leukaemia and lymphoma?

    PubMed

    Hooghe, R; Merchav, S; Gaidano, G; Naessens, F; Matera, L

    1998-10-01

    Growth hormone (GH) and prolactin (PRL) quality as lymphohaemopoietic growth and differentiation factors, and so does insulin-like growth factor (IGF)-I, which mediates many of GH activities. Although there is only limited evidence that endocrine, paracrine or autocrine GH or PRL play a role in human leukaemia and lymphoma, the expression of these factors or their receptors may have diagnostic or therapeutic implications. Indeed, the participation of GH, PRL or IGF-I in the development or progression of certain haematological malignancies or to the antitumour immune response has been documented. Examples discussed in this review include a rat lymphoma in which the PRL receptor acts as an oncogene; the rat Nb2 lymphoma, which is dependent on PRL for growth; and experiments showing that PRL stimulates natural killer cell activity and the development of lymphokine-activated killer cells.

  5. Monitoring minimal residual disease in acute myeloid leukaemia: a review of the current evolving strategies.

    PubMed

    Ommen, Hans Beier

    2016-02-01

    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.

  6. 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

  7. Acquired trisomy 12 and absent Y chromosome in a patients with acute undifferentiated leukaemia.

    PubMed

    Najfeld, V; Thorning, D; Doney, K C; Fialkow, P J

    1981-02-01

    A 60-year-old man developed pancytopenia and then acute leukaemia. The neoplastic cells in marrow were undifferentiated by electron microscopy and by immunological and cytochemical markers. The only other cells present in marrow were lymphocytes, plasma cells, macrophages and non-haematopoietic elements. Prior to chemotherapy, cytogenetic analysis of marrow cells showed two karyotypically distinct cell populations, one with 45,X,--Y and the other with a 46,X,--Y,+12 karyotype. All marrow cells stimulated by protein-A from staphylococcus aureus were 46,X,--Y,+12. Phytohaemagglutinin-stimulated cells were normal, 46,XY. These findings suggest strongly that most of the undifferentiated leukaemic cells were missing the Y chromosome. A subpopulation of these leukaemic cells also had trisomy 12. These observations and previously published findings suggest that trisomy 12 occurs non-randomly in haematological disorders, and in particular, may be associated with B-lymphoid malignancy. PMID:7256211

  8. 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

  9. Clonal evolution of aplastic anaemia to myelodysplasia/acute myeloid leukaemia and paroxysmal nocturnal haemoglobinuria.

    PubMed

    Tooze, J A; Marsh, J C; Gordon-Smith, E C

    1999-04-01

    Aplastic anaemia (AA) is a non-malignant haemopoietic disorder characterised by peripheral blood pancytopenia and a hypocellular bone marrow. Successful management of acquired AA including treatment with immunosuppressive agents, mainly antithymocyte globulin (ATG) and cyclosporin or allogeneic haemopoietic stem cell transplantation, has resulted in long-term survival of many patients. The later evolution of complicating clonal disorders such as paroxysmal nocturnal haemoglobinuria, myelodysplasia and acute myeloid leukaemia in patients treated with immunosuppressive therapy may be a manifestation of the natural history of the aplasia, the development of which may or may not be increased by immunosuppressive therapy. A persistent, profound deficiency and/or defect in the stem cell compartment, despite haematological recovery after immunosuppressive therapy, may create an unstable situation which predisposes to later clonal disorders. A review of the progression of AA to clonal disorders is now outlined.

  10. Considerations and challenges for patients with refractory and relapsed acute myeloid leukaemia.

    PubMed

    Kell, Jonathan

    2016-08-01

    Despite advances in understanding the complexities of acute myeloid leukaemia (AML), the treatment of refractory or relapsed AML (rrAML) remains a daunting clinical challenge. Numerous clinical trials have failed to identify new treatments or combinations of existing therapies that substantially improve outcomes and survival. This may be due, at least in part, to heterogeneity among study patients with respect to multiple inter-related factors that have been shown to affect treatment outcomes for patients with rrAML; such factors include age, cytogenetics, immunophenotypic changes, and (in the case of relapsed AML) duration of first complete remission, or if the patient has had a previous blood and marrow transplant (BMT). A clear understanding of disease characteristics and patient-related factors that influence treatment response, as well as expected outcomes with existing and emerging therapies, can aid clinicians in helping their patients navigate through this complex disease state.

  11. 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

  12. 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

  13. Light scatter characteristics of blast cells in acute myeloid leukaemia: association with morphology and immunophenotype.

    PubMed Central

    Vidriales, M B; Orfao, A; López-Berges, M C; González, M; López-Macedo, A; García, M A; Galende, J; San Miguel, J F

    1995-01-01

    AIMS--To analyse the forward scatter/side scatter (FSC/SSC) distribution of acute myeloblastic leukaemia (AML) blast cells in order to assess whether it correlates with their morphology, immunophenotype, and clinical and biological disease characteristics. METHODS--FSC/SSC patterns were established upon taking into account the localisation of the residual T lymphocytes in the FSC/SSC dot plot as an internal biological standard. One hundred and seventy one newly diagnosed AML patients were analysed and five different FSC/SSC patterns were established. These five patterns could be grouped into two major categories taking into account the FSC/SSC distribution of normal cells in a bone marrow aspirate: immature patterns (1 and 2) and mature patterns (3, 4, and 5). These FSC/SSC patterns were correlated with different clinical and biological characteristics of AML patients. RESULTS--No significant associations were detected in relation to the clinical and haematological disease characteristics and the prognosis of these patients. By contrast there was a significant correlation between the FSC/SSC pattern of the AML blast cells and the FAB classification. An increased reactivity for the antigens associated with myeloid differentiation such as CD13, CD33, CD11b, CD15, CD14, CD4, CD56, and/or CD16 was detected among cases showing a mature FSC/SSC pattern (3, 4, and 5), both in the whole series and even within each of the FAB AML subtypes. By contrast, the reactivity for the CD34 precursor cell associated antigen was higher among those cases displaying an immature FSC/SSC pattern, this being observed even within each FAB subgroup. CONCLUSIONS--The FSC/SSC pattern distribution of AML blast cells not only provides an additional objective and reproductible system for the classification of these leukaemias but it may also represent a connection between the FAB morphological groups and the immunophenotypic classification of AML patients. Images PMID:7629293

  14. Population mixing and the risk of childhood leukaemia in Switzerland: a census-based cohort study.

    PubMed

    Lupatsch, Judith E; Kuehni, Claudia E; Niggli, Felix; Ammann, Roland A; Egger, Matthias; Spycher, Ben D

    2015-12-01

    Childhood leukaemia (CL) may have an infectious cause and population mixing may therefore increase the risk of CL. We aimed to determine whether CL was associated with population mixing in Switzerland. We followed children aged <16 years in the Swiss National Cohort 1990-2008 and linked CL cases from the Swiss Childhood Cancer Registry to the cohort. We calculated adjusted hazard ratios (HRs) for all CL, CL at age <5 years and acute lymphoblastic leukaemia (ALL) for three measures of population mixing (population growth, in-migration and diversity of origin), stratified by degree of urbanisation. Measures of population mixing were calculated for all municipalities for the 5-year period preceding the 1990 and 2000 censuses. Analyses were based on 2,128,012 children of whom 536 developed CL. HRs comparing highest with lowest quintile of population growth were 1.11 [95 % confidence interval (CI) 0.65-1.89] in rural and 0.59 (95 % CI 0.43-0.81) in urban municipalities (interaction: p = 0.271). Results were similar for ALL and for CL at age <5 years. For level of in-migration there was evidence of a negative association with ALL. HRs comparing highest with lowest quintile were 0.60 (95 % CI 0.41-0.87) in urban and 0.61 (95 % CI 0.30-1.21) in rural settings. There was little evidence of an association with diversity of origin. This nationwide cohort study of the association between CL and population growth, in-migration and diversity of origin provides little support for the population mixing hypothesis.

  15. Clinical and haemato-pathological characteristics of adult acute lymphoblastic leukaemia.

    PubMed

    Islam, N; Rahman, M M; Aziz, M A; Begum, M; Ferdous, J; Rahman, M J

    2014-04-01

    Acute lymphoblastic leukaemia (ALL) is a heterogeneous group of disorders. It varies with respect to the morphologic, cytogenetic, molecular and immunologic features of the neoplastic cells reflecting the variable clinical-pathologic presentations and outcome of the patients. The aim of the study was to observe the clinical and haemato-pathological characteristics in newly diagnosed adult ALL patients. A total number of 61 patients morphologically diagnosed as acute lymphoblastic leukaemia aged 15 and above assigned for this observational study. The study was carried out in the Department of Haematology, BSMMU from January 2007 to December 2008. Among 61 patients, aged 15 to 80 years with median age 25 years, 79% were male and 21% were female. Most of the patients presented with anaemia (67%), fever (66%), lymphadenopathy (64%) and splenomegaly (57%). Other common clinical findings were hepatomegaly (39%), bone tenderness (44%) and bleeding manifestations (34%). Among haemato-pathological findings 67% patients had Hb level ≤10gm/dl, 46% patients had WBC count ≥30×10⁹/L, 67% patients had platelet count ≤100×10⁹/L, 93% patients had blast in peripheral blood and 61% patients had ≥90 % blasts in the bone marrow at the time of diagnosis. In this study adult ALL patients were analyzed only for their clinical and haemato-pathological characteristics. But their biologic characteristics were not analyzed due to lack of availability of facility. A progressive understanding of the biologic and genetic characteristics of ALL will allow us to identify different prognostic subgroups with specific molecular and cellular features. All the necessary measures have to be developed in our country in order to identify prognostically distinct subgroups of patients.

  16. 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

  17. 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

  18. 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.

  19. 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

  20. 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

  1. 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

  2. Clinico-pathological profile of acute promyelocytic leukaemia at Al-Amal Oncology-Haematology Centre, Qatar.

    PubMed

    Ibrahim, F A; Yassin, M A; El-Ayoubi, H R; Alhiji, I A; Albinali, A S; Almansour, S M; Qafoud, F M

    2010-09-01

    This cases series describes the profile of adult patients with acute promyelocytic leukaemia (APt) at a referral hospital in Qatar. Of 34 acute myeloid leukaemia (AML) cases diagnosed, 11(32%) were classified as APt. Disseminated intravascular coagulation was common at presentation (91%). Severe thrombocytopenia was seen in 73%, leukocytosis in 55% and severe anaemia in 45%. Only 2 patients were of the classic hypergranular type. In the remaining 9 patients, 3 morphological subtypes were recognized: microgranular variant (6 patients), hyperbasophilic (2 patients) and regular nuclear outline M3r (1 patient). Translocation t(15;17) was detected in 63% of cases. APL constitutes a high proportion of AML cases in Qatar, with considerable morphological heterogeneity and a oredominance of APL variants with unfavourable oresenting features. PMID:21218723

  3. 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

  4. Pneumocystis jerovecii pneumonia in a patient with untreated chronic lymphocytic leukaemia: a novel case and postulations concerning the mechanism.

    PubMed

    Kalkanis, Alexandros; Judson, Marc A; Napier, Mark B

    2013-11-28

    Chronic lymphocytic leukaemia (CLL), even when severe, is not directly associated with opportunistic infections. Opportunistic infections that occur with CLL are almost exclusively related to immunosuppression caused by chemotherapeutic drugs used to treat CLL. We report a case of Pneumocystis jirovecii (PJ) pneumonia that occurred in a patient with untreated CLL with pulmonary involvement. We suspect that PJ pneumonia resulted from an inadequate immune response in the lung parenchyma resulting from excessive local accumulation of CLL cells.

  5. 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

  6. High cost factors for leukaemia and lymphoma patients: a new analysis of costs within these diagnosis related groups

    PubMed Central

    Quantin, C.; Entezam, F.; Brunet-Lecomte, P.; Lepage, E.; Guy, H.; Dusserre, L.

    1999-01-01

    STUDY OBJECTIVE: To determine high cost factors to help managers and clinicians to analyse the reasons of adverse costs and provide indications for financial negotiation. DESIGN: To locate high cost or long stay patients, the analysis was designed on the basis of a mixture of Weibull distributions. In this new model, the proportion of high cost patients was expressed according to the multinomial logistic regression, permitting the determination of high cost factors. SETTING: The 1993 French reference database, constituted in the framework of the national study of DRG costs, conducted by the French Ministry of Health. The database of discharge abstracts recorded in 1993 in the Dijon public teaching hospital. PARTICIPANTS: The analyses were based on 1352 abstracts from the French reference database and 368 from the Dijon database concerning patients, aged 18 and over, suffering from leukaemia and lymphoma. MAIN RESULTS: High cost and long stay factors were the same: number of stays, death, transfer, acute leukaemia, neutropenia, septicaemia, high dose aplastic chemotherapy, central venous catheterisation, parenteral nutrition, protected or laminar airflow room, blood transfusion, and intravenous antibiotherapy. CONCLUSIONS: Taking into account high cost predictive factors, as shown in the case of leukaemia and lymphoma patients, would help to reduce the adverse effects of a prospective payment system.   PMID:10326049

  7. 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

  8. 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

  9. The effect of dietary intake changes on nutritional status in acute leukaemia patients after first induction chemotherapy.

    PubMed

    Malihi, Z; Kandiah, M; Chan, Y M; Esfandbod, M; Vakili, M; Hosseinzadeh, M; Zarif Yeganeh, M

    2015-07-01

    This study aimed to evaluate how changes in dietary intake among acute lymphoblastic and acute myeloid leukaemia (ALL and AML) patients affect nutritional status after the first induction chemotherapy. Dietary intake was assessed using 24-h recall and a 136-item food frequency questionnaire. Nutritional status was assessed by Patients Subjective Global Assessment questionnaire before starting induction therapy and again after 1 month. All newly diagnosed acute leukaemia patients aged 15 years old and older who attended three referral hospitals for initiation of their induction chemotherapy were included in the sample selection provided that they gave informed consent. A total of 30 AML and 33 ALL patients participated in the study. Dietary intake and nutritional status worsened after the chemotherapy treatment. Dietary intake in terms of macronutrients, micronutrients, food variety and diet diversity score changed significantly after the induction chemotherapy. No significant relationship was found between the changes in dietary indices and nutritional status. Chemotherapy-related side effects as an additional factor to cancer itself could affect dietary intake of leukaemia patients. The effectiveness of an early assessment of nutritional status and dietary intake should be further investigated in order to deter further deterioration.

  10. 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

  11. Deciphering KRAS and NRAS mutated clone dynamics in MLL-AF4 paediatric leukaemia by ultra deep sequencing analysis

    PubMed Central

    Trentin, Luca; Bresolin, Silvia; Giarin, Emanuela; Bardini, Michela; Serafin, Valentina; Accordi, Benedetta; Fais, Franco; Tenca, Claudya; De Lorenzo, Paola; Valsecchi, Maria Grazia; Cazzaniga, Giovanni; Kronnie, Geertruy te; Basso, Giuseppe

    2016-01-01

    To induce and sustain the leukaemogenic process, MLL-AF4+ leukaemia seems to require very few genetic alterations in addition to the fusion gene itself. Studies of infant and paediatric patients with MLL-AF4+ B cell precursor acute lymphoblastic leukaemia (BCP-ALL) have reported mutations in KRAS and NRAS with incidences ranging from 25 to 50%. Whereas previous studies employed Sanger sequencing, here we used next generation amplicon deep sequencing for in depth evaluation of RAS mutations in 36 paediatric patients at diagnosis of MLL-AF4+ leukaemia. RAS mutations including those in small sub-clones were detected in 63.9% of patients. Furthermore, the mutational analysis of 17 paired samples at diagnosis and relapse revealed complex RAS clone dynamics and showed that the mutated clones present at relapse were almost all originated from clones that were already detectable at diagnosis and survived to the initial therapy. Finally, we showed that mutated patients were indeed characterized by a RAS related signature at both transcriptional and protein levels and that the targeting of the RAS pathway could be of beneficial for treatment of MLL-AF4+ BCP-ALL clones carrying somatic RAS mutations. PMID:27698462

  12. Distinct morphophenotypic features of chronic B-cell leukaemias identified with CD1c and CD23 antibodies.

    PubMed

    Orazi, A; Cattoretti, G; Polli, N; Delia, D; Rilke, F

    1991-07-01

    Morphological criteria usually applied to diagnose various subtypes of B-cell chronic lymphoid leukaemia are largely subjective. Immunophenotyping of 61 relevant cases using a selected panel of monoclonal antibodies (mAb), showed that CD1c and CD23 mAb were able to separate B-cell chronic lymphocytic leukaemia (B-CLL) from other chronic B-cell lymphoproliferative diseases. Lymphocytes of B-CLL were CD1c-, CD23+, whereas those of other types of chronic B-cell leukaemia were CD1c+/-, CD23-, and CD38/-. Non-B-CLL cases had a significantly higher amount of large peroxidase-negative (unstained) cells analyzed with an automated blood cell counter (Technicon H6000). This type of volumetric assessment allowed a separation between typical and "atypical" B-CLL, which otherwise were both CD1c-, and CD23+. These combinations of phenotypic markers corresponded to well-defined haematopathologic entities, conventionally diagnosed on peripheral blood (PB) and bone marrow smears, and on histologic sections of lymph nodes and spleen.

  13. The development of a three-dimensional scaffold for ex vivo biomimicry of human acute myeloid leukaemia.

    PubMed

    Blanco, Teresa Mortera; Mantalaris, Athanasios; Bismarck, Alexander; Panoskaltsis, Nicki

    2010-03-01

    Acute myeloid leukaemia (AML) is a cancer of haematopoietic cells that develops in three-dimensional (3-D) bone marrow niches in vivo. The study of AML has been hampered by lack of appropriate ex vivo models that mimic this microenvironment. We hypothesised that fabrication and optimisation of suitable biomimetic scaffolds for culturing leukaemic cells ex vivo might facilitate the study of AML in its native 3-D niche. We evaluated the growth of three leukaemia subtype-specific cell lines, K-562, HL60 and Kasumi-6, on highly porous scaffolds fabricated from biodegradable and non-biodegradable polymeric materials, such as poly (L-lactic-co-glycolic acid) (PLGA), polyurethane (PU), poly (methyl-methacrylate), poly (D, L-lactade), poly (caprolactone), and polystyrene. Our results show that PLGA and PU supported the best seeding efficiency and leukaemic growth. Furthermore, the PLGA and PU scaffolds were coated with extracellular matrix (ECM) proteins, collagen type I (62.5 or 125 microg/ml) and fibronectin (25 or 50 microg/ml) to provide biorecognition signals. The 3 leukaemia subtype-specific lines grew best on PU scaffolds coated with 62.5 microg/ml collagen type I over 6 weeks in the absence of exogenous growth factors. In conclusion, PU-collagen scaffolds may provide a practical model to study the biology and treatment of primary AML in an ex vivo mimicry.

  14. 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

  15. 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

  16. Strong association of the HLA-DP6 supertype with childhood leukaemia is due to a single allele, DPB1*0601.

    PubMed

    Taylor, G M; Hussain, A; Verhage, V; Thompson, P D; Fergusson, W D; Watkins, G; Lightfoot, T; Harrison, C J; Birch, J M

    2009-05-01

    We previously reported that susceptibility to childhood B cell precursor ALL (BCP ALL) is associated with HLA-DPB1 alleles having glutamic acid (E) rather than lysine (K) in the P4 antigenic peptide-binding pocket. Clustering approximately 90% of DPB1 alleles into DPB69E (DP2, 6, 8) and DPB69K (DP1, 3, 4) supertypes revealed that DP2 and DP8 are associated with BCP ALL, but DP6 is also associated with non-BCP leukaemia. Here, we report that only one of seven alleles with the DP6 supertype (DPB1(*)0601) is associated with childhood leukaemia (leukaemia vs controls: odds ratio, 95% confidence interval [OR, CI]: 4.6, 2.0-10.4; corrected P=0.019), but not with childhood solid tumours or lymphomas. DPB1(*)0601 is also significantly associated with leukaemia subtypes, including BCP ALL, Pro-B ALL, T-ALL and AML. DPB1(*)0601 is significantly over-transmitted (76.9%) from parents to children with BCP ALL (OR; CI: 4.7; 1.01-22.2). Sequencing the coding region of DPB1(*)0601 revealed an exon 1-4 haplotype [T-DEAV-KIL-RVI] shared with DPB1(*)0301 and 0901, but no evidence of germline mutations in childhood leukaemia. These results suggest that the DPbeta0601 molecule may be functionally involved in childhood leukaemia. Analysis of peptide binding and T-cell activation by DPbeta0601-peptide complexes should help determine its role in childhood leukaemia causation.

  17. Geographical variation in mortality from leukaemia and other cancers in England and Wales in relation to proximity to nuclear installations, 1969-78.

    PubMed Central

    Cook-Mozaffari, P. J.; Darby, S. C.; Doll, R.; Forman, D.; Hermon, C.; Pike, M. C.; Vincent, T.

    1989-01-01

    The distribution of mortality from 11 causes of death (lymphoid leukaemia, other leukaemia, leukaemia of all types, Hodgkin's disease, other lymphomas, all lymphomas, multiple myeloma, lung cancer, other malignancies, all malignancies and all other causes) has been examined in three age groups throughout England and Wales over the period 1969-78. The reorganisation of local authority administration in 1974 meant that the smallest areas that could be examined were 400 county districts or (in some cases) approximate county districts formed by aggregating pre-1974 local authority areas. The variation in the numbers of deaths observed about the numbers expected was assessed using log-linear models to estimate the effect on the relative risk in each district associated with social class, rural status, population size, health authority region and proximity to one of 15 nuclear installations. Trends in risk with increasing proximity to an installation (as judged by the proportion of the population resident within 10 miles) were examined after adjustment for the other four variables. The results showed that in districts near to an installation there were significant excess mortalities in persons under 25 years of age from leukaemia (RR = 1.15, P = 0.01) and especially from lymphoid leukaemia (RR 1.21, P = 0.01) and from Hodgkin's disease (RR 1.24, P = 0.05) and a significant deficiency of mortality from lymphoid leukaemia in persons aged 25-64 years. No significant trends were observed with an increasing proportion of the population near to the installations and the greatest excess mortality from lymphoid leukaemia in young persons was observed in the districts with the intermediate proportion of the population (10.0-65.9%) near an installation. PMID:2930718

  18. Virus ecology of fluvial systems: a blank spot on the map?

    PubMed Central

    Peduzzi, Peter

    2016-01-01

    The ecology of viruses has been studied only in a limited number of rivers and streams. In light of a recent re-appraisal of the global fluvial surface area, issues such as abundance and production, host mortality and the influence of suspended particles and biofilms are addressed. Viral life cycles, potential impacts of viruses on water biochemistry and carbon flow, and viral diversity are considered. Variability in trophic levels along with the heterogeneous nature and hydrological dynamics of fluvial environments suggest a prevailingly physical control of virus-related processes under lotic conditions and more biological control under lentic conditions. Viral lysis likely contributes to a pool of rapidly cycling carbon in environments typically characterized by high proportions of recalcitrant terrestrial carbon. On average, 33.6% (equalling 0.605 Pg C year−1) of the globally respired carbon from fluvial systems may pass through a viral loop. Virus distribution and the proportion of organic material in horizontal transport versus processes in retention zones remain to be determined in detail. The need for up-scaling the contribution of virus-related processes in fluvial systems is of global relevance. Further, the role of climate change and the effect of anthropogenic alterations of fluvial systems on viruses require attention. The identification of these considerable knowledge gaps should foster future research efforts. PMID:26105126

  19. Can thymic epithelial cells be infected by human T-lymphotropic virus type 1?

    PubMed

    Moreira-Ramos, Klaysa; Castro, Flávia Madeira Monteiro de; Linhares-Lacerda, Leandra; Savino, Wilson

    2011-09-01

    The human T-lymphotropic virus type-1 (HTLV-1) is the cause of adult T cell leukaemias/lymphoma. Because thymic epithelial cells (TEC) express recently defined receptors for the virus, it seemed conceivable that these cells might be a target for HTLV-1 infection. We developed an in vitro co-culture system comprising HTLV-1+-infected T cells and human TECs. Infected T cells did adhere to TECs and, after 24 h, the viral proteins gp46 and p19 were observed in TECs. After incubating TECs with culture supernatants from HTLV-1+-infected T cells, we detected gp46 on TEC membranes and the HTLV-1 tax gene integrated in the TEC genome. In conclusion, the human thymic epithelium can be infected in vitro by HTLV-1, not only via cell-cell contact, but also via exposure to virus-containing medium. PMID:22012233

  20. 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

  1. WNT5A expression is regulated by the status of its promoter methylation in leukaemia and can inhibit leukemic cell malignant proliferation.

    PubMed

    Deng, Gang; Li, Zhao Quan; Zhao, Chen; Yuan, Yuan; Niu, Chang Chun; Zhao, Chen; Pan, Jing; Si, Wei Ke

    2011-02-01

    Although down-regulation of WNT5A expression has been reported in some types of leukaemias, the level of WNT5A expression has not been assessed in leukaemia complete remission (CR) cases, the relationship among WNT5A expression level, the status of its promoter methylation, and the curative effect of leukaemia has not been reported, and the effect of WNT5A on cell proliferation has not been assessed. In this study, we analyzed WNT5A expression in various kinds of leukaemia cases, leukaemia CR cases, non-malignant hematopoietic (NMH) cases, as well as in leukemic cell lines and CD34+ cells. The methylation status of the WNT5A promoter and the levels of the Wnt5a protein were also studied. We also investigated the effect of Wnt5a on leukemic cell proliferation. WNT5A expression level was higher in NMH but lower in leukaemia cases compared to that in CR-cases (P<0.01), and was expressed at low level in leukemic cell lines K562, U937 and Jurkat. Wnt5a protein was positive in NMH, CR cases and CD34+, but negative in leukaemia cases. WNT5A promoter was methylated in leukaemia cases and all leukemic cell lines, but not in NMH and CR cases. WNT5A expression was up-regulated after exposure to the demethylating agent 5-Aza-2'-deoxycytidine (Aza) in the K562, U937, Jurkat leukemic cell lines and in 83.3% (10/12) of CR patients after cure, respectively. The increased Wnt5a protein can inhibit K562 malignant proliferation and arrest cell cycle at the G2/M phase after exposure to Aza. These results indicate that WNT5A expression was restored in complete remission cases due to demethylation, and Wnt5a can inhibit leukaemic cell proliferation. We propose that WNT5A can act as a suppressor factor in leukemogenesis and can be used as a potential marker for curative effect assessment in leukaemia.

  2. 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

  3. 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

  4. 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, ...

  5. 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 ...

  6. 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 ...

  7. Dose intensification in acute myeloid leukaemia: greater effectiveness at lower cost. Principal report of the Medical Research Council's AML9 study. MRC Leukaemia in Adults Working Party.

    PubMed

    Rees, J K; Gray, R G; Wheatley, K

    1996-07-01

    Between 1984 and 1990, 972 patients aged 1-79 years with acute myeloid leukaemia (AML), from 85 British hospitals, were entered into the MRC's 9th AML trial. Patients were randomized between DAT 1 + 5 (daunorubicin for 1 d, with cytarabine and 6-thioguanine for 5 d) and DAT 3 + 10 (same dose drugs for 3 and 10 d respectively) as induction therapy. The 63% who achieved complete remission (CR) were randomized to receive two courses of DAT 2 + 7 alternating with two courses of either MAZE (m-AMSA, 5-azacytidine, etoposide) or COAP (cyclophosphamide, vincristine, cytarabine, prednisone). Finally, those still in CR were randomized to receive either 1 year of maintenance treatment with eight courses of cytarabine and thioguanine followed by four courses of COAP, or no further cytotoxic therapy. Resistance to induction therapy was less common with the DAT 3 + 10 regimen than with DAT 1 + 5 (13% v 23%; P = 0.0001) and hence, despite a 5% increase in the risk of induction death, the CR rate was higher (66% v 61%; P = 0.15). Moreover, CR was achieved more rapidly with DAT 3 + 10 (median 34 v 46 d; P < 0.0001) and thus patients required less time in hospital (mean 20 v 29 d) and less blood product support. 5-year relapse-free survival (28% v 23%; P = 0.05) and survival (23% v 18%; P < 0.05) were also better with DAT 3 + 10. Post-remission intensification of therapy with MAZE resulted in fewer relapses (66% v 74% at 5 years; P = 0.03) but patients allocated MAZE required considerably more supportive care and 14 (4.5%) died following 312 MAZE courses, whereas no deaths occurred following COAP. 5-year survival was not significantly higher with MAZE (37% v 31%). Finally, although 1 year of outpatient maintenance treatment appeared to delay, but not prevent, recurrence it did not improve 5-year survival which was non-significantly worse for those allocated maintenance treatment (41% v 44%). We conclude that the more intensive induction regimen, DAT 3 + 10, is not only more

  8. Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results.

    PubMed

    Delgado, Julio; Espinet, Blanca; Oliveira, Ana C; Abrisqueta, Pau; de la Serna, Javier; Collado, Rosa; Loscertales, Javier; Lopez, Montserrat; Hernandez-Rivas, Jose A; Ferra, Christelle; Ramirez, Angel; Roncero, Josep M; Lopez, Cristina; Aventin, Anna; Puiggros, Anna; Abella, Eugenia; Carbonell, Felix; Costa, Dolors; Carrio, Anna; Gonzalez, Marcos

    2012-04-01

    Patients with chronic lymphocytic leukaemia (CLL) whose tumour cells harbour a 17p deletion (17p-) are universally considered to have a poor prognosis. The deletion can be detected at diagnosis or during the evolution of the disease, particularly in patients who have received chemotherapy. We sought to evaluate the natural history of patients with 17p- CLL, identify predictive factors within this prognostic subgroup, and evaluate the results of different therapeutic approaches. Data from 294 patients with 17p- CLL followed up at 20 different institutions was retrospectively collected and analysed. Median age was 68 (range 27-98) years at the time of fluorescence in situ hybridization analysis. After 17p- documentation, 52% received treatment, achieving an overall response rate of 50%. Median overall survival was 41 months, and was significantly shorter in patients with elevated beta(2)-microglobulin concentration (P < 0·001), B symptoms (P = 0·016), higher percentage of cells with deletion (P < 0·001), and acquired deletions (P = 0·012). These findings suggest that patients with 17p- CLL have a variable prognosis that can be refined using simple clinical and laboratory features, including 17p- clone size, beta2-microglobulin concentration, presence of B symptoms and type of deletion (de novo versus acquired).

  9. Clinical characteristics and outcomes in patients with acute promyelocytic leukaemia and hyperleucocytosis.

    PubMed

    Daver, Naval; Kantarjian, Hagop; Marcucci, Guido; Pierce, Sherry; Brandt, Mark; Dinardo, Courtney; Pemmaraju, Naveen; Garcia-Manero, Guillermo; O'Brien, Susan; Ferrajoli, Alessandra; Verstovsek, Srdan; Popat, Uday; Hosing, Chitra; Anderlini, Paolo; Borthakur, Gautam; Kadia, Tapan; Cortes, Jorge; Ravandi, Farhad

    2015-03-01

    The clinical characteristics, treatment options and outcomes in patients with acute promyelocytic leukaemia (APL) and hyperleucocytosis remain poorly defined. This study reviewed 242 consecutive patients with APL; 29 patients (12%) had a white blood cell count (WBC) ≥ 50 × 10(9) /l at presentation (median WBC 85·5 × 10(9) /l). Patients with hyperleucocytosis had inferior complete remission (CR) rates (69% vs. 88%; P = 0·004) and higher 4-week mortality (24% vs. 9%; P = 0·018) compared to patients without hyperleucocytosis. We noted a trend towards inferior 3-year disease-free survival (DFS) (69% vs. 80%; P = 0·057) and inferior 3-year overall survival (OS) (74% vs. 92%; P = 0·2) for patients with hyperleucocytosis. Leukapheresis was performed in 11 (38%) of the 29 patients with hyperleucocytosis. CR rate and 3-year OS were not significantly improved in patients who received leukapheresis. CR rate and 3-year OS for the 15 patients with hyperleucocytosis treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) plus cytotoxic therapy (idarubicin or gemtuzumab ozogamicin) combinations were 100% and 100% vs. 57% and 35% for the 14 patients treated with non-ATRA/ATO combinations (P = 0·004 and P = 0·002). Leukapheresis does not improve the outcomes in patients with APL presenting with hyperleucocytosis. ATRA/ATO-based combinations are superior to other regimens in these patients. PMID:25312977

  10. Noma in a child with acute leukaemia: when the 'face of poverty' finds an ally.

    PubMed

    Singh, Amitabh; Mandal, Anirban; Seth, Rachna; Kabra, Sushil Kumar

    2016-01-01

    A 2-year-6-month old, appropriately immunised, well-thriving boy, symptomatic for the past 6 months, presented with recurrent fever, progressive pallor, lymphadenopathy and a raw area on the right cheek, with discharging sinus. The necrotising infection of the face developed after one and half months of febrile illness. This febrile illness with bicytopaenia was diagnosed as enteric fever and treated with antibiotics. Skin grafting was performed for the full-thickness defect of the face. The patient continued to have a non-healing oral ulcer with progressive pallor and was finally diagnosed as having acute lymphoblastic leukaemia. Immunodeficiency was ruled out by appropriate investigations. Noma is an indirect measure of extreme poverty, but malignancy is known to predispose to this debilitating condition. The worldwide incidence of Noma is reported to be 30,000-140,000, with a preponderance in sub-Saharan Africa. This case emphasises the need for a thorough search for the underlying illness predisposing to a rare opportunistic infection such as Noma in a well-thriving child. PMID:26740267

  11. PTCH1 expression at diagnosis predicts imatinib failure in chronic myeloid leukaemia patients in chronic phase.

    PubMed

    Alonso-Dominguez, Juan M; Grinfeld, Jacob; Alikian, Mary; Marin, David; Reid, Alistair; Daghistani, Mustafa; Hedgley, Corinne; O'Brien, Stephen; Clark, Richard E; Apperley, Jane; Foroni, Letizia; Gerrard, Gareth

    2015-01-01

    The tyrosine kinase inhibitor (TKI) imatinib has revolutionized the management of chronic myeloid leukaemia (CML). However, around 25% of patients fail to sustain an adequate response. We sought to identify gene-expression biomarkers that could be used to predict imatinib response. The expression of 29 genes, previously implicated in CML pathogenesis, were measured by TaqMan Low Density Array in 73 CML patient samples. Patients were divided into low and high expression for each gene and imatinib failure (IF), probability of achieving CCyR, progression free survival and CML related OS were compared by Kaplan-Meier and log-rank. Results were validated in a second cohort of 56 patients, with a further technical validation using custom gene-expression assays in a conventional RT-qPCR in a sub-cohort of 37 patients. Patients with low PTCH1 expression showed a worse clinical response for all variables in all cohorts. PTCH1 was the most significant predictor in the multivariate analysis compared with Sokal, age and EUTOS. PTCH1 expression assay showed the adequate sensitivity, specificity and predictive values to predict for IF. Given the different treatments available for CML, measuring PTCH1 expression at diagnosis may help establish who will benefit best from imatinib and who is better selected for second generation TKI. PMID:25250944

  12. 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.

  13. 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

  14. 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

  15. Pharmacological inhibitors of NF-kappaB accelerate apoptosis in chronic lymphocytic leukaemia cells.

    PubMed

    Pickering, B M; de Mel, S; Lee, M; Howell, M; Habens, F; Dallman, C L; Neville, L A; Potter, K N; Mann, J; Mann, D A; Johnson, P W M; Stevenson, F K; Packham, G

    2007-02-22

    Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a critical role in the inappropriate survival of various types of malignant cells. Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy in the Western world. Although overexpression and regulation of NF-kappaB has been described in CLL, its function remains unclear. Exposure of CLL cells to BAY117082 or Kamebakaurin, potent pharmacological inhibitors of the NF-kappaB pathway, accelerated apoptosis in approximately 70% of cases. Sensitivity to NF-kappaB pathway inhibitors was not related to the prognostic markers VH status, CD38 or Zap70 expression, or to the levels of nuclear NF-kappaB. Normal peripheral B cells were resistant to the apoptosis-inducing effects of these compounds. Cell death induced by the inhibitors was associated with activation of caspase-9 and -3, and loss of mitochondrial membrane polarization, but did not involve changes in the expression of Bcl-2 or Mcl-1. Inhibitors caused an increase in c-jun NH2-terminal kinase activity in CLL, but this did not appear to be important for apoptosis. Microarray analysis identified some potential novel NF-kappaB target genes, including interleukin-16- and the Bcl-2- related survival protein Bcl-w. These results demonstrate that a substantial proportion of CLL are dependent on NF-kappaB for enhanced survival and suggest that inhibition of NF-kappaB may have therapeutic potential.

  16. 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

  17. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

    DOE PAGES

    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

  18. The pre-B-cell receptor checkpoint in acute lymphoblastic leukaemia.

    PubMed

    Eswaran, J; Sinclair, P; Heidenreich, O; Irving, J; Russell, L J; Hall, A; Calado, D P; Harrison, C J; Vormoor, J

    2015-08-01

    The B-cell receptor (BCR) and its immature form, the precursor-BCR (pre-BCR), have a central role in the control of B-cell development, which is dependent on a sequence of cell-fate decisions at specific antigen-independent checkpoints. Pre-BCR expression provides the first checkpoint, which controls differentiation of pre-B to immature B-cells in normal haemopoiesis. Pre-BCR signalling regulates and co-ordinates diverse processes within the pre-B cell, including clonal selection, proliferation and subsequent maturation. In B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), B-cell development is arrested at this checkpoint. Moreover, malignant blasts avoid clonal extinction by hijacking pre-BCR signalling in favour of the development of BCP-ALL. Here, we discuss three mechanisms that occur in different subtypes of BCP-ALL: (i) blocking pre-BCR expression; (ii) activating pre-BCR-mediated pro-survival and pro-proliferative signalling, while inhibiting cell cycle arrest and maturation; and (iii) bypassing the pre-BCR checkpoint and activating pro-survival signalling through pre-BCR independent alternative mechanisms. A complete understanding of the BCP-ALL-specific signalling networks will highlight their application in BCP-ALL therapy.

  19. A comparative assessment of the curative potential of reduced intensity allografts in acute myeloid leukaemia.

    PubMed

    Russell, N H; Kjeldsen, L; Craddock, C; Pagliuca, A; Yin, J A; Clark, R E; Howman, A; Hills, R K; Burnett, A K

    2015-07-01

    Allogeneic stem cell transplantation (SCT) provides the best mechanism of preventing relapse in acute myeloid leukaemia (AML). However non-relapse mortality (NRM) negates this benefit in older patients. Reduced intensity conditioning (RIC) permits SCT with reduced NRM, but its contribution to cure is uncertain. In the MRC AML15 Trial, patients in remission without favourable risk disease could receive SCT from a matched sibling or unrelated donor (MUD). If aged >45 years, a RIC was recommended and in patients aged 35-44 years, either RIC or myeloablative conditioning was permitted. The aim was to determine which approach improved survival and within which prespecified cytogenetic groups. RIC transplants significantly reduced relapse (adjusted hazard ratio (HR) 0.66 (0.50-0.85), P=0.002) compared to chemotherapy The 5-year overall survival from a sibling RIC (61%) was superior to a MUD RIC (37%; adjusted HR 1.50 (1.01-2.21), P=0.04) due to lower NRM (34 vs 14%, P=0.002) In adjusted analyses, there was a survival benefit for sibling RIC over chemotherapy (59 vs 49%, HR 0.75 (0.57-0.97), P=0.03), with consistent results in intermediate and adverse-risk patients. In patients aged 35-44 years, best outcomes were seen with a sibling RIC transplant, although a comparison with chemotherapy and myeloablative transplant was not significant in adjusted analyses (P=0.3).

  20. 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.

  1. 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

  2. A critical review of which children with acute myeloid leukaemia need stem cell procedures.

    PubMed

    Hasle, Henrik

    2014-07-01

    The last decades have seen parallel improvements in chemotherapy-based and haematopoietic stem cell transplantation (HSCT) regimens for acute myeloid leukaemia (AML) in children. There has been no consensus on indication for HSCT. Reserving HSCT for high-risk and relapsed patients spare many patients from the long-term toxicity of this treatment. The results of matched unrelated donor HSCT equal family donor transplantation and the presence of a matched sibling should no longer be a transplant indication. Minimal residual disease measured by flow cytometry may identify poor responders benefitting from HSCT in first complete remission (CR1) and those with a favourable response to induction therapy who do not need HSCT even with adverse cytogenetic aberrations. FLT3-internal tandem duplication without NPM1 mutation has a very high relapse rate despite favourable response and HSCT is indicated in CR1 in these cases. Finding the optimal indications for HSCT is a delicate balance between risk of relapse and late effects.

  3. An Intelligent Decision Support System for Leukaemia Diagnosis using Microscopic Blood Images

    PubMed Central

    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

  4. 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

  5. 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

    2015-10-09

    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.

  6. Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma.

    PubMed

    Nysom, K; Holm, K; Hesse, B; Ulrik, C S; Jacobsen, N; Bisgaard, H; Hertz, H

    1996-05-01

    Longitudinal data were analysed on the lung function of 25 of 29 survivors of childhood leukaemia or lymphoma, who had been conditioned with cyclophosphamide and total body irradiation before allogeneic bone marrow transplantation, to test whether children are particularly vulnerable to pulmonary damage after transplantation. None developed chronic graft-versus-host disease. Transfer factor and lung volumes were reduced immediately after bone marrow transplantation, but increased during the following years. However, at the last follow up, 4-13 years (median 8) after transplantation, patients had significantly reduced transfer factor, total lung capacity, and forced vital capacity (-1.0, -1.2, and -0.8 SD score, respectively), and increased ratio of forced expiratory volume in one second to forced vital capacity (+0.9 SD score). None of the patients had pulmonary symptoms, and changes were unrelated to their age at bone marrow transplantation. In conclusion, patients had subclinical restrictive pulmonary disease at a median of eight years after total body irradiation and allogeneic bone marrow transplantation.

  7. [Cytotoxicity of polyphenolic/flavonoid compounds in a leukaemia cell culture].

    PubMed

    Josipović, Pavle; Orsolić, Nada

    2008-12-01

    Flavonoid components of propolis are biologically active substances with antioxidative, immunostimulative, immunomodulative, and anti-inflamatory properties. The aim of the study was to investigate their cytotoxic effect on different leukaemia cell lines. For this purpose we used five different flavonoids (quercetin, caffeic acid, chrysin, naringenin, and naringin) and five types of leukemia cell lines (MOLT, JURKAT, HL-60, RAJI and U937). Cells were cultured at 37 degrees C in the RPMI-1640 medium supplemented with 10% FCS in humified atmosphere with 5% of CO2. Flavonoids were added in the following concentrations: 100 microg mL(-1), 50 microg mL(-1), 25 microg mL(-1), or 12.5 microg mL(-1). The results show different dose- and cell-type-dependent cytotoxicity. Among the flavonoids, quercetin showed the strongest cytotoxic effect in all cell lines. Caffeic acid and chrisyn also expressed a high level of cytotoxicty. Treatment of U937 and HL-60 cell lines with low concentrations of chrisyn or naringenin stimulated cell proliferation. These results suggest a biphase effect of the tested compounds on monocyte cell lines. Cytotoxicity and growth stimulation mechanisms caused directly by flavonoids should further be investigated on the molecular level.

  8. Longitudinal assessment of nutritional status in children treated for acute lymphoblastic leukaemia in Cuba.

    PubMed

    González, A; Cortina, L; González, P; González, C; García, T; de Svarch, E G

    2004-05-01

    Malnutrition has a deleterious effect on the results of therapy for malignant diseases in childhood. The impact of radiotherapy on growth is well known but the impact of cytotoxic drugs on nutritional status is more controversial. The purpose of this study was to determine the nutritional status of a cohort of children treated for acute lymphoblastic leukaemia (ALL) in Cuba. The study involved 49 children admitted to a single center and treated with a Berlin-Frankfurt-Munster-based protocol. Nutritional assessment included measurements of height, weight, body mass index and skin-fold thickness, made at diagnosis, after the intensive phase of treatment and at the end of therapy. Z-scores were used for height and comparison of percentiles for the rest of the variables. All the patients were above the third percentile in all the measurements. There were no statistically significant differences between the results at diagnosis, after intensive therapy and at the end of treatment. Although the sample was small, there was no demonstrable effect of chemotherapy on nutritional status in this Cuban paediatric population, in contrast to that reported in children with ALL in other developing countries.

  9. 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

  10. 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

  11. 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

    2016-05-20

    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.

  12. 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

  13. 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

  14. 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

  15. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

    PubMed

    Shlush, Liran I; Zandi, Sasan; Mitchell, Amanda; Chen, Weihsu Claire; Brandwein, Joseph M; Gupta, Vikas; Kennedy, James A; Schimmer, Aaron D; Schuh, Andre C; Yee, Karen W; McLeod, Jessica L; Doedens, Monica; Medeiros, Jessie J F; Marke, Rene; Kim, Hyeoung Joon; Lee, Kwon; McPherson, John D; Hudson, Thomas J; Brown, Andrew M K; Yousif, Fouad; Trinh, Quang M; Stein, Lincoln D; Minden, Mark D; Wang, Jean C Y; Dick, John E

    2014-02-20

    In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.

  16. Microsatellite instability in patients with chronic B-cell lymphocytic leukaemia

    PubMed Central

    Niv, E; Bomstein, Y; Yuklea, M; Lishner, M

    2005-01-01

    The purpose of our study was to evaluate the microsatellite instability (MSI) at selected loci with known involvement in the oncogenesis of chronic B-cell lymphocytic leukaemia (B-CLL). DNA from B cells (tumour cells) and from T cells (normal controls) of 27 samples of 26 patients with previously untreated B-CLL was extracted. Microsatellite instability in six microsatellite markers was tested using GeneScan Analysis Software. The rate of replication errors positive phenotype (RER+) was determined (MSI in more than 30% of examined loci). RER+ was found in four out of 27 paients (14.8%). A larger proportion of patients with stage C B-CLL exhibited RER+ than those with stage A or B (P<0.05). A higher prevalence of RER+ was demonstrated in a subgroup of patients with additional malignancies (three out of eight patients) in comparison with patients with B-CLL alone (1/19) (P=0.031). In conclusion, our study demonstrated that MSI might have a more prominent role in pathogenesis of B-CLL than reported todate. This may result from a selection of microsatellite markers adjacent to chromosomal loci, which are involved in B-cell malignancies, and using GeneScan Analysis Software, which is most modern and precise method of microsatellite analysis. PMID:15812543

  17. Analysis of rearranged immunoglobulin genes indicating a process of clonal evolution in chronic lymphocytic leukaemia.

    PubMed

    Hakim, I; Rechavi, G; Brok-Simoni, F; Grossman, Z; Amariglio, N; Mandel, M; Ramot, B; Ben-Bassat, I; Katzir, N

    1993-07-01

    Chronic lymphocytic leukaemia (CLL) is known to be a stable monoclonal neoplasm. In contrast to early studies demonstrating no more than two hybridizing immunoglobulin heavy chain bands corresponding to the two expected alleles, we have demonstrated an unexpected multiband pattern when the HindIII-digested DNA samples from 38 CLL patients were analysed by Southern blot hybridization using JH and C mu gene probes. In order to characterize the genetic basis for the multiband pattern, we molecularly cloned the immunoglobulin heavy chain genes of one of the patients whose leukaemic DNA sample demonstrated three hybridizing JH bands and a loss of the germline band. The cloned rearranged immunoglobulin genes could be divided, based on the restriction mapping and the hybridization with the various probes, into two basic patterns representing two alleles. In one of the cloned rearranged immunoglobulin genes a secondary rearrangement occurred that resulted in the addition of 300 base-pair long sequence into the switch region, and the creation of a HindIII restriction site. The results of the study suggest that clonal evolution occurs in some CLL, and that many of these neoplasms are indeed oligoclonal due to the accumulation of secondary genetic changes.

  18. 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

  19. Cost-utility analysis of imatinib mesilate for the treatment of advanced stage chronic myeloid leukaemia.

    PubMed

    Gordois, A; Scuffham, P; Warren, E; Ward, S

    2003-08-18

    Imatinib mesilate (Glivec), Novartis Pharmaceuticals) is a novel therapy for the treatment of chronic myeloid leukaemia (CML). We evaluated the cost-effectiveness of imatinib (600 mg daily) when used for the treatment of patients in advanced stages of CML (accelerated phase and blast crisis) against conventional therapies of combination chemotherapy (DAT) and palliative care in hospital or at home. A Markov model simulated the transitions of hypothetical patient cohorts and outcomes were modelled for 5 years from the start of treatment. Costs were estimated from the perspective of the UK National Health Service. Over 5 years, a patient in accelerated phase will, on average, accrue an additional 2.09 QALYs with imatinib compared to conventional therapies, while patients in blast crisis will accrue an additional 0.58 quality-adjusted life-years (QALYs) with imatinib compared to conventional therapies. The costs per additional QALY gained from treatment with imatinib compared with conventional therapies were pound 29344 (accelerated phase) and pound 42239 (blast crisis). The results were particularly sensitive to the price of imatinib, improvements in quality of life, and the duration of haematological responses. We conclude that treatment of CML with imatinib confers considerably greater survival and quality of life than conventional treatments but at a cost. PMID:12915870

  20. Noma in a child with acute leukaemia: when the 'face of poverty' finds an ally.

    PubMed

    Singh, Amitabh; Mandal, Anirban; Seth, Rachna; Kabra, Sushil Kumar

    2016-01-06

    A 2-year-6-month old, appropriately immunised, well-thriving boy, symptomatic for the past 6 months, presented with recurrent fever, progressive pallor, lymphadenopathy and a raw area on the right cheek, with discharging sinus. The necrotising infection of the face developed after one and half months of febrile illness. This febrile illness with bicytopaenia was diagnosed as enteric fever and treated with antibiotics. Skin grafting was performed for the full-thickness defect of the face. The patient continued to have a non-healing oral ulcer with progressive pallor and was finally diagnosed as having acute lymphoblastic leukaemia. Immunodeficiency was ruled out by appropriate investigations. Noma is an indirect measure of extreme poverty, but malignancy is known to predispose to this debilitating condition. The worldwide incidence of Noma is reported to be 30,000-140,000, with a preponderance in sub-Saharan Africa. This case emphasises the need for a thorough search for the underlying illness predisposing to a rare opportunistic infection such as Noma in a well-thriving child.

  1. Hypogammaglobulinaemia associated with abnormalities of both B and T lymphocytes in patients with chronic lymphatic leukaemia.

    PubMed Central

    Hersey, P; Wotherspoon, J; Reid, G; Gunz, F W

    1980-01-01

    The underlying basis for hypogammaglobulinaemia in patients with chronic lymphatic leukaemia (CLL) was investigated by measurement if immunoglobulin produced in vitro in cultures of pokeweek mitogen-stimulated B and T lymphocytes. B and T cells were separated by sheep red blood cell rosette techniques and, by culture of these cells from CLL patients in various combinations with B or T cells from normal subjects, it was possible to measure independently the function of B lymphocytes and the helper or suppressor function of T lymphocytes. By these methods it was found that the B lymphocytes of six of eight patients failed to produce immunoglobulins in vitro. B lymphocytes from two patients appeared to produce immunoglobulins in vitro. T lymphocytes from five of the eight patients had low or undetectable helper T cell function and in six patients their T lymphocytes had excessive suppressor activity in comparison to T lymphocyte populations from normal subjects. Whether the primary abnormality in the CLL T cell populations was a deficiency of helper T cells or excess of suppressor T cells was uncertain from these studies. These results suggest that immunoglobulin production by B lymphocytes from most patients with CLL was abnormal but also that T cells from CLL patients may be abnormal in respect to their role in immunoglobulin production at an early stage of the disease. These findings may assist in understanding the pathogenesis of this disease and lead to new approaches in treatment. PMID:6445798

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

    PubMed

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

    2016-08-01

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

  3. 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.

  4. Distinctive genotypes in infants with T-cell acute lymphoblastic leukaemia.

    PubMed

    Mansur, Marcela B; van Delft, Frederik W; Colman, Susan M; Furness, Caroline L; Gibson, Jane; Emerenciano, Mariana; Kempski, Helena; Clappier, Emmanuelle; Cave, Hélène; Soulier, Jean; Pombo-de-Oliveira, Maria S; Greaves, Mel; Ford, Anthony M

    2015-11-01

    Infant T-cell acute lymphoblastic leukaemia (iT-ALL) is a very rare and poorly defined entity with a poor prognosis. We assembled a unique series of 13 infants with T-ALL, which allowed us to identify genotypic abnormalities and to investigate prenatal origins. Matched samples (diagnosis/remission) were analysed by single nucleotide polymorphism-array to identify genomic losses and gains. In three cases, we identified a recurrent somatic deletion on chromosome 3. These losses result in the complete deletion of MLF1 and have not previously been described in T-ALL. We observed two cases with an 11p13 deletion (LMO2-related), one of which also harboured a deletion of RB1. Another case presented a large 11q14·1-11q23·2 deletion that included ATM and only five patients (38%) showed deletions of CDKN2A/B. Four cases showed NOTCH1 mutations; in one case FBXW7 was the sole mutation and three cases showed alterations in PTEN. KMT2A rearrangements (KMT2A-r) were detected in three out of 13 cases. For three patients, mutations and copy number alterations (including deletion of PTEN) could be backtracked to birth using neonatal blood spot DNA, demonstrating an in utero origin. Overall, our data indicates that iT-ALL has a diverse but distinctive profile of genotypic abnormalities when compared to T-ALL in older children and adults. PMID:26205622

  5. Hospital environment fungal contamination and aspergillosis risk in acute leukaemia patients in Sousse (Tunisia).

    PubMed

    Gheith, Soukeina; Ranque, Stéphane; Bannour, Wadiaa; Ben Youssef, Yosra; Khelif, Abderrahim; Ben Said, Moncef; Njah, Mansour; Saghrouni, Fatma

    2015-06-01

    Hospital environment is considered the main source of invasive aspergillosis (IA) in leukemic patients. This study aimed to describe Aspergillus colonisation in leukemic patients and their hospital environment and to test whether Aspergillus environmental contamination was associated with IA. For a 2-year period including 14-month renovation work, 91 acute leukaemia inpatients at the hematology department of University hospital in Sousse (Tunisia) were prospectively included. The incidence of probable IA (EORTC/MSG criteria) was 9.9%. Fifty-six Aspergillus were isolated from 53 (6.5%) of 811 sputa collected from 35 (38.5%) patients. Aspergillus spp. were isolated in 59.7% of 494 air samples and in 52.8% of 1579 surface samples taken in the patients' room. Aspergillus section Nigri (72.7%) was the most frequent. Aspergillus contamination peaked in autumn and winter on surface and in summer and autumn in air samples and was higher (P = 0.03) during the renovation work period. Multivariate analysis showed that for each Aspergillus section Nigri CFU airborne contamination IA risk increased by 1.05 (P = 0.04). In Tunisia, Aspergillus section Nigri and Flavi, but not Fumigati, are chiefly involved in IA. Our findings support swift implementation of airborne fungal contamination control measures in areas where immunocompromised patient are hospitalised.

  6. 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

  7. Differentiated HL-60 promyelocytic leukaemia cells produce a factor inducing differentiation.

    PubMed

    Djulbegović, B; Christmas, S E; Moore, M

    1987-01-01

    The bipotential human promyelocytic leukaemia cell line HL-60 can be induced to differentiate into monocytic or granulocytic cells by treatment with 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) or dimethylsulphoxide (DMSO) respectively. Conditioned media (CM) from 1,25(OH)2D3- or DMSO-treated cells were able to induce monocytic differentiation in fresh HL-60 cells as measured by induction of non-specific esterase and macrophage surface markers. CM from 1,25(OH)2D3-treated cells also led to a dose dependent loss of proliferative capacity in soft agar colony assays. These effects were not due to a toxic effect of the CM or to residual inducer present in the CM. gamma-interferon and GM-CSF were apparently not responsible for these effects. CM from the human histiocytic lymphoma cell line U937 led to only a low level of induction of macrophage differentiation in fresh HL-60 cells. The defect in HL-60 leukaemic cells may therefore be at the level of induction of an autonomously-produced differentiation factor.

  8. Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results.

    PubMed

    Delgado, Julio; Espinet, Blanca; Oliveira, Ana C; Abrisqueta, Pau; de la Serna, Javier; Collado, Rosa; Loscertales, Javier; Lopez, Montserrat; Hernandez-Rivas, Jose A; Ferra, Christelle; Ramirez, Angel; Roncero, Josep M; Lopez, Cristina; Aventin, Anna; Puiggros, Anna; Abella, Eugenia; Carbonell, Felix; Costa, Dolors; Carrio, Anna; Gonzalez, Marcos

    2012-04-01

    Patients with chronic lymphocytic leukaemia (CLL) whose tumour cells harbour a 17p deletion (17p-) are universally considered to have a poor prognosis. The deletion can be detected at diagnosis or during the evolution of the disease, particularly in patients who have received chemotherapy. We sought to evaluate the natural history of patients with 17p- CLL, identify predictive factors within this prognostic subgroup, and evaluate the results of different therapeutic approaches. Data from 294 patients with 17p- CLL followed up at 20 different institutions was retrospectively collected and analysed. Median age was 68 (range 27-98) years at the time of fluorescence in situ hybridization analysis. After 17p- documentation, 52% received treatment, achieving an overall response rate of 50%. Median overall survival was 41 months, and was significantly shorter in patients with elevated beta(2)-microglobulin concentration (P < 0·001), B symptoms (P = 0·016), higher percentage of cells with deletion (P < 0·001), and acquired deletions (P = 0·012). These findings suggest that patients with 17p- CLL have a variable prognosis that can be refined using simple clinical and laboratory features, including 17p- clone size, beta2-microglobulin concentration, presence of B symptoms and type of deletion (de novo versus acquired). PMID:22224845

  9. 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.

  10. Virus Maturation

    PubMed Central

    Veesler, David; Johnson, John E.

    2013-01-01

    We examined virus maturation of selected non-enveloped and enveloped ssRNA viruses; retroviruses; bacteriophages and herpes virus. Processes associated with maturation in the RNA viruses range from subtle (noda and picornaviruses) to dramatic (tetraviruses and togaviruses). The elaborate assembly and maturation pathway of HIV is discussed in contrast to the less sophisticated but highly efficient processes associated with togaviruses. Bacteriophage assembly and maturation are discussed in general terms with specific examples chosen for emphasis. Finally the herpes viruses are compared with bacteriophages. The data support divergent evolution of noda, picorna and tetraviruses from a common ancestor and divergent evolution of alpha and flaviviruses from a common ancestor. Likewise, bacteriophages and herpes viruses almost certainly share a common ancestor in their evolution. Comparing all the viruses, we conclude that maturation is a convergent process that is required to solve conflicting requirements in biological dynamics and function. PMID:22404678

  11. The incidence of childhood leukaemia around the La Hague nuclear waste reprocessing plant (France): a survey for the years 1978-1998

    PubMed Central

    Guizard, A; Boutou, O; Pottier, D; Troussard, X; Pheby, D; Launoy, G; Slama, R; Spira, A; ARKM

    2001-01-01

    BACKGROUND—A previous study has suggested an increased incidence rate of leukaemia from 1978 to 1992 in people aged 0 to 24 years and living in the vicinity of the La Hague nuclear waste reprocessing plant without considering age and cytological type.
SETTING—The Nord Cotentin region (France) and the island of Alderney (United Kingdom).
STUDY OBJECTIVE—To describe the occurrence of leukaemia for each age group and cytological type from 1978 to 1998 in the same area, using accurate reference incidence rates and adequate estimation of the at risk population.
DESIGN—A geographical study of incidence using three zones defined according to their distance from the site (0 to 10 km: Beaumont-Hague electoral ward, 10 to 20 km and 20 to 35 km) has been conducted. The risk of leukaemia was estimated from the standardised incidence ratio (SIR) of the number of cases observed to the number expected. Exact 95% confidence intervals (CI) have been computed.
PARTICIPANTS—All people under the age of 25 years living in the study region between 1978 and 1998.
MAIN RESULTS—The observed number of cases of leukaemia in the study region as a whole was consistent with the expected value (SIR=1.03; 95%CI: 0.73, 1.41). No cases were observed on Alderney. The SIR in the Beaumont-Hague electoral ward was 2.17 (95%CI: 0.71, 5.07). The highest SIR was observed in the 5 to 9 years age group (SIR=6.38; 95%CI: 1.32, 18.65). This consists in acute lymphoblastic leukaemia cases.
CONCLUSION—This study indicates an increased incidence of leukaemia in the area situated at less than 10 km from the plant. Monitoring and further investigations should be targeted at acute lymphoblastic leukaemia occurring during the childhood incidence peak (before 10 years) in children living near the La Hague site and may be other nuclear reprocessing plants.


Keywords: leukaemia; childhood; nuclear plant PMID:11413175

  12. Relationship between cytomegalovirus (CMV) reactivation, CMV-driven immunity, overall immune recovery and graft-versus-leukaemia effect in children.

    PubMed

    Jeljeli, Mohamed; Guérin-El Khourouj, Valérie; Porcher, Raphael; Fahd, Mony; Leveillé, Sandrine; Yakouben, Karima; Ouachée-Chardin, Marie; LeGoff, Jerome; Cordeiro, Debora Jorge; Pédron, Beatrice; Baruchel, Andre; Dalle, Jean-Hugues; Sterkers, Ghislaine

    2014-07-01

    The interplay between immune recovery, cytomegalovirus (CMV)-reactivation, CMV-driven immunity and graft-versus-leukaemia effect (GVL) was analysed in 108 children (median age: 8 years) who underwent haematopoietic-stem cell transplantation (HSCT) for acute leukaemia. Follow-up was 2 years unless death or relapse occurred. CMV-polymerase chain reaction (PCR) was programmed weekly until month +3 post-HSCT. Immunomonitoring consisted of sequential lymphocyte subset enumerations and analyses of T-cell proliferative and γ-interferon responses to CMV and to adenovirus. In the 108 recipients, the 2-year relapse rate (RR) was 25% (median time to onset 4·5 months; range: 24 d-17 months). CMV reactivation occurrence was 31% (median time to onset 26 d). Donor/recipient CMV serostatus did not influence RR. Among the 89 recipients disease-free after day +120, i) early CMV-reactivation before day +30 was more frequent (P = 0·01) in the relapse recipient group opposed to the non-relapse group. ii) CD8(+) /CD28(-) and CD4(+) CD45RA(-) T-cell expansions induced by CMV did not influence RR, iii) Recovery of anti-CMV and also anti-adenovirus immunity and of naïve CD4(+) T-cells was faster in the non-relapse group (P = 0·008; 0·009 and 0·002 respectively). In contrast to adult acute myeloid leukaemia, CMV reactivation was associated with increased RR in this paediatric series. Accelerated overall immune recovery rather than CMV-driven immunity had a favourable impact on RR.

  13. 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.

  14. 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

  15. Amino-acid substitutions at codon 13 of the N-ras oncogene in human acute myeloid leukaemia

    NASA Astrophysics Data System (ADS)

    Bos, Johannes L.; Toksoz, Deniz; Marshall, Christopher J.; Verlaan-de Vries, Matty; Veeneman, Gerrit H.; van der Eb, Alex J.; van Boom, Jacques H.; Janssen, Johannes W. G.; Steenvoorden, Ada C. M.

    1985-06-01

    DNAs from four out of five patients with acute myeloid leukaemia (AML) tested by an in vivo selection assay in nude mice using transfected mouse NIH 3T3 cells were found to contain an activated N-ras oncogene. Using a set of synthetic oligonucleotide probes, we have detected a mutation at codon 13 in all four genes. The same codon is mutated in an additional AML DNA that is positive in the focus-formation assay on 3T3 cells. DNA from the peripheral blood of one patient in remission does not contain a codon 13 mutation.

  16. Alternating hemiparesis and orolingual apraxia as manifestations of methotrexate neurotoxicity in a paediatric case of acute lymphoblastic leukaemia.

    PubMed

    Yap, Siew Mei; MacEneaney, Peter; Ryan, Clodagh; O'Toole, Orna

    2016-01-01

    A 15-year-old girl with a recent diagnosis of acute lymphoblastic leukaemia was admitted to hospital with pancytopaenia after having received high-dose intrathecal methotrexate 1 day prior. During the next week she had intermittent episodes of alternating hemiparesis associated with speech arrest lasting minutes to hours at a time. The episodes were not associated with altered level of consciousness or headache. MRI of the brain showed features consistent with methotrexate encephalopathy. This report discusses the typical clinical and radiological features of methotrexate neurotoxicity in addition to differential diagnoses and the proposed pathophysiological mechanisms. PMID:27113788

  17. Analysis of Arbovirus Isolates from Australia Identifies Novel Bunyaviruses Including a Mapputta Group Virus from Western Australia That Links Gan Gan and Maprik Viruses

    PubMed Central

    Kapoor, Vishal; Diviney, Sinead M.; Certoma, Andrea; Wang, Jianning; Johansen, Cheryl A.; Chowdhary, Rashmi; Mackenzie, John S.; Lipkin, W. Ian

    2016-01-01

    The Mapputta group comprises antigenically related viruses indigenous to Australia and Papua New Guinea that are included in the family Bunyaviridae but not currently assigned to a specific genus. We determined and analyzed the genome sequences of five Australian viruses isolated from mosquitoes collected during routine arbovirus surveillance in Western Australia (K10441, SW27571, K13190, and K42904) and New South Wales (12005). Based on matching sequences of all three genome segments to prototype MRM3630 of Trubanaman virus (TRUV), NB6057 of Gan Gan virus (GGV), and MK7532 of Maprik virus (MPKV), isolates K13190 and SW27571 were identified as TRUV, 12005 as GGV, and K42904 as a Mapputta group virus from Western Australia linking GGV and MPKV. The results confirmed serum neutralization data that had linked SW27571 to TRUV. The fifth virus, K10441 from Willare, was most closely related to Batai orthobunyavirus, presumably representing an Australian variant of the virus. Phylogenetic analysis also confirmed the close relationship of our TRUV and GGV isolates to two other recently described Australian viruses, Murrumbidgee virus and Salt Ash virus, respectively. Our findings indicate that TRUV has a wide circulation throughout the Australian continent, demonstrating for the first time its presence in Western Australia. Similarly, the presence of a virus related to GGV, which had been linked to human disease and previously known only from the Australian southeast, was demonstrated in Western Australia. Finally, a Batai virus isolate was identified in Western Australia. The expanding availability of genomic sequence for novel Australian bunyavirus variants supports the identification of suitably conserved or diverse primer-binding target regions to establish group-wide as well as virus-specific nucleic acid tests in support of specific diagnostic and surveillance efforts throughout Australasia. PMID:27764175

  18. 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

  19. [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