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Sample records for acquired c1 inhibitor

  1. Angiooedema due to acquired deficiency of C1-esterase inhibitor associated with leucocytoclastic vasculitis.

    PubMed

    Farkas, H; Szongoth, M; Bély, M; Varga, L; Fekete, B; Karádi, I; Füst, G

    2001-01-01

    A hereditary and an acquired type of C1-esterase inhibitor deficiency have been described. Manifestations characteristic of both forms include recurrent subcutaneous and submucosal angiooedema. Acquired C1-esterase inhibitor deficiency has been observed in association with lymphoproliferative disorders, malignancy, autoimmune diseases and infections. We report on a case with the acquired form of the disease accompanied by leucocytoclastic vasculitis. Treatment with antimalarial agents resulted in complete resolution of symptoms and signs. Furthermore, C1-esterase inhibitor concentration and activity, as well as C1 levels, all returned to normal. PMID:11720182

  2. Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment.

    PubMed

    Zeerleder, Sacha; Levi, Marcel

    2016-01-01

    Uncontrolled generation of bradykinin (BK) due to insufficient levels of protease inhibitors controlling contact phase (CP) activation, increased activity of CP proteins, and/or inadequate degradation of BK into inactive peptides increases vascular permeability via BK-receptor 2 (BKR2) and results in subcutaneous and submucosal edema formation. Hereditary and acquired angioedema due to C1-inhibitor deficiency (C1-INH-HAE and -AAE) are diseases characterized by serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation. A decreased activity of C1-inhibitor is the hallmark of C1-INH-HAE (types 1 and 2) due to a mutation in the C1-inhibitor gene, whereas the deficiency in C1-inhibitor in C1-INH-AAE is the result of autoimmune phenomena. In HAE with normal C1-inhibitor, a significant percentage of patients have an increased activity of factor XIIa due to a FXII mutation (FXII-HAE). Treatment of C1-inhibitor-dependent angioedema focuses on restoring control of BK generation by inhibition of CP proteases by correcting the balance between CP inhibitors and BK breakdown or by inhibition of BK-mediated effects at the BKR2 on endothelial cells. This review will address the pathophysiology, clinical picture, diagnosis and available treatment in C1-inhibitor-dependent angioedema focusing on BK-release and its regulation. Key Messages Inadequate control of bradykinin formation results in the formation of characteristic subcutaneous and submucosal edemas of the skin, upper airways, facial structures, abdomen and extremities as seen in hereditary and acquired C1-inhibitor-dependent angioedema. Diagnosis of hereditary and acquired C1-inhibitor-dependent angioedema may be troublesome as illustrated by the fact that there is a significant delay in diagnosis; a certain grade of suspicion is therefore crucial for quick diagnosis. Submucosal edema formation in

  3. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients.

    PubMed

    Agostoni, A; Cicardi, M

    1992-07-01

    Two hundred and twenty-six patients with inherited C1 inhibitor (C1-INH) deficiency, also known as hereditary angioedema (HAE), have been studied. They belonged to 80 unrelated families, and in 11 of them C1-INH was functionally deficient but antigenically normal (type II HAE). Genetic analysis of type 1 families demonstrated restriction fragment length polymorphisms in 11% and abnormal mRNAs in 25%. In type II families, the site of the mutation appeared to determine the rate of catabolism of the dysfunctional C1-INH and its antigenic plasma levels. Clinical symptoms (subcutaneous and mucous swellings) generally first appeared within the second decade of life. The frequency of symptoms was highly variable from patient to patient, but a few patients remained asymptomatic throughout their lives. Prophylactic treatment with attenuated androgens was administered to 59 patients and was totally effective in 57, without significant side effects. Sixty-seven laryngeal and 15 abdominal attacks were treated with C1-INH plasma concentrate, yielding initial regression of symptoms in 30 to 90 minutes. The acquired deficiency of C1-INH, also known as acquired angioedema, was diagnosed in 9 patients. Eight of them had an autoantibody against C1-INH; the only patient without the autoantibody had associated chronic lymphocytic leukemia. Prophylactic treatment with attenuated androgens was effective in this last patient, while those with the autoantibody against C1-INH benefited from prophylaxis with antifibrinolytic agents. Replacement therapy with C1-INH concentrate was necessary only for patients with autoantibodies and required doses 3 or 4 times higher than those used in HAE. PMID:1518394

  4. The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity.

    PubMed

    Wu, Maddalena Alessandra; Castelli, Roberto

    2016-02-01

    Several clinical and biological features of lymphoproliferative diseases have been associated with an increased risk of developing autoimmune manifestations. Acquired deficiency of C1-inhibitor (C1-INH) (AAE) is a rare syndrome clinically similar to hereditary angioedema (HAE) characterized by local increase in vascular permeability (angioedema) of the skin and the gastrointestinal and oro-pharyngo-laryngeal mucosa. Bradykinin, a potent vasoactive peptide, released from high molecular weight kininogen when it is cleaved by plasma kallikrein (a serine protease controlled by C1-INH), is the mediator of symptoms. In total 46% of AAE patients carry an underlying hematological disorder including monoclonal gammopathy of uncertain significance (MGUS) or B cell malignancies. However, 74% of AAE patients have anti-C1-INH autoantibodies without hematological, clinical or instrumental evidence of lymphoproliferative disease. Unlike HAE patients, AAE patients usually have late-onset symptoms, do not have a family history of angioedema and present variable response to treatment due to the hypercatabolism of C1-INH. Experiments show that C1-INH and/or the classical complement pathway were consumed by the neoplastic lymphatic tissues and/or anti-C1-INH neutralizing autoantibodies. Therapy of AAE follows two directions: 1) prevention/reversal of the symptoms of angioedema; and 2) treatment of the associated disease. Different forms of B cell disorders coexist and/or evolve into each other in AAE and seem to be dominated by an altered control of B cell proliferation, thus AAE represents an example of the strict link between autoimmunity and lymphoproliferation. PMID:26068904

  5. Acquired C1 esterase inhibitor deficiency in lymphomas: prevalence, symptoms, and response to treatment.

    PubMed

    Bekos, Christine; Perkmann, Thomas; Krauth, Maria; Raderer, Markus; Lechner, Klaus; Jaeger, Ulrich

    2016-09-01

    We retrospectively studied the prevalence of C1 esterase inhibitor (C1 INH) deficiency in 131 patients with various lymphomas. We determined C1 INH activity, C1 INH antigen, and C4 concentration at diagnosis and after chemotherapy. In follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) consecutive patients were studied. In these entities, the prevalence of C1 INH deficiency was 10.2% in DLBCL, 4.1% in CLL, and 0% in FL and Hodgkin lymphoma. In indolent lymphomas, we identified only single cases of C1 INH deficiency, predominantly in splenic marginal zone lymphomas (SMZL) (four cases). Only three patients were symptomatic while the majority (11 cases) was asymptomatic. In DLBCL patients who were successfully treated with chemotherapy, complete normalization of C1 INH activity and C4 was observed. In contrast, C1 INH deficiency remained in SMZL patients after splenectomy. We conclude that C1 INH deficiency in lymphomas is frequently asymptomatic and responsive to immunochemotherapy. PMID:26795750

  6. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond.

    PubMed

    Agostoni, Angelo; Aygören-Pürsün, Emel; Binkley, Karen E; Blanch, Alvaro; Bork, Konrad; Bouillet, Laurence; Bucher, Christoph; Castaldo, Anthony J; Cicardi, Marco; Davis, Alvin E; De Carolis, Caterina; Drouet, Christian; Duponchel, Christiane; Farkas, Henriette; Fáy, Kálmán; Fekete, Béla; Fischer, Bettina; Fontana, Luigi; Füst, George; Giacomelli, Roberto; Gröner, Albrecht; Hack, C Erik; Harmat, George; Jakenfelds, John; Juers, Mathias; Kalmár, Lajos; Kaposi, Pál N; Karádi, István; Kitzinger, Arianna; Kollár, Tímea; Kreuz, Wolfhart; Lakatos, Peter; Longhurst, Hilary J; Lopez-Trascasa, Margarita; Martinez-Saguer, Inmaculada; Monnier, Nicole; Nagy, István; Németh, Eva; Nielsen, Erik Waage; Nuijens, Jan H; O'grady, Caroline; Pappalardo, Emanuela; Penna, Vincenzo; Perricone, Carlo; Perricone, Roberto; Rauch, Ursula; Roche, Olga; Rusicke, Eva; Späth, Peter J; Szendei, George; Takács, Edit; Tordai, Attila; Truedsson, Lennart; Varga, Lilian; Visy, Beáta; Williams, Kayla; Zanichelli, Andrea; Zingale, Lorenza

    2004-09-01

    Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder. PMID:15356535

  7. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema.

    PubMed

    Zuraw, Bruce L; Bernstein, Jonathan A; Lang, David M; Craig, Timothy; Dreyfus, David; Hsieh, Fred; Khan, David; Sheikh, Javed; Weldon, David; Bernstein, David I; Blessing-Moore, Joann; Cox, Linda; Nicklas, Richard A; Oppenheimer, John; Portnoy, Jay M; Randolph, Christopher R; Schuller, Diane E; Spector, Sheldon L; Tilles, Stephen A; Wallace, Dana

    2013-06-01

    These parameters were developed by the Joint Task Force on Practice Parameters (JTFPP), representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the JTFPP, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. The Joint Task Force on Practice Parameters understands that the cost of diagnostic tests and therapeutic agents is an important concern that might appropriately influence the work-up and treatment chosen for a given patient. The JTFPP recognizes that the emphasis of our primary recommendations regarding a medication might vary, for example, depending on third-party payer issues and product patent expiration dates. However, because the cost of a given test or agent is so widely variable and there is a paucity of pharmacoeconomic data, the JTFPP generally does not consider cost when formulating practice parameter recommendations. In some instances the cost benefit of an intervention is considered relevant, and commentary might be provided. These parameters are not designed for use by pharmaceutical companies in drug promotion

  8. A nationwide study of acquired C1-inhibitor deficiency in France: Characteristics and treatment responses in 92 patients.

    PubMed

    Gobert, Delphine; Paule, Romain; Ponard, Denise; Levy, Pierre; Frémeaux-Bacchi, Véronique; Bouillet, Laurence; Boccon-Gibod, Isabelle; Drouet, Christian; Gayet, Stéphane; Launay, David; Martin, Ludovic; Mekinian, Arsène; Leblond, Véronique; Fain, Olivier

    2016-08-01

    Acquired angioedema (AAE) due to C1-inhibitor (C1INH) deficiency is rare. Treatment options for acute attacks are variable and used off-label. Successful treatment of the associated lymphoma with rituximab seems to prevent acute attacks in subjects with AAE. The aim of this study was to describe AAE manifestations, its associated diseases, and patients' responses to treatments in a representative cohort.A retrospective nationwide study was conducted in France. The inclusion criteria were recurrent angioedema attacks and an acquired decrease in functional C1INH <50% of the reference value.A total of 92 cases were included, with a median age at onset of 62 years. Facial edema and abdominal pain were the most frequent symptoms. Fifteen patients were hospitalized in the intensive care unit because of laryngeal edema, and 1 patient died. Anti-C1INH antibodies were present in 43 patients. The associated diseases were primarily non-Hodgkin lymphoma (n = 44, with 24 splenic marginal zone lymphomas) and monoclonal gammopathy of undetermined significance (n = 24). Three patients had myeloma, 1 had amyloid light-chain (of immunoglobulin) (AL) amyloidosis, 1 patient had a bronchial adenocarcinoma, and 19 patients had no associated disease. Icatibant relieved the symptoms in all treated patients (n = 26), and plasma-derived C1INH concentrate in 19 of 21 treated patients. Six patients experienced thromboembolic events under tranexamic acid prophylaxis. Rituximab prevented angioedema in 27 of 34 patients as a monotherapy or in association with chemotherapy. Splenectomy controlled AAE in 7 patients treated for splenic marginal zone lymphoma. After a median follow-up of 4.2 years, angioedema was on remission in 52 patients.AAE cases are primarily associated with indolent lymphoma-especially splenic marginal zone lymphoma-and monoclonal gammopathy of undetermined significance but not with autoimmune diseases or other conditions. Icatibant and plasma-derived C1INH concentrate control

  9. Hereditary angioedema with normal C1 inhibitor.

    PubMed

    Bork, Konrad

    2013-11-01

    Until recently it was assumed that hereditary angioedema was a disease that results exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity, and protein in plasma were described. Since then, numerous patients and families with that condition have been reported. Most of the patients were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. In some families mutations in the coagulation factor XII (Hageman factor) gene were detected. PMID:24176211

  10. Platelet C1- inhibitor. A secreted alpha-granule protein.

    PubMed Central

    Schmaier, A H; Smith, P M; Colman, R W

    1985-01-01

    In order to characterize which proteins of the contact phase of coagulation interact with platelets, human platelets were studied immunochemically and functionally to determine if they contain C1- inhibitor. By means of monospecific antibody to C1- inhibitor, a competitive enzyme-linked immunosorbent assay (CELISA) was developed to measure directly platelet C1- inhibitor. With the CELISA, from 33 to 115 ng of C1- inhibitor antigen per 10(8) platelets from 15 normal donors was quantified in lysates of washed human platelets solubilized in nonionic detergent. The mean concentration in 10(8) platelets was 62 +/- 33 ng (SD). Plasma C1- inhibitor either in the platelet suspension medium or on the surface of the platelets could account for only from 6.5 to 16% of the total antigen measured in the solubilized platelets. Upon functional studies, platelets contained 84 +/- 36 ng (SD) of C1- inhibitor activity in 10(8) platelets. As assessed by the CELISA, platelet C1- inhibitor antigen was immunochemically identical to plasma and purified C1- inhibitor. In contrast, the mean concentration of platelet C1- inhibitor antigen in platelets from four patients with classical hereditary angioedema was 8.3 ng/10(8) platelets (range, 5.3 to 11.3 ng/10(8) platelets). 25 and 31% of the total platelet C1- inhibitor was secreted without cell lysis from normal platelets after exposure to collagen (20 micrograms/ml) and thrombin (1 U/ml), respectively, and this secretion was blocked by metabolic inhibitors. Platelet subcellular fractionation showed that platelet C1- inhibitor resided mostly in alpha-granules, similar to the location of platelet fibrinogen. Thus, human platelets contained C1- inhibitor, which became available by platelet secretion. The identification of platelet C1- inhibitor suggests that platelets may modulate the activation of the proteins of early blood coagulation and the classical complement pathways. Images PMID:3965505

  11. C1-inhibitor (C1-INH) autoantibodies in hereditary angioedema. Strong correlation with the severity of disease in C1-INH concentrate naïve patients.

    PubMed

    Varga, Lilian; Széplaki, Gábor; Visy, Beáta; Füst, George; Harmat, George; Miklós, Katalin; Németh, Julianna; Cervenak, László; Karádi, István; Farkas, Henriette

    2007-02-01

    The presence of autoantibodies to C1-inhibitor (C1-INH-Abs) is a hallmark of acquired C1-inhibitor deficiency. However, only scarce data are available on their prevalence in hereditary angioedema (HAE). In a prospective study performed between 2001 and 2004 in 95 patients with Type I or II HAE, serum samples were taken one to three times a year and clinical status of the patients was registered. Serum samples were tested for total activity of the classical pathway, C1q, C3, C4 and C1-inhibitor (C1-INH) concentration and activity levels, as well as the presence of IgG, IgA and IgM type anti-C1-inhibitor antibodies (C1-INH-Ab). Fifty-four healthy age and gender matched persons served as control. Significant differences between the patients and controls in the occurrence of elevated (2S.D. higher than mean of control) C1-INH-Abs titers was found only in the case of IgM type C1-INH-Abs. Elevated (>4.22AU/ml) IgM C1-INH-Abs levels were found in 31 and 4% of the patients and controls, respectively (p<0.001). Surprisingly, high titer IgM C1-INH-Abs were present with equal frequency in the 41 HAE patients ever treated with C1-INH concentrate and in the 54 C1-INH treatment naïve patients. In the latter group, strong positive correlation between the levels of the IgM C1-INH-Abs and the most severe disease (score 1) (p=0.0021) and the yearly attack rate (p=0.0173) were obtained. In addition, the levels of the IgM C1-INH-Abs exhibited strong negative correlation to the C1-inhibitor concentration and functional activity, total classical complement pathway activity, and a positive correlation to total IgM concentration. Taken together, these data indicate that IgM type C1-INH-Abs are present with highly elevated frequency in HAE patients irrespectively of the previous treatment with C1-INH concentrate. Most probable production of these autoantibodies is the consequence of the activation of complement and other plasma enzyme systems during HAE attacks. Determination of IgM C1

  12. Characterization of C1 inhibitor binding to neutrophils.

    PubMed Central

    Chang, N S; Boackle, R J; Leu, R W

    1991-01-01

    In a previous study we have isolated neutrophil membrane proteins that non-covalently bind to native C1-INH (105,000 MW) and a non-functional, degraded C1-INH (88,000 MW; C1-INH-88). To further characterize the binding nature, we have designed a novel kinetic C1 titration assay which enables not only a quantification of the removal of fluid-phase C1-INH by neutrophils, but also a concomitant measure of residual C1-INH function. Native C1-INH, when adsorbed to EDTA-pretreated neutrophils, lost its function in the inhibition of fluid-phase C1. The non-functional C1-INH-88, which is probably devoid of a reactive centre, was found to block the binding of native C1-INH to neutrophils. Pretreatment of neutrophils with serine esterase inhibitors did not abrogate binding capacity of the cells for C1-INH, whereas the binding affinity for C1-INH was lost when the cells were pretreated with trypsin. An array of human peripheral blood leucocytes and several lymphoid cell lines has surface binding sites for C1-INH, but not on human erythrocytes and U937 cells. Binding was further confirmed using (i) C1-INH-microsphere beads to neutrophils, in which the binding was blocked when pretreating neutrophils with excess C1-INH or with trypsin, and (ii) radiolabelled C1-INH to neutrophils, which was competitively blocked by unlabelled non-functional C1-INH-88. Desialylation of C1-INH significantly reduced its binding affinity for neutrophils, indicating that the membrane receptor sites on neutrophils could be specific for the binding of sialic acid residues on C1-INH. Overall, our studies indicate that neutrophils or other leucocytes possess specific surface binding sites for the sialic acid-containing portion of C1-INH. PMID:2045131

  13. High prevalence of splenic marginal zone lymphoma among patients with acquired C1 inhibtor deficiency.

    PubMed

    Castelli, Roberto; Wu, Maddalena Alessandra; Arquati, Massimo; Zanichelli, Andrea; Suffritti, Chiara; Rossi, Davide; Cicardi, Marco

    2016-03-01

    Marginal zone lymphoma represents about 10% of all non-Hodgkin lymphomas (NHLs). 33% of patients with acquired angioedema (AAE) due to acquired C1-inhibitor (C1-INH) deficiency (C1-INH-AAE) have or will develop NHLs. C1-INH-AAE is a rare condition. We report the follow-up of 72 C1-INH-AAE patients, followed for a median of 15 years (range 1-24). Median age was 71 (range 64-79) years; median age at onset of angioedema symptoms was 57·5 (range 50-66) years and it was 63 [range 45-80) years at diagnosis]. Twenty patients were diagnosed with low-grade non-follicular B-cell lymphomas (75% were splenic MZL), one with follicular and three with high-grade lymphomas (two diffuse large B-cell lymphomas and one mantle cell lymphoma). Fifteen NHLs were diagnosed at onset of AAE or thereafter (3 months to 7 years), eight had already been diagnosed at onset of angioedema. Two of 24 patients remain on watchful wait. Thirthen of 24 received chemotherapy, two received rituximab. Three underwent splenectomy. All 18 patients receiving therapy for NHL experienced post-treatment reduction in AAE symptoms. Our study suggests that clonal B-cell proliferation is the pathology underlying AAE leading to production of C1-INH-neutralizing autoantibodies and to NHLs. The post-germinal centre origin of NHL suggests that immune stimulation may contribute to lymphomagenesis. PMID:26728240

  14. Influence of C1-inhibitor on inflammation, edema and shock.

    PubMed

    Dickneite, G

    1993-12-01

    C1-Inhibitor (Berinert, C1 INH), a 104 kDa protein, inhibits complement components (C1 esterase) as well as enzymes of the contact phase of coagulation (Factor XII, Factor XI) and kallikrein, thus regulating kinin generation. C1 INH is used for the treatment of the hereditary angioneurotic edema. This paper will give a survey about the evidence in recent literature concerning the potential efficacy of the compound on other diseases associated with shock, capillary leakage and inflammation as well. In our own experiments we evaluated whether the compound could influence acute inflammatory reactions or the severe systemic inflammatory response syndrome (SIRS) as a consequence of an experimental septic shock. To prevent the sepsis-induced DIC we co-infused the thrombin inhibitors AT III or rec. hirudin in combination with C1 INH. Coinfusion of C1-inhibitor (50-200 U/kg x h) with either rec. hirudin or AT III significantly improved survival rate compared to thrombin inhibitor alone. PMID:8172580

  15. Treatment of type I and II hereditary angioedema with Rhucin, a recombinant human C1 inhibitor.

    PubMed

    Varga, Lilian; Farkas, Henriette

    2008-11-01

    Hereditary and acquired angioedema are of outstanding clinical importance, as edematous attacks associated with these conditions can thrust afflicted patients into mortal danger. Currently, C1 inhibitor concentrate - a human blood product - is available as a replacement therapy. In view of the limited number of donors, as well as the risk of transmission of blood-borne infections, it is a reasonable expectation to develop a therapeutic alternative based on recombinant technology, which would eliminate all these shortcomings. Pharming (Leiden, The Netherlands) has developed Rhucin, a recombinant human C1 inhibitor, as a proprietary product, which is currently being evaluated in Phase III clinical trials. Ongoing studies conducted within the framework of the development program are almost complete and their interim findings are reassuring. This should facilitate successful regulatory approval in the near future, which is indispensable in order to make Rhucin available for patients with hereditary angioedema or other disorders amenable to C1 inhibitor replacement. PMID:20477114

  16. Fluid-phase interaction of C1 inhibitor (C1 Inh) and the subcomponents C1r and C1s of the first component of complement, C1.

    PubMed

    Chesne, S; Villiers, C L; Arlaud, G J; Lacroix, M B; Colomb, M G

    1982-01-01

    Interactions between proenzymic or activated complement subcomponents of C1 and C1 Inh (C1 inhibitor) were analysed by sucrose-density-gradient ultracentrifugation and sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. The interaction of C1 Inh with dimeric C1r in the presence of EDTA resulted into two bimolecular complexes accounting for a disruption of C1r. The interaction of C1 Inh with the Ca2+-dependent C1r2-C1s2 complex (8.8 S) led to an 8.5 S inhibited C1r-C1s-C1 Inh complex (1:1:2), indicating a disruption of C1r2 and of C1s2 on C1 Inh binding. The 8.5 S inhibited complex was stable in the presence of EDTA; it was also formed from a mixture of C1r, C1s and C1 Inh in the presence of EDTA or from bimolecular complexes of C1r-C1 Inh and C1s-C1 Inh. C1r II, a modified C1r molecule, deprived of a Ca2+-binding site after autoproteolysis, did not lead to an inhibited tetrameric complex on incubation with C1s and C1 Inh. These findings suggest that, when C1 Inh binds to C1r2-C1s2 complex, the intermonomer links inside C1r2 or C1s2 are weakened, whereas the non-covalent Ca2+-independent interaction between C1r2 and C1s2 is strengthened. The nature of the proteinase-C1 Inh link was investigated. Hydroxylamine (1M) was able to dissociate the complexes partially (pH 7.5) or totally (pH 9.0) when the incubation was performed in denaturing conditions. An ester link between a serine residue at the active site of C1r or C1s and C1 Inh is postulated. PMID:6282262

  17. Prophylaxis in hereditary angioedema (HAE) with C1 inhibitor deficiency.

    PubMed

    Greve, Jens; Strassen, Ulrich; Gorczyza, Marina; Dominas, Nina; Frahm, Uta-Marie; Mühlberg, Heike; Wiednig, Michaela; Zampeli, Vasiliki; Magerl, Markus

    2016-03-01

    Hereditary angioedema (HAE) is a rare congenital disorder characterized by recurrent episodes of subcutaneous or submucosal edema. Laryngeal manifestations can be life-threatening. In the majority of cases, the disease can be adequately treated with an on-demand approach - in some cases, however, short- or long-term prophylaxis is indicated. Attenuated androgens used to be the drugs of choice, but they are associated with considerable side effects and no longer commercially available in the German-speaking countries of the EU. They are currently being replaced by more effective and more tolerable agents such C1-inhibitors, the kallikrein inhibitor ecallantide, and the B2 receptor antagonist icatibant, which have recently obtained market authorization. These new drugs have had a major impact, especially on the indications and procedures for long-term prophylaxis. According to the most recent international consensus papers and our own experience, self-administered C1-inhibitors are now the first option for long-term prophylactic therapy. The decision for prophylaxis should no longer be based on single parameters such as the frequency of attacks but on adequate overall disease control including quality of life. More drugs are currently being developed, which may lead to further changes in the treatment algorithms of HAE. PMID:26972189

  18. Pediatric hereditary angioedema due to C1-inhibitor deficiency

    PubMed Central

    2010-01-01

    Hereditary angioedema (HAE) resulting from the deficiency of the C1 inhibitor (C1-INH) is a rare, life-threatening disorder. It is characterized by attacks of angioedema involving the skin and/or the mucosa of the upper airways, as well as the intestinal mucosa. In approximately 50 per cent of cases, clinical manifestations may appear during childhood. The complex management of HAE in pediatric patients is in many respects different from the management of adults. Establishing the diagnosis early, preferably before the onset of clinical symptoms, is essential in cases with a positive family history. Complement studies usually afford accurate diagnosis, whereas molecular genetics tests may prove helpful in uncertain cases. Appropriate therapy, supported by counselling, suitable modification of lifestyle, and avoidance of triggering factors (which primarily include mechanical trauma, mental stress and airway infections in children) may spare the patient unnecessary surgery and may prevent mortality. Prompt control of edematous attacks, short-term prophylaxis and intermittent therapy are recommended as the primary means for the management of pediatric cases. Medicinal products currently used for the treatment of children with hereditary angioedema include antifibrinolytics, attenuated androgens, and C1-INH replacement therapy. Current guidelines favour antifibrinolytics for long-term prophylaxis because of their favorable safety profile but efficacy may be lacking. Attenuated androgens administered in the lowest effective dose are another option. C1-INH replacement therapy is also an effective and safe agent for children. Regular monitoring and follow-up of patients are necessary. PMID:20667121

  19. C1 inhibitor deficiency: 2014 United Kingdom consensus document

    PubMed Central

    Longhurst, H J; Tarzi, M D; Ashworth, F; Bethune, C; Cale, C; Dempster, J; Gompels, M; Jolles, S; Seneviratne, S; Symons, C; Price, A; Edgar, D

    2015-01-01

    C1 inhibitor deficiency is a rare disorder manifesting with recurrent attacks of disabling and potentially life-threatening angioedema. Here we present an updated 2014 United Kingdom consensus document for the management of C1 inhibitor-deficient patients, representing a joint venture between the United Kingdom Primary Immunodeficiency Network and Hereditary Angioedema UK. To develop the consensus, we assembled a multi-disciplinary steering group of clinicians, nurses and a patient representative. This steering group first met in 2012, developing a total of 48 recommendations across 11 themes. The statements were distributed to relevant clinicians and a representative group of patients to be scored for agreement on a Likert scale. All 48 statements achieved a high degree of consensus, indicating strong alignment of opinion. The recommendations have evolved significantly since the 2005 document, with particularly notable developments including an improved evidence base to guide dosing and indications for acute treatment, greater emphasis on home therapy for acute attacks and a strong focus on service organization. PMID:25605519

  20. C1 inhibitor deficiency: 2014 United Kingdom consensus document.

    PubMed

    Longhurst, H J; Tarzi, M D; Ashworth, F; Bethune, C; Cale, C; Dempster, J; Gompels, M; Jolles, S; Seneviratne, S; Symons, C; Price, A; Edgar, D

    2015-06-01

    C1 inhibitor deficiency is a rare disorder manifesting with recurrent attacks of disabling and potentially life-threatening angioedema. Here we present an updated 2014 United Kingdom consensus document for the management of C1 inhibitor-deficient patients, representing a joint venture between the United Kingdom Primary Immunodeficiency Network and Hereditary Angioedema UK. To develop the consensus, we assembled a multi-disciplinary steering group of clinicians, nurses and a patient representative. This steering group first met in 2012, developing a total of 48 recommendations across 11 themes. The statements were distributed to relevant clinicians and a representative group of patients to be scored for agreement on a Likert scale. All 48 statements achieved a high degree of consensus, indicating strong alignment of opinion. The recommendations have evolved significantly since the 2005 document, with particularly notable developments including an improved evidence base to guide dosing and indications for acute treatment, greater emphasis on home therapy for acute attacks and a strong focus on service organization. PMID:25605519

  1. In pursuit of excellence: an integrated care pathway for C1 inhibitor deficiency

    PubMed Central

    Manson, A L; Price, A; Dempster, J; Clinton-Tarestad, P; Greening, C; Enti, R; Hill, S; Grigoriadou, S; Buckland, M S; Longhurst, H J

    2013-01-01

    There are estimated to be approximately 1500 people in the United Kingdom with C1 inhibitor (C1INH) deficiency. At BartsHealth National Health Service (NHS) Trust we manage 133 patients with this condition and we believe that this represents one of the largest cohorts in the United Kingdom. C1INH deficiency may be hereditary or acquired. It is characterized by unpredictable episodic swellings, which may affect any part of the body, but are potentially fatal if they involve the larynx and cause significant morbidity if they involve the viscera. The last few years have seen a revolution in the treatment options that are available for C1 inhibitor deficiency. However, this occurs at a time when there are increased spending restraints in the NHS and the commissioning structure is being overhauled. Integrated care pathways (ICP) are a tool for disseminating best practice, for facilitating clinical audit, enabling multi-disciplinary working and for reducing health-care costs. Here we present an ICP for managing C1 inhibitor deficiency. PMID:23607500

  2. Hereditary angio-oedema with normal C1 inhibitor in a family with affected women and men.

    PubMed

    Bork, K; Gül, D; Dewald, G

    2006-03-01

    Recurrent angio-oedema is a sign of various acquired and inherited disease entities, including hereditary angio-oedema types I and II that result from a genetic deficiency of C1 inhibitor, and a recently described type of dominantly inherited angio-oedema, which does not show a deficiency of C1 inhibitor. Until now, this new type of hereditary angio-oedema, designated as hereditary angio-oedema type III, has been assumed to be a disorder specific to females. We now describe a four-generation family with dominantly inherited angio-oedema and normal C1 inhibitor in which, in contrast to all previous observations, not only five female but also three male family members were clinically affected. One male patient was mainly affected following the intake of angiotensin-converting enzyme inhibitors. Our current observation leads to new considerations about the classification of hereditary angio-oedema with normal C1 inhibitor. Either hereditary angio-oedema with normal C1 inhibitor can be an entity affecting females predominantly, but not exclusively; in that case, men appear to have a much reduced chance of clinical manifestations. Alternatively, our present observation of hereditary angio-oedema with normal C1 inhibitor affecting both sexes may represent a new disease entity, presumably with a different underlying defect. PMID:16445789

  3. The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema

    PubMed Central

    Hermanrud, Thorbjørn; Duus, Nicolaj; Bygum, Anette; Rasmussen, Eva Rye

    2016-01-01

    Angioedema of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to pharmaceuticals influencing the generation or degradation of the vasoactive molecule bradykinin. Plasma-derived C1-esterase inhibitor concentrate is a well-established treatment option of hereditary and acquired complement C1-esterase inhibitor deficiency, which are also mediated by an increased level of bradykinin resulting in recurrent angioedema. We here present a case of severe angiotensin converting enzyme-inhibitor related angioedema (ACEi-AE) of the hypopharynx that completely resolved rapidly after the infusion of plasma-derived C1-inhibitor concentrate adding to the sparse reports in the existing literature. PMID:27123347

  4. The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema.

    PubMed

    Hermanrud, Thorbjørn; Duus, Nicolaj; Bygum, Anette; Rasmussen, Eva Rye

    2016-01-01

    Angioedema of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to pharmaceuticals influencing the generation or degradation of the vasoactive molecule bradykinin. Plasma-derived C1-esterase inhibitor concentrate is a well-established treatment option of hereditary and acquired complement C1-esterase inhibitor deficiency, which are also mediated by an increased level of bradykinin resulting in recurrent angioedema. We here present a case of severe angiotensin converting enzyme-inhibitor related angioedema (ACEi-AE) of the hypopharynx that completely resolved rapidly after the infusion of plasma-derived C1-inhibitor concentrate adding to the sparse reports in the existing literature. PMID:27123347

  5. [Acquired angioedema with C1-INH deficiency and accompanying chronic spontaneous urticaria in a patient with chronic lymphatic B cell leukemia].

    PubMed

    Klossowski, N; Braun, S A; von Gruben, V; Losem, C; Plewe, D; Homey, B; Meller, S

    2015-10-01

    Acquired angioedema due to C1 inhibitor deficiency (C1-INH-AAE) is characterized by recurrent edema of the subcutaneous and/or submucosal tissue without wheals and negative family history of angioedema. Here, we present the case of a patient with a chronic lymphatic B cell leukemia who suffered from both C1-INH-AAE and chronic spontaneous urticaria. Oral corticosteroids, antihistamines, and the anti-IgE antibody omalizumab were applied to treat the chronic urticaria in combination with the plasma-derived C1 esterase inhibitor concentrate Berinert® and the bradykinin B2 receptor antagonist icatibant, but the symptoms did not improved significantly. Thus, polychemotherapy targeting the slow-growing lymphoproliferative disease including rituximab was initiated, which resulted in remission of both the urticaria and the angioedema. PMID:26335859

  6. A common neoepitope is created when the reactive center of C1-inhibitor is cleaved by plasma kallikrein, activated factor XII fragment, C1 esterase, or neutrophil elastase.

    PubMed Central

    de Agostini, A; Patston, P A; Marottoli, V; Carrel, S; Harpel, P C; Schapira, M

    1988-01-01

    The reactive center of C1-inhibitor, a plasma protease inhibitor that belongs to the serpin superfamily, is located on a peptide loop which is highly susceptible to proteolytic cleavage. With plasma kallikrein, C1s and beta-Factor XIIa, this cleavage occurs at the reactive site residue P1 (Arg444); with neutrophil elastase, it takes place near P1, probably at residue P3 (Val442). After these cleavages, C1-inhibitor is inactivated and its conformation is modified. Moreover, in vivo, cleaved C1-inhibitor is removed from the blood stream more rapidly than the intact serpin, which suggests that proteolysis unmasks sites responsible for cellular recognition and the uptake of the cleaved inhibitor. In the study reported here, we show, using an MAb, that an identical neoepitope is created on C1-inhibitor after the cleavage of its exposed loop by plasma kallikrein, C1s, beta-Factor XIIa, and by neutrophil elastase. Images PMID:2457036

  7. CpG mutations in the reactive site of human C1 inhibitor.

    PubMed

    Skriver, K; Radziejewska, E; Silbermann, J A; Donaldson, V H; Bock, S C

    1989-02-25

    C1 inhibitor plays an important role in the regulation of vascular permeability through its ability to inactivate enzymes which release polypeptide kinins. Dysfunctional C1 inhibitor molecules are present in the plasma of affected members of the Da and Ri hereditary angioneurotic edema kindreds. We constructed genomic libraries from Da and Ri patient DNAs which had been cleaved with BclI to generate a fragment containing 21 kilobases of the C1 inhibitor locus. C1 inhibitor gene-containing recombinants originating from mutant Da and Ri alleles were differentiated from those derived from normal alleles by linkage analysis using the intragenic HgiAI restriction fragment length polymorphism. Nucleotide sequencing of the complete protein-coding regions of the mutant alleles identified two different mutations in a CpG dinucleotide corresponding to the first two bases of arginine codon 444. These single base mutations changed the identity of the functionally critical P1 reactive site residue from arginine to cysteine (Da) or histidine (Ri). The additional cysteine residue in C1 inhibitor Da suggests how it is covalently bound to albumin in plasma. The presence of CpG dinucleotides in the codons specifying the P1 arginines of C1 inhibitor and antithrombin III explains the high incidence of histidine and cysteine substitutions observed among dysfunctional mutants of these serine protease inhibitors. PMID:2563376

  8. Treatment of hereditary angioedema with plasma-derived C1 inhibitor

    PubMed Central

    Prematta, Michael J; Prematta, Tracy; Craig, Timothy J

    2008-01-01

    Background: Plasma-derived C1 inhibitor (C1-INH) concentrate is a treatment option for acute hereditary angioedema (HAE) attacks and is considered the standard-of-care in many countries, although it is not yet available in the United States. Studies are still being conducted to establish its safety and efficacy as required by the FDA. Objective: To review the medical literature to determine if C1-INH concentrate is a safe and effective treatment for acute HAE attacks. Methods: The following keywords were searched in PubMed and OVID: C1 esterase inhibitor, C1-inhibitor, C1 inhibitor, and hereditary angioedema treatment. English-language articles were searched from 1966 to the present to look for studies demonstrating the efficacy and the safety of C1-INH concentrate. Results: The English-language literature search revealed several studies showing significantly improved relief of HAE symptoms with the administration of C1-INH concentrate – many studies demonstrated some improvement of symptoms within 30 minutes. Side effects have been similar to placebo, and no proven cases of viral transmission have occurred in over 20 years. Conclusion: C1-INH concentrate appears to be a very safe and effective treatment option for HAE. PMID:19209279

  9. Unexpected postpartum hemorrhage due to an acquired factor VIII inhibitor.

    PubMed

    Paidas, Michael J; Hossain, Nazli

    2014-09-01

    Unexplained postpartum hemorrhage (PPH) refractory to standard hemostatic measures should trigger a heightened clinical suspicion of an acquired bleeding disorder. When hemostatic medical interventions and surgical procedures fail to control the bleeding, then significant postoperative blood loss, debilitating morbidity, loss of fertility, and death may occur. In the setting of an autoantibody inhibitor to factor VIII (FVIII), control of life-threatening PPH and avoidance of subsequent bleeding episodes depends on a timely and accurate diagnosis, prompt hemostatic treatment and eradication of FVIII inhibitors, and appropriate long-term patient care and management. Acquired postpartum hemophilia due to a FVIII inhibitor is a rare cause of PPH; however, delayed treatment can lead to increased maternal morbidity and mortality. Acquired FVIII inhibitors also pose an emerging bleeding threat to the neonate as a result of possible transplacental transfer of FVIII autoantibodies to the fetus during the last trimester of pregnancy. The purpose of this review is to increase awareness among hematologists and obstetricians/gynecologists regarding the occurrence of FVIII neutralizing autoantibodies as a cause of PPH, and emphasize the importance of collaboration between obstetrician/gynecologists and hematology specialists to optimize the diagnostic evaluation, treatment, and long-term management of women who experience PPH due to an acquired FVIII inhibitor. PMID:24338123

  10. Inactivation of factor XII active fragment in normal plasma. Predominant role of C-1-inhibitor.

    PubMed

    de Agostini, A; Lijnen, H R; Pixley, R A; Colman, R W; Schapira, M

    1984-06-01

    To define the factors responsible for the inactivation of the active fragment derived from Factor XII (Factor XIIf ) in plasma, we studied the inactivation kinetics of Factor XIIf in various purified and plasma mixtures. We also analyzed the formation of 125I-Factor XIIf -inhibitor complexes by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). In purified systems, the bimolecular rate constants for the reactions of Factor XIIf with C-1-inhibitor, alpha 2-antiplasmin, and antithrombin III were 18.5, 0.91, and 0.32 X 10(4) M-1 min-1, respectively. Furthermore, SDS-PAGE analysis revealed that 1:1 stoichiometric complexes were formed between 125I-Factor XIIf and each of these three inhibitors. In contrast, kinetic and SDS-PAGE studies indicated that Factor XIIf did not react with alpha 1-antitrypsin or alpha 2-macroglobulin. The inactivation rate constant of Factor XIIf by prekallikrein-deficient plasma was 14.4 X 10(-2) min-1, a value that was essentially identical to the value predicted from the studies in purified systems (15.5 X 10(-2) min-1). This constant was reduced to 1.8 X 10(-2) min-1 when Factor XIIf was inactivated by prekallikrein-deficient plasma that had been immunodepleted (less than 5%) of C-1-inhibitor. In addition, after inactivation in normal plasma, 74% of the active 125I-Factor XIIf was found to form a complex with C-1-inhibitor, whereas 26% of the enzyme formed complexes with alpha 2-antiplasmin and antithrombin III. Furthermore, 42% of the labeled enzyme was still complexed with C-1-inhibitor when 125I-Factor XII was inactivated in hereditary angioedema plasma that contained 32% of functional C-1-inhibitor. This study quantitatively demonstrates the dominant role of C-1-inhibitor in the inactivation of Factor XIIf in the plasma milieu. PMID:6725552

  11. Presence of C1-Inhibitor Polymers in a Subset of Patients Suffering from Hereditary Angioedema

    PubMed Central

    Madsen, Daniel Elenius; Hansen, Søren; Gram, Jørgen; Bygum, Anette; Drouet, Christian; Sidelmann, Johannes Jakobsen

    2014-01-01

    Hereditary angioedema (HAE) is a potentially life-threatening disease caused by mutations in the gene encoding the serine protease inhibitor (serpin) C1 inhibitor (C1-inh). The mutations cause decreased functional plasma levels of C1-inh, which triggers unpredictable recurrent edema attacks. Subjects suffering from HAE have been classified in type I patients with decreased functional and antigenic levels of C1-inh, and type II patients with decreased functional but normal antigenic C1-inh levels. However, a few reports have demonstrated that some mutations cause C1-inh polymerization in vitro, and it is speculated that C1-inh polymers may exist in patient plasma, challenging the current classification of HAE patients. To investigate the presence of C1-inh polymers in patient plasma samples, we developed an immunological method, where monoclonal antibodies produced against polymerized C1-inh were applied in native PAGE western blotting. Using this approach we analyzed genuine plasma samples from 31 Danish HAE families, and found that plasma samples from three genotypically distinct HAE type I families (classified upon C1-inh plasma concentrations) contained C1-inh polymers. Identical C1-inh polymerization phenotypes were observed in four affected family members from one of these families. Genotyping of the families revealed that the polymerogenic mutations of two families were located in proximity to the reactive center loop insertion site in C1-inh (p.Ile271Thr and p.Ser258_Pro260del),and one mutation affected helix C (p.Thr167Asn). In conclusion, we demonstrate that C1-inh polymers are present in the plasma of a subgroup of HAE type I patients. PMID:25369003

  12. Contact system activation in patients with HAE and normal C1 inhibitor function.

    PubMed

    Ghannam, Arije; Defendi, Federica; Charignon, Delphine; Csopaki, Françoise; Favier, Bertrand; Habib, Mohammed; Cichon, Sven; Drouet, Christian

    2013-11-01

    In addition to hereditary angioedema (HAE) with C1 inhibitor (C1INH) deficiency, a type of HAE with dominant inheritance and normal C1INH function (HAE with normal C1INH) has been described. This relates to contact phase activation with exaggerated kinin formation, and mutations in the coagulation factor XII gene have been identified in some affected families, but the cause of the disease has remained elusive in a majority of families. Several triggering factors are responsible for developing kinin forming system, with participation of endothelium and mast cell component. Angioedema conditions meet the accumulation of kinins with failed kinin catabolism. PMID:24176216

  13. C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease.

    PubMed

    Beinrohr, László; Harmat, Veronika; Dobó, József; Lörincz, Zsolt; Gál, Péter; Závodszky, Péter

    2007-07-20

    C1 inhibitor, a member of the serpin family, is a major down-regulator of inflammatory processes in blood. Genetic deficiency of C1 inhibitor results in hereditary angioedema, a dominantly inheritable, potentially lethal disease. Here we report the first crystal structure of the serpin domain of human C1 inhibitor, representing a previously unreported latent form, which explains functional consequences of several naturally occurring mutations, two of which are discussed in detail. The presented structure displays a novel conformation with a seven-stranded beta-sheet A. The unique conformation of the C-terminal six residues suggests its potential role as a barrier in the active-latent transition. On the basis of surface charge pattern, heparin affinity measurements, and docking of a heparin disaccharide, a heparin binding site is proposed in the contact area of the serpin-proteinase encounter complex. We show how polyanions change the activity of the C1 inhibitor by a novel "sandwich" mechanism, explaining earlier reaction kinetic and mutagenesis studies. These results may help to improve therapeutic C1 inhibitor preparations used in the treatment of hereditary angioedema, organ transplant rejection, and heart attack. PMID:17488724

  14. Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of C1 inhibitor therapy.

    PubMed

    Kaplan, Allen P

    2010-11-01

    A functional abnormality of C1 inhibitor (C1INH) is present in types I and II hereditary angioedema (HAE), and normal C1INH may be rendered ineffective in the newly described type III HAE. C1INH inhibits factor XIIa, factor XII fragment (XIIf), kallikrein, and plasmin. Thus, in its absence, there is marked activation of the bradykinin-forming cascade resulting in severe angioedema. Factor XII may autoactivate on binding to endothelial cell surface gC1qR (receptor for the globular heads of C1q) thus initiating the cascade. Alternatively, stimuli that activate endothelial cells may liberate (or express at the cell surface) heat shock protein 90 or the enzyme prolylcarboxypeptidase, either of which can interact with the prekallikrein-high-molecular-weight kininogen complex to convert prekallikrein to kallikrein stoichiometrically. The kallikrein produced can cleave high-molecular-weight kininogen to produce bradykinin and also recruit factor XII by enzymatically activating it. Patients with type I or II HAE have mutant C1INH so that control of C1 activation is lost. Autoactivation of C1r in the absence of C1INH leads to C1s activation followed by C4 cleavage and depletion. An attack of swelling is accompanied by conversion of factor XIIa to factor XIIf and further enzymatic activation of C1r so that C4 levels drop further and C2 is depleted. New therapies for HAE focus on the bradykinin-forming cascade and include a kallikrein inhibitor and a bradykinin B-2 receptor antagonist in addition to administration of purified C1INH. PMID:20889195

  15. Purified human C1-esterase inhibitor is safe in acute relapses of neuromyelitis optica

    PubMed Central

    Levy, Michael

    2014-01-01

    Objective: To minimize complement-mediated damage in acute relapses of neuromyelitis optica (NMO) by adding treatment with a complement inhibitor, purified C1-esterase inhibitor, to the current standard of care (high-dose glucocorticoids). Method: We conducted an open-label phase 1b safety and proof-of-concept trial in 10 patients with NMO–immunoglobulin G seropositive NMO or NMO spectrum disease (NMOSD) who presented with acute transverse myelitis and/or optic neuritis. In addition to treating with 1 g of daily IV methylprednisolone, we infused 2,000 units of C1-esterase inhibitor daily for 3 days, beginning on day 1 of hospitalization. The primary outcome measure was safety, and the secondary efficacy measure was change in Expanded Disability Status Scale (EDSS) scores. Results: Ten patients with NMO/NMOSD were enrolled, 7 of whom presented with acute transverse myelitis and 3 with acute optic neuritis. C1-esterase inhibitor proved to be safe in all 10 patients, with no serious adverse events recorded. There were no thromboembolic events or related lab abnormalities in any of the subjects. EDSS scores dropped from a median of 4.5 on admission to 4.0 on discharge and then down to 2.5 on 30-day follow-up. All but 1 patient returned to preattack EDSS or better and only 2 patients required escalation to plasmapheresis. Conclusions: C1-esterase inhibitor is a safe add-on therapy for patients with NMO/NMOSD presenting with acute transverse myelitis and optic neuritis. Preliminary evidence suggests a promising benefit with C1-esterase inhibitor in reducing neurologic damage and improving outcomes. A placebo-controlled trial is necessary to confirm these findings. Classification of evidence: This study provides Class IV evidence that for patients with NMO with acute transverse myelitis or optic neuritis, C1-esterase inhibitor is safe and improves disability. PMID:25340061

  16. Degradation of C1-inhibitor by plasmin: implications for the control of inflammatory processes.

    PubMed Central

    Wallace, E. M.; Perkins, S. J.; Sim, R. B.; Willis, A. C.; Feighery, C.; Jackson, J.

    1997-01-01

    BACKGROUND: A correct balance between protease and inhibitor activity is critical in the maintenance of homoeostasis; excessive activation of enzyme pathways is frequently associated with inflammatory disorders. Plasmin is an enzyme ubiquitously activated in inflammatory disorder, and C1-inhibitor (C1-Inh) is a pivotal inhibitor of protease activity, which is particularly important in the regulation of enzyme cascades generated in plasma. The nature of the interaction between plasmin and C1-Inh is poorly understood. MATERIALS AND METHODS: C1-Inh was immunoadsorbed from the plasma of normal individuals (n = 21), from that of patients with systemic lupus erythematosus (n = 18) or adult respiratory distress syndrome (n = 9), and from the plasma and synovial fluid of patients with rheumatoid arthritis (n = 18). As plasmin is a putative enzyme responsible for C1-Inh was examined using SDS-PAGE. In addition, peptides cleaved from C1-Inh by plasmin were isolated and sequenced and the precise cleavage sites determined from the known primary sequence of C1-Inh. Homology models of C1-Inh were then constructed. RESULTS: Increased levels of cleaved and inactivated C1-Inh were found in each of the inflammatory disorders examined. Through SDS-PAGE analysis it was shown that plasmin rapidly degraded C1-Inh in vitro. The pattern of C1-Inh cleavage seen in vivo in patients with inflammatory disorders and that produced in vitro following incubation with plasmin were very similar. Homology models of C1-Inh indicate that the majority of the plasmin cleavage sites are adjacent to the reactive site of the inhibitor. CONCLUSIONS: This study suggests that local C1-Inh degradation by plasmin may be a central and critical event in the loss of protease inhibition during inflammation. These findings have important implications for our understanding of pathogenic mechanisms in inflammation and for the development of more effectively targeted therapeutic regimes. These findings may also explain

  17. Oversulfated chondroitin sulfate inhibits the complement classical pathway by potentiating C1 inhibitor.

    PubMed

    Zhou, Zhao-Hua; Rajabi, Mohsen; Chen, Trina; Karnaukhova, Elena; Kozlowski, Steven

    2012-01-01

    Oversulfated chondroitin sulfate (OSCS) has become the subject of multidisciplinary investigation as a non-traditional contaminant in the heparin therapeutic preparations that were linked to severe adverse events. In this study, it was found that OSCS inhibited complement fixation on bacteria and bacterial lysis mediated by the complement classical pathway. The inhibition of complement by OSCS is not due to interference with antibody/antigen interaction or due to consumption of C3 associated with FXII-dependent contact system activation. However, OSCS complement inhibition is dependent on C1 inhibitor (C1inh) since the depletion of C1inh from either normal or FXII-deficient complement plasma prevents OSCS inhibition of complement activity. Surface plasmon resonance measurements revealed that immobilized C1inhibitor bound greater than 5-fold more C1s in the presence of OSCS than in presence of heparin. Although heparin can also inhibit complement, OSCS and OSCS contaminated heparin are more potent inhibitors of complement. Furthermore, polysulfated glycosaminoglycan (PSGAG), an anti-inflammatory veterinary medicine with a similar structure to OSCS, also inhibited complement in the plasma of dogs and farm animals. This study provides a new insight that in addition to the FXII-dependent activation of contact system, oversulfated and polysulfated chondroitin-sulfate can inhibit complement activity by potentiating the classical complement pathway regulator C1inh. This effect on C1inh may play a role in inhibiting inflammation as well as impacting bacterial clearance. PMID:23077587

  18. Rhucin, a recombinant C1 inhibitor for the treatment of hereditary angioedema and cerebral ischemia.

    PubMed

    Longhurst, Hilary

    2008-03-01

    Pharming NV and Esteve are developing Rhucin, a recombinant human C1 esterase inhibitor. Rhucin is currently undergoing phase III clinical trials in North America and is awaiting regulatory approval in Western Europe for the treatment of prophylactic and acute hereditary angioedema. Pharming is also investigating Rhucin for the potential treatment of cerebral ischemic injury. PMID:18311668

  19. New insight into the effects of heparinoids on complement inhibition by C1-inhibitor.

    PubMed

    Poppelaars, F; Damman, J; de Vrij, E L; Burgerhof, J G M; Saye, J; Daha, M R; Leuvenink, H G; Uknis, M E; Seelen, M A J

    2016-06-01

    Complement activation is of major importance in numerous pathological conditions. Therefore, targeted complement inhibition is a promising therapeutic strategy. C1-esterase inhibitor (C1-INH) controls activation of the classical pathway (CP) and the lectin pathway (LP). However, conflicting data exist on inhibition of the alternative pathway (AP) by C1-INH. The inhibitory capacity of C1-INH for the CP is potentiated by heparin and other glycosaminoglycans, but no data exist for the LP and AP. The current study investigates the effects of C1-INH in the presence or absence of different clinically used heparinoids on the CP, LP and AP. Furthermore, the combined effects of heparinoids and C1-INH on coagulation were investigated. C1-INH, heparinoids or combinations were analysed in a dose-dependent fashion in the presence of pooled serum. Functional complement activities were measured simultaneously using the Wielisa(®) -kit. The activated partial thrombin time was determined using an automated coagulation analyser. The results showed that all three complement pathways were inhibited significantly by C1-INH or heparinoids. Next to their individual effects on complement activation, heparinoids also enhanced the inhibitory capacity of C1-INH significantly on the CP and LP. For the AP, significant potentiation of C1-INH by heparinoids was found; however, this was restricted to certain concentration ranges. At low concentrations the effect on blood coagulation by combining heparinoids with C1-INH was minimal. In conclusion, our study shows significant potentiating effects of heparinoids on the inhibition of all complement pathways by C1-INH. Therefore, their combined use is a promising and a potentially cost-effective treatment option for complement-mediated diseases. PMID:26874675

  20. Complement Blockade with a C1 Esterase Inhibitor in Paroxysmal Nocturnal Hemoglobinuria

    PubMed Central

    DeZern, Amy E.; Uknis, Marc; Yuan, Xuan; Mukhina, Galina L; Varela, Juan; Saye, JoAnne; Pu, Jeffrey; Brodsky, Robert A.

    2014-01-01

    Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, hematopoietic stem cell disorder that manifests with a complement-mediated hemolytic anemia, bone marrow failure and a propensity for thrombosis. These patients experience both intra- and extravascular hemolysis in the context of underlying complement activation. Currently eculizumab effectively blocks the intravascular hemolysis PNH. There remains an unmet clinical need for a complement inhibitor with activity early in the complement cascade to block complement at the classical and alternative pathways. C1 esterase inhibitor (C1INH) is an endogenous human plasma protein that has broad inhibitory activity in the complement pathway through inhibition of the classical pathway by binding C1r and C1s and inhibits the mannose-binding lectin-associated serine proteases in the lectin pathway. In this study, we show that commercially available plasma derived C1INH prevents lysis induced by the alternative complement pathway, of PNH erythrocytes in human serum. Importantly, C1INH was able to block the accumulation of C3 degradation products on CD55 deficient erythrocytes from PNH patient on eculizumab therapy. This could suggest a role for inhibition of earlier phases of the complement cascade than that currently inhibited by eculizumab for incomplete or non-responders to that therapy. PMID:25034232

  1. [Hereditary angioneurotic edema: a molecular disease caused by a defect in the O-glycosylation of C1 esterase inhibitor (C1-INH)].

    PubMed

    Ollier-Hartmann, M P; Strecker, G; Montreuil, J; Hartmann, L

    1984-01-01

    A quantitative and qualitative study of neutral and aminosaccharides in C 1-esterase inhibitor (C 1-INH), protein of the complement system, was performed. We observe a mixed glycosylation of the molecule with an N-glycosylated: O-glycosylated chain ratio of 1: 4. The loss of the inhibitory activity of the molecule in hereditary angioedema (O ANH) is associated with an O-glycosylation deficiency which differs according to the two molecular variants: C 1-INH (1 A) and C 1-INH (II) previously described. PMID:6440668

  2. Transinhibition of C1 inhibitor synthesis in type I hereditary angioneurotic edema.

    PubMed Central

    Kramer, J; Rosen, F S; Colten, H R; Rajczy, K; Strunk, R C

    1993-01-01

    To ascertain the mechanism for decreased synthesis of C1 inhibitor (C1 INH) in certain patients with the autosomal dominant disorder hereditary angioneurotic edema, we studied expression of C1 INH in fibroblasts in which the mutant and wild type mRNA and protein could be distinguished because of deletion of exon 7 (delta Ex7). In the HANE delta Ex7 cells, the amount of wild type mRNA (2.1 kb) was expressed at 52 +/- 2% (n = 5) of normal, whereas the mutant mRNA was 17 +/- 1% (n = 5) of normal. Rates of synthesis of both wild type and mutant proteins (11 +/- 3 and 3 +/- 1% of normal, respectively) were lower than predicted from the mRNA levels. There was no evidence of increased C1 INH protein catabolism. These data indicate that there are multiple levels of control of C1 INH synthesis in type I hereditary angioneurotic edema. Pretranslational regulation results in < 50% of the mutant truncated 1.9-kb mRNA. In addition, translational regulation results in decreased synthesis of both wild type and mutatn C1 INH proteins. These data suggest a transinhibition of wild type C1 INH translation by mutant mRNA and/or protein. Images PMID:8450054

  3. Treatment response after repeated administration of C1 esterase inhibitor for successive acute hereditary angioedema attacks.

    PubMed

    Craig, Timothy J; Bewtra, Againdra K; Hurewitz, David; Levy, Robyn; Janss, Gerti; Jacobson, Kraig W; Packer, Flint; Bernstein, Jonathan A; Rojavin, Mikhail A; Machnig, Thomas; Keinecke, Heinz-Otto; Wasserman, Richard L

    2012-01-01

    Placebo-controlled studies established the efficacy of replacement therapy with C1 esterase inhibitor (C1-INH) concentrate for treating single acute hereditary angioedema (HAE) attacks, but only limited data from prospective studies are available on repeated treatment of successive HAE attacks. This study evaluates the association between repeated treatments with 20 U/kg of C1-INH concentrate (Berinert; CSL Behring, Marburg, Germany) for HAE attacks at any body location and treatment response. In a post hoc analysis of an open-label extension study (International Multicenter Prospective Angioedema C1-INH Trial [I.M.P.A.C.T.2]), the association between repeated treatment with C1-INH and times to onset of symptom relief and complete resolution of HAE symptoms was assessed in patients who were treated for at least 15 attacks by linear regression on the ordinal attack number. Eighteen patients received C1-INH concentrate for at least 15 HAE attacks over a mean duration of 34 months. Demographic and baseline characteristics of these patients were similar to those of all patients in the study. The distribution of body locations and the intensity of HAE attacks were similar for each of the first 15 attacks and subsequent attacks. The extent of previous use of C1-INH concentrate had no effect on the time to onset of symptom relief, the time to complete resolution of HAE symptoms, or the time between attacks treated with C1-INH concentrate; the median of individual linear regression coefficients was not statistically significantly different from 0. Treatment with 20 U/kg of C1-INH concentrate provided consistent treatment response in patients treated for multiple successive HAE attacks at any body location. (Clinicaltrials.gov identifier: NCT00292981). PMID:22856636

  4. C1 Inhibitor Limits Organ Injury and Prolongs Survival in Swine Subjected to Battlefield Simulated Injury.

    PubMed

    Campbell, James C; Li, Yansong; van Amersfoort, Edwin; Relan, Anurag; Dubick, Michael; Sheppard, Forest; Pusateri, Anthony; Niemeyer, Debra; Tsokos, George C; Dalle Lucca, Jurandir J

    2016-09-01

    Complement system activation is recognized as a deleterious component of the mammalian physiological response to traumatic injury with severe hemorrhage (TH). Female Yorkshire swine were subjected to a simulated austere prehospital battlefield scenario. Each animal underwent controlled hemorrhage of 22 mL/kg at 100 mL/min rate for approximately 10 min followed by soft tissue injury, femur fracture, and spleen injury. Subsequent blood loss was uncontrolled. Twenty-eight minutes postinjury the animals were randomized into treatment or no treatment with recombinant human C1 esterase inhibitor (C1INH) (500 IU/kg, n = 11) and into receiving or not permissive hypotensive resuscitation (n = 14) with infusion of 45 mL/kg lactated Ringer's solution (2× blood lost). Observation and animal maintenance continued for 6 h at which time the animals had either expired or were euthanized. Heart, lung, and small intestine tissue samples were collected. Pharmacokinetic, hemodynamic, and metabolic parameters as well as survival time, plasma complement activity and tissue deposition, cytokine levels, and tissue injury were determined. We found that administration of C1INH protected tissues from damage, reduced the levels of inflammatory cytokines, and improved blood chemistry. Immunohistochemical analyses revealed that C1INH administration following TH markedly reduced complement activation and deposition in tissues. Importantly, C1INH administration prolonged survival of animals particularly in those which received resuscitation fluid infusion. Our data urge early administration of C1INH to limit organ damage and prolong survival of those injured in the battlefield. PMID:27405065

  5. C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation

    PubMed Central

    Albert-Weissenberger, Christiane; Mencl, Stine; Schuhmann, Michael K.; Salur, Irmak; Göb, Eva; Langhauser, Friederike; Hopp, Sarah; Hennig, Nelli; Meuth, Sven G.; Nolte, Marc W.; Sirén, Anna-Leena; Kleinschnitz, Christoph

    2014-01-01

    Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings. PMID:25249935

  6. C1 Esterase Inhibitor Reduces Lower Extremity Ischemia/Reperfusion Injury and Associated Lung Damage

    PubMed Central

    Duehrkop, Claudia; Banz, Yara; Spirig, Rolf; Miescher, Sylvia; Nolte, Marc W.; Spycher, Martin; Smith, Richard A. G.; Sacks, Steven H.; Rieben, Robert

    2013-01-01

    Background Ischemia/reperfusion injury of lower extremities and associated lung damage may result from thrombotic occlusion, embolism, trauma, or surgical intervention with prolonged ischemia and subsequent restoration of blood flow. This clinical entity is characterized by high morbidity and mortality. Deprivation of blood supply leads to molecular and structural changes in the affected tissue. Upon reperfusion inflammatory cascades are activated causing tissue injury. We therefore tested preoperative treatment for prevention of reperfusion injury by using C1 esterase inhibitor (C1 INH). Methods and Findings Wistar rats systemically pretreated with C1 INH (n = 6), APT070 (a membrane-targeted myristoylated peptidyl construct derived from human complement receptor 1, n = 4), vehicle (n = 7), or NaCl (n = 8) were subjected to 3h hind limb ischemia and 24h reperfusion. The femoral artery was clamped and a tourniquet placed under maintenance of a venous return. C1 INH treated rats showed significantly less edema in muscle (P<0.001) and lung and improved muscle viability (P<0.001) compared to controls and APT070. C1 INH prevented up-regulation of bradykinin receptor b1 (P<0.05) and VE-cadherin (P<0.01), reduced apoptosis (P<0.001) and fibrin deposition (P<0.01) and decreased plasma levels of pro-inflammatory cytokines, whereas deposition of complement components was not significantly reduced in the reperfused muscle. Conclusions C1 INH reduced edema formation locally in reperfused muscle as well as in lung, and improved muscle viability. C1 INH did not primarily act via inhibition of the complement system, but via the kinin and coagulation cascade. APT070 did not show beneficial effects in this model, despite potent inhibition of complement activation. Taken together, C1 INH might be a promising therapy to reduce peripheral ischemia/reperfusion injury and distant lung damage in complex and prolonged surgical interventions requiring tourniquet application

  7. Suppression of complement regulatory protein C1 inhibitor in vascular endothelial activation by inhibiting vascular cell adhesion molecule-1 action

    SciTech Connect

    Zhang, Haimou; Qin, Gangjian; Liang, Gang; Li, Jinan; Chiu, Isaac; Barrington, Robert A.; Liu, Dongxu . E-mail: dxliu001@yahoo.com

    2007-07-13

    Increased expression of adhesion molecules by activated endothelium is a critical feature of vascular inflammation associated with the several diseases such as endotoxin shock and sepsis/septic shock. Our data demonstrated complement regulatory protein C1 inhibitor (C1INH) prevents endothelial cell injury. We hypothesized that C1INH has the ability of an anti-endothelial activation associated with suppression of expression of adhesion molecule(s). C1INH blocked leukocyte adhesion to endothelial cell monolayer in both static assay and flow conditions. In inflammatory condition, C1INH reduced vascular cell adhesion molecule (VCAM-1) expression associated with its cytoplasmic mRNA destabilization and nuclear transcription level. Studies exploring the underlying mechanism of C1INH-mediated suppression in VCAM-1 expression were related to reduction of NF-{kappa}B activation and nuclear translocation in an I{kappa}B{alpha}-dependent manner. The inhibitory effects were associated with reduction of inhibitor I{kappa}B kinase activity and stabilization of the NF-{kappa}B inhibitor I{kappa}B. These findings indicate a novel role for C1INH in inhibition of vascular endothelial activation. These observations could provide the basis for new therapeutic application of C1INH to target inflammatory processes in different pathologic situations.

  8. Purification and characterization of two functionally distinct forms of C1 inhibitor from a patient with angioedema.

    PubMed Central

    Curd, J G; Yelvington, M; Ziccardi, R J; Mathison, D A; Griffin, J H

    1981-01-01

    A minority of patients with hereditary angioedema (HAE) have normal concentrations of a dysfunctional C1 inhibitor protein (C1INH) in their plasmas. We purified C1INH from the plasmas of one such patient before and during treatment with the anabolic steroid stanozolol. Both the pretreatment plasma and plasma obtained during stanozolol treatment contained varying amounts of two extremely similar C1INH proteins that were functionally distinct. The pretreatment plasma contained primarily (94%) dysfunctional C1INH that did not inactivate or complex with either purified C1s, activated Hageman factor, or kallikrein and small amounts (6%) of functionally normal C1INH. Stanozolol treatment increased the plasma concentrations of both of these proteins as well as the proportion (23%) of functional C1INH in the plasma. The purified dysfunctional and functional C1INHs had identical or nearly identical molecular sizes, charges, amino acid compositions, and amino sugar contents, and could not be distinguished physicochemically from each other or from normal C1INH. From these studies of purified C1INH proteins we concluded that HAE associated with dysfunctional C1INH is due to a defect at the structural locus for one C1INH gene and that both the dysfunctional C1INH gene and the normal C1INH gene products are present in the plasma of the affected subject. Treatment with stanozolol comparably increased the synthesis of both C1INH proteins. The disproportionate rise in the level of the normal C1INH protein is consistent with the view that it is more rapidly catabolized as a consequence of its interaction with the proteases it inactivates. PMID:6976242

  9. Synthesis of C1 inhibitor in fibroblasts from patients with type I and type II hereditary angioneurotic edema.

    PubMed Central

    Kramer, J; Katz, Y; Rosen, F S; Davis, A E; Strunk, R C

    1991-01-01

    Patients with hereditary angioneurotic edema (HANE) have serum levels of functionally active inhibitor of the first component of complement (C1 INH) between 5 and 30% of normal, instead of the 50% expected from the single normal allele. Increases in rates of catabolism have been documented in patients with HANE and certainly account for some of decrease in C1 INH level. A possible role for a decrease in synthesis of C1 INH in producing serum levels of C1 INH below the expected 50% of normal has not been well studied. We studied the synthesis of C1 INH in skin fibroblast lines, which produce easily detectable amounts of C1 INH. In type I HANE cells, C1 INH synthesis was 19.6 +/- 4.0% (mean +/- SD) of normal, much less than the 50% predicted. In type II HANE cells, the total amount of C1 INH synthesis (functional and dysfunctional) was 98.9 +/- 17% of normal; the functional protein comprised 43% of the total. Thus, type II HANE cells synthesized functional C1 INH at a much greater rate than for the type I cells. In both type I and II HANE cells, amounts of steady-state C1 INH mRNA levels paralleled rates of C1 INH synthesis, indicating that control of C1 INH synthesis occurred at pretranslational levels. Both type I and type II fibroblasts synthesized normal amounts of C1r and C1s. These data suggest that the lower than expected amounts of functionally active C1 INH in type I HANE may be due, in part, to a decrease in rate of synthesis of the protein, and that the expressions of the normal C1 INH allele in HANE is influenced by the type of abnormal allele present. Images PMID:1902490

  10. Angiotensin-converting enzyme inhibitors-induced angioedema treated by C1 esterase inhibitor concentrate (Berinert®): about one case and review of the therapeutic arsenal

    PubMed Central

    Lipski, Samuel Michael; Casimir, Georges; Vanlommel, Martine; Jeanmaire, Mathieu; Dolhen, Pierre

    2015-01-01

    Key Clinical Message C1 esterase inhibitor (Berinert®) is generally used to treat severe attack of hereditary angioedema. We describe here the case of a patient who presented with a severe angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) endangering her life. It could be successfully treated with that medicine. PMID:25767713

  11. Angiotensin-converting enzyme inhibitors-induced angioedema treated by C1 esterase inhibitor concentrate (Berinert®): about one case and review of the therapeutic arsenal.

    PubMed

    Lipski, Samuel Michael; Casimir, Georges; Vanlommel, Martine; Jeanmaire, Mathieu; Dolhen, Pierre

    2015-02-01

    C1 esterase inhibitor (Berinert®) is generally used to treat severe attack of hereditary angioedema. We describe here the case of a patient who presented with a severe angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) endangering her life. It could be successfully treated with that medicine. PMID:25767713

  12. Mutations analysis of C1 inhibitor coding sequence gene among Portuguese patients with hereditary angioedema.

    PubMed

    Martinho, A; Mendes, J; Simões, O; Nunes, R; Gomes, J; Dias Castro, E; Leiria-Pinto, P; Ferreira, M B; Pereira, C; Castel-Branco, M G; Pais, L

    2013-04-01

    Mutations that modify the amino acid sequence of C1-INH (except Val458Met) are associated with HAE. More than 200 different mutations scattering the entire C1-INH gene have been reported. The main objective of this study was to report the mutational findings in a HAE cohort of 138 Portuguese patients followed in specialized consultation all over the country. DNA was extracted from peripheral blood with QiaSymphony BioRobot (QIAGEN Portugal). The sequence reactions were performed by using a DNA sequencing kit (Big Dye terminator cycle sequencing v1.1/v3.1 from Applied Biosystems) and sequencing products were immediately submitted to direct sequencing on an Applied Biosystem 3130 DNA Analyser. DNA sequences were analyzed at four different stages. Raw data and sequence alignments of all 8 exons and intron-exon boundaries were performed for each patient individually with SeqScape software and using SERPING1 gene NG_009625 of 24,300 bp (12-March-2011) as reference sequence. Sequence comparisons among patients and controls were performed with software CodonCode Aligner v.3.7 from CodonCode Corp and with Geneious 4.5 from Biomatters Lda. A total of 94 point mutations were observed among patients, and 67% of them were located on exon 8. In addition, we noticed one not described stop codon at position c.1459 C>T in three different patients. Translation termination was also found on exon 3 and 7, as a result of mutations at positions c.481A>7, c.1174C>T. In this population, the prevalence of the missense mutation p.Arg444Cys was 39 out of 42. Mutational analysis revealed 22 different pathogenic mutations, of which 64% were not described on HAE database. Although identification of disease causing mutations is not necessary to establish HAE diagnosis, studies on gene expression and characterization of rearrangements in SERPING1 gene are suggested in order to get new insights on function and genetic tests of C1 inhibitor. PMID:23123409

  13. Recombinations between Alu repeat sequences that result in partial deletions within the C1 inhibitor gene.

    PubMed

    Ariga, T; Carter, P E; Davis, A E

    1990-12-01

    Genomic DNA sequence analysis was used to define the extent of deletions within the C1 inhibitor gene in two families with type I hereditary angioneurotic edema. Southern blot analysis initially indicated the presence of the partial deletions. One deletion was approximately 2 kb and included exon VII, whereas the other was approximately 8.5 kb and included exons IV-VI. Genomic libraries from an affected member of each family were constructed and clones containing the deletions were analyzed. Sequence analysis of the deletion joints of the mutants and corresponding regions of the normal gene in the two families demonstrated that both deletion joints resulted from recombination of two Alu repetitive DNA elements. Alu repeat sequences from introns VI and VII combined to make a novel Alu in family A, and Alu sequences in introns III and VI were spliced to make a new Alu in family B. The splice sites in the Alu sequences of both mutants were located in the left arm of the Alu element, and both recombination joints overlapped one of the RNA polymerase III promoter sequences. Because the involved Alu sequences, in both instances, were oriented in the same direction, unequal crossingover is the most likely mechanism to account for these mutations. PMID:2276734

  14. Peptide inhibitor of complement c1, a novel suppressor of classical pathway activation: mechanistic studies and clinical potential.

    PubMed

    Sharp, Julia A; Whitley, Pamela H; Cunnion, Kenji M; Krishna, Neel K

    2014-01-01

    The classical pathway of complement plays multiple physiological roles including modulating immunological effectors initiated by adaptive immune responses and an essential homeostatic role in the clearance of damaged self-antigens. However, dysregulated classical pathway activation is associated with antibody-initiated, inflammatory diseases processes like cold agglutinin disease, acute intravascular hemolytic transfusion reaction (AIHTR), and acute/hyperacute transplantation rejection. To date, only one putative classical pathway inhibitor, C1 esterase inhibitor (C1-INH), is currently commercially available and its only approved indication is for replacement treatment in hereditary angioedema, which is predominantly a kinin pathway disease. Given the variety of disease conditions in which the classical pathway is implicated, development of therapeutics that specifically inhibits complement initiation represents a major unmet medical need. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement. In vitro studies have demonstrated that these peptide inhibitors of complement C1 (PIC1) bind to the collagen-like region of the initiator molecule of the classical pathway, C1q. PIC1 binding to C1q blocks activation of the associated serine proteases (C1s-C1r-C1r-C1s) and subsequent downstream complement activation. Rational design optimization of PIC1 has resulted in the generation of a highly potent derivative of 15 amino acids. PIC1 inhibits classical pathway mediated complement activation in ABO incompatibility in vitro and inhibiting classical pathway activation in vivo in rats. This review will focus on the pre-clinical development of PIC1 and discuss its potential as a therapeutic in antibody-mediated classical pathway disease, specifically AIHTR. PMID:25202312

  15. Peptide Inhibitor of Complement C1, a Novel Suppressor of Classical Pathway Activation: Mechanistic Studies and Clinical Potential

    PubMed Central

    Sharp, Julia A.; Whitley, Pamela H.; Cunnion, Kenji M.; Krishna, Neel K.

    2014-01-01

    The classical pathway of complement plays multiple physiological roles including modulating immunological effectors initiated by adaptive immune responses and an essential homeostatic role in the clearance of damaged self-antigens. However, dysregulated classical pathway activation is associated with antibody-initiated, inflammatory diseases processes like cold agglutinin disease, acute intravascular hemolytic transfusion reaction (AIHTR), and acute/hyperacute transplantation rejection. To date, only one putative classical pathway inhibitor, C1 esterase inhibitor (C1-INH), is currently commercially available and its only approved indication is for replacement treatment in hereditary angioedema, which is predominantly a kinin pathway disease. Given the variety of disease conditions in which the classical pathway is implicated, development of therapeutics that specifically inhibits complement initiation represents a major unmet medical need. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement. In vitro studies have demonstrated that these peptide inhibitors of complement C1 (PIC1) bind to the collagen-like region of the initiator molecule of the classical pathway, C1q. PIC1 binding to C1q blocks activation of the associated serine proteases (C1s–C1r–C1r–C1s) and subsequent downstream complement activation. Rational design optimization of PIC1 has resulted in the generation of a highly potent derivative of 15 amino acids. PIC1 inhibits classical pathway mediated complement activation in ABO incompatibility in vitro and inhibiting classical pathway activation in vivo in rats. This review will focus on the pre-clinical development of PIC1 and discuss its potential as a therapeutic in antibody-mediated classical pathway disease, specifically AIHTR. PMID:25202312

  16. The comparative pathology of the glycosidase inhibitors swainsonine, castanospermine, calystegines A3, B2 and C1 in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To characterize and compare the toxicity and pathology of glycosidase inhibitors swainsonine, castanospermine, calystegine A3, calystegine B2 and calystegine C1, 48 Swiss Webster, male mice were randomly divided into 16 groups of 3 animals each. All mice were implanted with subcutaneous osmotic min...

  17. Human C1-Inhibitor Suppresses Malaria Parasite Invasion and Cytoadhesion via Binding to Parasite Glycosylphosphatidylinositol and Host Cell Receptors.

    PubMed

    Mejia, Pedro; Diez-Silva, Monica; Kamena, Faustin; Lu, Fengxin; Fernandes, Stacey M; Seeberger, Peter H; Davis, Alvin E; Mitchell, James R

    2016-01-01

    Plasmodium falciparum-induced severe malaria remains a continuing problem in areas of endemicity, with elevated morbidity and mortality. Drugs targeting mechanisms involved in severe malaria pathology, including cytoadhesion of infected red blood cells (RBCs) to host receptors and production of proinflammatory cytokines, are still necessary. Human C1-inhibitor (C1INH) is a multifunctional protease inhibitor that regulates coagulation, vascular permeability, and inflammation, with beneficial effects in inflammatory disease models, including septic shock. We found that human C1INH, at therapeutically relevant doses, blocks severe malaria pathogenic processes by 2 distinct mechanisms. First, C1INH bound to glycan moieties within P. falciparum glycosylphosphatidylinositol (PfGPI) molecules on the parasite surface, inhibiting parasite RBC invasion and proinflammatory cytokine production by parasite-stimulated monocytes in vitro and reducing parasitemia in a rodent model of experimental cerebral malaria (ECM) in vivo. Second, C1INH bound to host CD36 and chondroitin sulfate A molecules, interfering with cytoadhesion of infected RBCs by competitive binding to these receptors in vitro and reducing sequestration in specific tissues and protecting against ECM in vivo. This study reveals that C1INH is a potential therapeutic antimalarial molecule able to interfere with severe-disease etiology at multiple levels through specific interactions with both parasite PfGPIs and host cell receptors. PMID:26347576

  18. Adaptive and Acquired Resistance to EGFR Inhibitors Converge on the MAPK Pathway

    PubMed Central

    Ma, Pengfei; Fu, Yujie; Chen, Minjiang; Jing, Ying; Wu, Jie; Li, Ke; Shen, Ying; Gao, Jian-Xin; Wang, Mengzhao; Zhao, Xiaojing; Zhuang, Guanglei

    2016-01-01

    Both adaptive and acquired resistance significantly limits the efficacy of the epidermal growth factor receptor (EGFR) kinase inhibitors. However, the distinct or common mechanisms of adaptive and acquired resistance have not been fully characterized. Here, through systematic modeling of erlotinib resistance in lung cancer, we found that feedback reactivation of MAPK signaling following erlotinib treatment, which was dependent on the MET receptor, contributed to the adaptive resistance of EGFR inhibitors. Interestingly, acquired resistance to erlotinib was also associated with the MAPK pathway activation as a result of CRAF or NRAS amplification. Consequently, combined inhibition of EGFR and MAPK impeded the development of both adaptive and acquired resistance. These observations demonstrate that adaptive and acquired resistance to EGFR inhibitors can converge on the same pathway and credential cotargeting EGFR and MAPK as a promising therapeutic approach in EGFR mutant tumors. PMID:27279914

  19. Hereditary angioedema in a Jordanian family with a novel missense mutation in the C1-inhibitor N-terminal domain.

    PubMed

    Jaradat, Saied A; Caccia, Sonia; Rawashdeh, Rifaat; Melhem, Motasem; Al-Hawamdeh, Ali; Carzaniga, Thomas; Haddad, Hazem

    2016-03-01

    Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) is an autosomal dominant disease caused by mutations in the SERPING1 gene. A Jordanian family, including 14 individuals with C1-INH-HAE clinical symptoms, was studied. In the propositus and his parents, SERPING1 had four mutations leading to amino acid substitutions. Two are known polymorphic variants (c.167T>C; p.Val34Ala and c.1438G>A; p.Val458Met), the others are newly described. One (c.203C>T; p.Thr46Ile) is located in the N-terminal domain of the C1-inhibitor protein and segregates with angioedema symptoms in the family. The other (c.800C>T; p.Ala245Val) belongs to the serpin domain, and derives from the unaffected father. DNA from additional 24 family members were screened for c.203C>T mutation in the target gene. All individuals heterozygous for the c.203C>T mutation had antigenic and functional plasma levels of C1-inhibitor below 50% of normal, confirming the diagnosis of type I C1-INH-HAE. Angioedema symptoms were present in 14 of 16 subjects carrier for the c.203T allele. Among these subjects, those carrying the c.800T variation had more severe and frequent symptoms than subjects without this mutation. This family-based study provides the first evidence that multiple amino acid substitutions in SERPING1 could influence C1-INH-HAE phenotype. PMID:26895475

  20. Substrate properties of C1 inhibitor Ma (alanine 434----glutamic acid). Genetic and structural evidence suggesting that the P12-region contains critical determinants of serine protease inhibitor/substrate status.

    PubMed

    Skriver, K; Wikoff, W R; Patston, P A; Tausk, F; Schapira, M; Kaplan, A P; Bock, S C

    1991-05-15

    The serine protease inhibitor (serpin) C1 inhibitor inactivates enzymes involved in the regulation of vascular permeability. A patient from the Ma family with the genetic disorder hereditary angioedema inherited a dysfunctional C1 inhibitor allele. Relative to normal plasma, the patients's plasma contained an additional C1 inhibitor immunoreactive band, which comigrated with normal C1 inhibitor cleaved by plasma kallikrein, C1s, or factor XIIa. C1 inhibitor Ma did not react with a monoclonal antibody to a neoepitope that is present in complexed and cleaved normal C1 inhibitor, suggesting conformational differences between cleaved normal C1- inhibitor and cleaved C1 inhibitor Ma. Molecular cloning and sequencing of exon 8 of the C1 inhibitor Ma allele revealed a single C to A mutation, changing alanine 434 to glutamic acid. Ala 434 of C1 inhibitor aligns with the P12 residue of the prototypical serpin alpha 1-antitrypsin. The P12 amino acid of all inhibitory serpins is alanine, and it is present in a highly conserved region on the amino-terminal side of the serpin-reactive center loop. Whereas normal C1 inhibitor expressed by transfected COS-1 cells formed complexes with and was cleaved by kallikrein, fXIIa, and C1s, COS-1-expressed Ala434---Glu C1 inhibitor was cleaved by these enzymes but did not form complexes with them. These results, together with evidence from other studies, suggest that serpin protease inhibitor activity is the result of protein conformational change that occurs when the P12 region of a serpin moves from a surface location, on the reactive site loop of the native molecule, to an internal location within sheet A of the complexed inhibitor. PMID:2026621

  1. 86 The Efficacy and Safety of Human Plasma-derived C1-Inhibitor Concentrate Administered for the Treatment of Attacks in Pediatric Patients with Hereditary Angioedema Due to C1-Inhibitor Deficiency

    PubMed Central

    Farkas, Henriette; Csuka, Dorottya; Zotter, Zsuzsanna; Szabó, Erika; Kelemen, Zsuzsanna; Varga, Lilian; Fejes, János; Harmat, George

    2012-01-01

    Background Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a life-threatening, rare disease characterized by recurrent edematous attacks. In 50% of cases, the initial onset of symptoms occurs between 5 and 11 years of age. There are limited data on the emergency treatment of acute episodes in pediatric patients. Our aim was to analyze the efficacy and safety of human plasma-derived C1-INH concentrate in our pediatric patient population with HAE-C1-INH. Methods 50 pediatric patients (23 boys, 27 girls; 45 HAE type I, 5 HAE type II patients) were enrolled. The follow-up period began at the time of diagnosis and ended when the patient turned 18 years old. The indications for the use of C1-INH concentrate were upper airway oedema of any severity; moderate-to-severe abdominal edema; edema of face, neck, or lips and severe edema of the extremities and trunk. Clinical and laboratory data were entered into the Hungarian HAE Registry. Results 152 attacks out of 1392 experienced by 42 patients were treated with C1-INH concentrate (28% of attacks at home and 72% at the clinic). The distribution of C1-INH-treated attacks by location was as follows: 38% subcutaneous, 32% abdominal, 30% upper airway. In all locations, the clinical symptoms were consistently relieved by 500 IU C1-INH concentrate. An additional 500 IU dose of C1-INH concentrate was required in 4 cases only. The symptoms improved within 15 to 60 minutes of drug administration. Time to complete resolution was 24 to 48 hours in subcutaneous edema, 12 to 24 hours in abdominal attacks, and less than 12 hours when the edema involved the upper airways. No progression or recurrence of the attack was observed. Repeated administration did not reduce therapeutic efficacy of the drug. Adverse events did not occur. Transmission of viral infections (HIV, HBV, HBC, Parvo virus B19) was not detected. Comparing the first and last year of follow-up, anti-C1-INH antibodies (IgA, IgG, IgM types) did not show any

  2. C1 Inhibitor in Acute Antibody-Mediated Rejection Nonresponsive to Conventional Therapy in Kidney Transplant Recipients: A Pilot Study.

    PubMed

    Viglietti, D; Gosset, C; Loupy, A; Deville, L; Verine, J; Zeevi, A; Glotz, D; Lefaucheur, C

    2016-05-01

    Complement inhibitors have not been thoroughly evaluated in the treatment of acute antibody-mediated rejection (ABMR). We performed a prospective, single-arm pilot study to investigate the potential effects and safety of C1 inhibitor (C1-INH) Berinert added to high-dose intravenous immunoglobulin (IVIG) for the treatment of acute ABMR that is nonresponsive to conventional therapy. Kidney recipients with nonresponsive active ABMR and acute allograft dysfunction were enrolled between April 2013 and July 2014 and received C1-INH and IVIG for 6 months (six patients). The primary end point was the change in eGFR at 6 months after inclusion (M+6). Secondary end points included the changes in histology and DSA characteristics and adverse events as evaluated at M+6. All patients showed an improvement in eGFR between inclusion and M+6: from 38.7 ± 17.9 to 45.2 ± 21.3 mL/min/1.73 m(2) (p = 0.0277). There was no change in histological features, except a decrease in the C4d deposition rate from 5/6 to 1/6 (p = 0.0455). There was a change in DSA C1q status from 6/6 to 1/6 positive (p = 0.0253). One deep venous thrombosis was observed. In a secondary analysis, C1-INH patients were compared with a similar historical control group (21 patients). C1-INH added to IVIG is safe and may improve allograft function in kidney recipients with nonresponsive acute ABMR. PMID:26693703

  3. COOH-terminal substitutions in the serpin C1 inhibitor that cause loop overinsertion and subsequent multimerization.

    PubMed

    Eldering, E; Verpy, E; Roem, D; Meo, T; Tosi, M

    1995-02-10

    The region COOH-terminal to the reactive center loop is highly conserved in the serine protease inhibitor (serpin) family. We have studied the structural consequences of three substitutions (Val451-->Met, Phe455-->Ser, and Pro476-->Ser) found in this region of C1 inhibitor in patients suffering from hereditary angioedema. Equivalent substitutions have been described in alpha 1-antitrypsin and antithrombin III. The mutant C1 inhibitor proteins were only partially secreted upon transient transfection into COS-7 cells and were found to be dysfunctional. Immunoprecipitation of conditioned media demonstrated that in the intact, uncleaved form they all bind to a monoclonal antibody which recognizes specifically the protease-complexed or reactive center-cleaved normal C1 inhibitor. A second indication for an intrinsic conformational change was the increased thermostability compared to the normal protein. Furthermore, gel filtration studies showed that the Val451-->Met and Pro476-->Ser mutant proteins, and to a lesser extent Phe455-->Ser, were prone to spontaneous multimerization. Finally, a reduced susceptibility to reactive center cleavage by trypsin was observed for all three mutants, and the cleaved Val451-->Met and Pro476-->Ser mutants failed to adopt the conformation recognized by a cleavage-specific monoclonal antibody. Investigation of plasmas of patients with the Val451-->Met or Pro476-->Ser substitutions showed that these dysfunctional proteins circulate at low levels and are recognized by the complex-specific antibody. These results strongly indicate a conformational change as a result of these carboxylterminal substitutions, such that anchoring of the reactive center loop at the COOH-terminal side is not achieved properly. We propose that this results in overinsertion of the loop into beta-sheet A, which subsequently leads to multimerization. PMID:7852321

  4. Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association

    PubMed Central

    Andrejević, Slađana; Korošec, Peter; Šilar, Mira; Košnik, Mitja; Mijanović, Radovan; Bonači-Nikolić, Branka; Rijavec, Matija

    2015-01-01

    Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA) are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T). Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444) or group 2 (missense, excluding mutations at Arg444). Significant differences were found in the clinical severity score (P = 0.005), prevalence of laryngeal (P = 0.040) and facial (P = 0.013) oedema, and long-term prophylaxis (P = 0.023) between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038). Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a clear effect

  5. Concurrent acquired inhibitors to factor VIII and IX, a laboratory artifact: a case report

    PubMed Central

    Doma, Saša Anžej; Hillarp, Andreas; Pajič, Tadej; Andoljšek, Dušan; Černelč, Peter; Preldžnik Zupan, Irena

    2016-01-01

    Acquired inhibitors to coagulation factors other than factor VIII are extremely rare. We describe a case of a 59-year-old woman with abnormal bleeding, diagnosed with concurrent inhibitor antibodies to factor VIII and IX by Bethesda testing. We demonstrate that anti-FVIII antibodies of a very high titre are capable of disturbing the aPTT-based Bethesda assay, resulting in falsely-positive antibodies to factor IX. The case also illustrates the usefulness of the immunological assay (ELISA) in complementing the inhibitor diagnosis. PMID:27346976

  6. Molecular phylogeny of C1 inhibitor depicts two immunoglobulin-like domains fusion in fishes and ray-finned fishes specific intron insertion after separation from zebrafish

    SciTech Connect

    Kumar, Abhishek; Bhandari, Anita; Sarde, Sandeep J.; Goswami, Chandan

    2014-07-18

    Highlights: • C1 inhibitors of fishes have two Ig domains fused in the N-terminal end. • Spliceosomal introns gain in two Ig domains of selected ray-finned fishes. • C1 inhibitors gene is maintained from 450 MY on the same locus. • C1 inhibitors gene is missing in frog and lampreys. • C1 inhibitors of tetrapod and fishes differ in the RCL region. - Abstract: C1 inhibitor (C1IN) is a multi-facet serine protease inhibitor in the plasma cascades, inhibiting several proteases, notably, regulates both complement and contact system activation. Despite huge advancements in the understanding of C1IN based on biochemical properties and its roles in the plasma cascades, the phylogenetic history of C1IN remains uncharacterized. To date, there is no comprehensive study illustrating the phylogenetic history of C1IN. Herein, we explored phylogenetic history of C1IN gene in vertebrates. Fishes have C1IN with two immunoglobulin like domains attached in the N-terminal region. The RCL regions of CIIN from fishes and tetrapod genomes have variations at the positions P2 and P1′. Gene structures of C1IN gene from selected ray-finned fishes varied in the Ig domain region with creation of novel intron splitting exon Im2 into Im2a and Im2b. This intron is limited to ray-finned fishes with genome size reduced below 1 Gb. Hence, we suggest that genome compaction and associated double-strand break repairs are behind this intron gain. This study reveals the evolutionary history of C1IN and confirmed that this gene remains the same locus for ∼450 MY in 52 vertebrates analysed, but it is not found in frogs and lampreys.

  7. Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib.

    PubMed

    Acquaviva, Jaime; Smith, Donald L; Jimenez, John-Paul; Zhang, Chaohua; Sequeira, Manuel; He, Suqin; Sang, Jim; Bates, Richard C; Proia, David A

    2014-02-01

    Activating BRAF kinase mutations serve as oncogenic drivers in over half of all melanomas, a feature that has been exploited in the development of new molecularly targeted approaches to treat this disease. Selective BRAF(V600E) inhibitors, such as vemurafenib, typically induce initial, profound tumor regressions within this group of patients; however, durable responses have been hampered by the emergence of drug resistance. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90, in melanoma lines harboring the BRAF(V600E) mutation. Ganetespib exposure resulted in the loss of mutant BRAF expression and depletion of mitogen-activated protein kinase and AKT signaling, resulting in greater in vitro potency and antitumor efficacy compared with targeted BRAF and MAP-ERK kinase (MEK) inhibitors. Dual targeting of Hsp90 and BRAF(V600E) provided combinatorial benefit in vemurafenib-sensitive melanoma cells in vitro and in vivo. Importantly, ganetespib overcame mechanisms of intrinsic and acquired resistance to vemurafenib, the latter of which was characterized by reactivation of extracellular signal-regulated kinase (ERK) signaling. Continued suppression of BRAF(V600E) by vemurafenib potentiated sensitivity to MEK inhibitors after acquired resistance had been established. Ganetespib treatment reduced, but not abolished, elevations in steady-state ERK activity. Profiling studies revealed that the addition of a MEK inhibitor could completely abrogate ERK reactivation in the resistant phenotype, with ganetespib displaying superior combinatorial activity over vemurafenib. Moreover, ganetespib plus the MEK inhibitor TAK-733 induced tumor regressions in vemurafenib-resistant xenografts. Overall these data highlight the potential of ganetespib as a single-agent or combination treatment in BRAF(V600E)-driven melanoma, particularly as a strategy to overcome acquired resistance to selective BRAF inhibitors. PMID:24398428

  8. Fibulin-1C, C1 Esterase Inhibitor and Glucose Regulated Protein 75 Interact with the CREC Proteins, Calumenin and Reticulocalbin

    PubMed Central

    Aune Westergaard Hansen, Gry; Ludvigsen, Maja; Jacobsen, Christian; Cangemi, Claudia; Melholt Rasmussen, Lars; Vorum, Henrik; Honoré, Bent

    2015-01-01

    Affinity purification, immunoprecipitation, gel electrophoresis and mass spectrometry were used to identify fibulin-1C, C1 esterase inhibitor and glucose regulated protein 75, grp75, as binding partners of the CREC proteins, calumenin and reticulocalbin. Surface plasmon resonance was used to verify the interaction of all three proteins with each of the CREC proteins. Fibulin-1C interacts with calumenin and reticulocalbin with an estimated dissociation constant around 50-60 nM. The interaction, at least for reticulocalbin, was not dependent upon the presence of Ca2+. C1 esterase inhibitor interacted with both proteins with an estimated dissociation constant at 1 μM for reticulocalbin and 150 nM for calumenin. The interaction, at least for calumenin, was dependent upon the presence of Ca2+ with strong interaction at 3.5 mM while no detectable interaction could be found at 0.1 mM. Grp75 binds with an affinity of approximately 3-7 nM with reticulocalbin as well as with calumenin. These interactions suggest functional participation of the CREC proteins in chaperone activity, cell proliferation and transformation, cellular aging, haemostasis and thrombosis as well as modulation of the complement system in fighting bacterial infection. PMID:26161649

  9. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib

    PubMed Central

    Kwak, Eunice L.; Sordella, Raffaella; Bell, Daphne W.; Godin-Heymann, Nadia; Okimoto, Ross A.; Brannigan, Brian W.; Harris, Patricia L.; Driscoll, David R.; Fidias, Panos; Lynch, Thomas J.; Rabindran, Sridhar K.; McGinnis, John P.; Wissner, Allan; Sharma, Sreenath V.; Isselbacher, Kurt J.; Settleman, Jeffrey; Haber, Daniel A.

    2005-01-01

    Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib. PMID:15897464

  10. Hereditary angioedema and pregnancy: successful management of recurrent and frequent attacks of angioedema with C1-inhibitor concentrate, danazol and tranexamic acid – a case report

    PubMed Central

    Milingos, D S; Madhuvrata, P; Dean, J; Shetty, A; Campbell, D M

    2009-01-01

    Hereditary angioedema (HAE) is a rare but potentially life-threatening condition caused by deficiency of C1 esterase inhibitor. It is characterized by subcutaneous swelling in any part of the skin, gastrointestinal and respiratory tracts. We present the case of a pregnant woman with known HAE that deteriorated during pregnancy with frequent attacks that were managed successfully with danazol, tranexamic acid and regular intravenous administration of C1 esterase inhibitor.

  11. Molecular phylogeny of C1 inhibitor depicts two immunoglobulin-like domains fusion in fishes and ray-finned fishes specific intron insertion after separation from zebrafish.

    PubMed

    Kumar, Abhishek; Bhandari, Anita; Sarde, Sandeep J; Goswami, Chandan

    2014-07-18

    C1 inhibitor (C1IN) is a multi-facet serine protease inhibitor in the plasma cascades, inhibiting several proteases, notably, regulates both complement and contact system activation. Despite huge advancements in the understanding of C1IN based on biochemical properties and its roles in the plasma cascades, the phylogenetic history of C1IN remains uncharacterized. To date, there is no comprehensive study illustrating the phylogenetic history of C1IN. Herein, we explored phylogenetic history of C1IN gene in vertebrates. Fishes have C1IN with two immunoglobulin like domains attached in the N-terminal region. The RCL regions of CIIN from fishes and tetrapod genomes have variations at the positions P2 and P1'. Gene structures of C1IN gene from selected ray-finned fishes varied in the Ig domain region with creation of novel intron splitting exon Im2 into Im2a and Im2b. This intron is limited to ray-finned fishes with genome size reduced below 1 Gb. Hence, we suggest that genome compaction and associated double-strand break repairs are behind this intron gain. This study reveals the evolutionary history of C1IN and confirmed that this gene remains the same locus for ∼450 MY in 52 vertebrates analysed, but it is not found in frogs and lampreys. PMID:24878530

  12. EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer.

    PubMed

    Amato, Katherine R; Wang, Shan; Tan, Li; Hastings, Andrew K; Song, Wenqiang; Lovly, Christine M; Meador, Catherine B; Ye, Fei; Lu, Pengcheng; Balko, Justin M; Colvin, Daniel C; Cates, Justin M; Pao, William; Gray, Nathanael S; Chen, Jin

    2016-01-15

    Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors. PMID:26744526

  13. Peptide Inhibitor of Complement C1 (PIC1) Rapidly Inhibits Complement Activation after Intravascular Injection in Rats

    PubMed Central

    Sharp, Julia A.; Hair, Pamela S.; Pallera, Haree K.; Kumar, Parvathi S.; Mauriello, Clifford T.; Nyalwidhe, Julius O.; Phelps, Cody A.; Park, Dalnam; Thielens, Nicole M.; Pascal, Stephen M.; Chen, Waldon; Duffy, Diane M.; Lattanzio, Frank A.; Cunnion, Kenji M.; Krishna, Neel K.

    2015-01-01

    The complement system has been increasingly recognized to play a pivotal role in a variety of inflammatory and autoimmune diseases. Consequently, therapeutic modulators of the classical, lectin and alternative pathways of the complement system are currently in pre-clinical and clinical development. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement and is referred to as Peptide Inhibitor of Complement C1 (PIC1). In this study, we determined that the lead PIC1 variant demonstrates a salt-dependent binding to C1q, the initiator molecule of the classical pathway. Additionally, this peptide bound to the lectin pathway initiator molecule MBL as well as the ficolins H, M and L, suggesting a common mechanism of PIC1 inhibitory activity occurs via binding to the collagen-like tails of these collectin molecules. We further analyzed the effect of arginine and glutamic acid residue substitution on the complement inhibitory activity of our lead derivative in a hemolytic assay and found that the original sequence demonstrated superior inhibitory activity. To improve upon the solubility of the lead derivative, a pegylated, water soluble variant was developed, structurally characterized and demonstrated to inhibit complement activation in mouse plasma, as well as rat, non-human primate and human serum in vitro. After intravenous injection in rats, the pegylated derivative inhibited complement activation in the blood by 90% after 30 seconds, demonstrating extremely rapid function. Additionally, no adverse toxicological effects were observed in limited testing. Together these results show that PIC1 rapidly inhibits classical complement activation in vitro and in vivo and is functional for a variety of animal species, suggesting its utility in animal models of classical complement-mediated diseases. PMID:26196285

  14. Peptide Inhibitor of Complement C1 (PIC1) Rapidly Inhibits Complement Activation after Intravascular Injection in Rats.

    PubMed

    Sharp, Julia A; Hair, Pamela S; Pallera, Haree K; Kumar, Parvathi S; Mauriello, Clifford T; Nyalwidhe, Julius O; Phelps, Cody A; Park, Dalnam; Thielens, Nicole M; Pascal, Stephen M; Chen, Waldon; Duffy, Diane M; Lattanzio, Frank A; Cunnion, Kenji M; Krishna, Neel K

    2015-01-01

    The complement system has been increasingly recognized to play a pivotal role in a variety of inflammatory and autoimmune diseases. Consequently, therapeutic modulators of the classical, lectin and alternative pathways of the complement system are currently in pre-clinical and clinical development. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement and is referred to as Peptide Inhibitor of Complement C1 (PIC1). In this study, we determined that the lead PIC1 variant demonstrates a salt-dependent binding to C1q, the initiator molecule of the classical pathway. Additionally, this peptide bound to the lectin pathway initiator molecule MBL as well as the ficolins H, M and L, suggesting a common mechanism of PIC1 inhibitory activity occurs via binding to the collagen-like tails of these collectin molecules. We further analyzed the effect of arginine and glutamic acid residue substitution on the complement inhibitory activity of our lead derivative in a hemolytic assay and found that the original sequence demonstrated superior inhibitory activity. To improve upon the solubility of the lead derivative, a pegylated, water soluble variant was developed, structurally characterized and demonstrated to inhibit complement activation in mouse plasma, as well as rat, non-human primate and human serum in vitro. After intravenous injection in rats, the pegylated derivative inhibited complement activation in the blood by 90% after 30 seconds, demonstrating extremely rapid function. Additionally, no adverse toxicological effects were observed in limited testing. Together these results show that PIC1 rapidly inhibits classical complement activation in vitro and in vivo and is functional for a variety of animal species, suggesting its utility in animal models of classical complement-mediated diseases. PMID:26196285

  15. Cinryze as the first approved C1 inhibitor in the USA for the treatment of hereditary angioedema: approval, efficacy and safety.

    PubMed

    Lunn, Michael; Santos, Carah; Craig, Timothy

    2010-01-01

    Hereditary angioedema (HAE) is a clinical disorder characterized by a deficiency of C1 esterase inhibitor (C1-INH). HAE has traditionally been divided into two subtypes. Unique among the inherited deficiencies of the complement system, HAE Types I and II are inherited as an autosomal dominant disorder. The generation of an HAE attack is caused by the depletion and/or consumption of C1-inhibitor manifested as subcutaneous or submucosal edema of the upper airway, face, extremities, or gastrointestinal tract. Attacks can be severe and potentially life-threatening, particularly with laryngeal involvement. Despite the availability of C1-INH for the treatment of HAE since the 1980s in Europe and other countries, HAE treatment in the United States was limited to androgen therapy. The human plasma-derived C1 esterase inhibitor (Cinryze™), distributed by Lev Pharmaceuticals, was approved in October 2008 for the prevention of HAE attacks based on the results of a phase III clinical trial. This review aims to describe the history of C1-INH replacement in HAE as well as the pharmacology, efficacy and safety of C1-INH, concentrating on Cinryze as the first approved chronic replacement treatment for the prophylaxis of HAE attacks. PMID:22282695

  16. TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins.

    PubMed

    Shi, Ju; Rose, Eileen L; Singh, Andrew; Hussain, Sami; Stagliano, Nancy E; Parry, Graham C; Panicker, Sandip

    2014-06-26

    Activation of the classical pathway (CP) of complement is often associated with autoimmune disorders in which disease pathology is linked to the presence of an autoantibody. One such disorder is cold agglutinin disease (CAD), an autoimmune hemolytic anemia in which autoantibodies (cold agglutinins) bind to red blood cells (RBCs) at low temperatures. Anemia occurs as a result of autoantibody-mediated CP activation on the surface of the erythrocyte, leading to the deposition of complement opsonins that drive extravascular hemolysis in the liver. Here we test the effects of TNT003, a mouse monoclonal antibody targeting the CP-specific serine protease C1s, on CP activity induced by cold agglutinins on human RBCs. We collected 40 individual CAD patient samples and showed that TNT003 prevented cold agglutinin-mediated deposition of complement opsonins that promote phagocytosis of RBCs. Furthermore, we show that by preventing CP activation, TNT003 also prevents cold agglutinin-driven generation of anaphylatoxins. Finally, we provide evidence that CP activity in CAD patients terminates prior to activation of the terminal cascade, supporting the hypothesis that the primary route of RBC destruction in these patients occurs via extravascular hemolysis. Our results support the development of a CP inhibitor for the treatment of CAD. PMID:24695853

  17. NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor

    PubMed Central

    Galvani, Elena; Sun, Jing; Leon, Leticia G.; Sciarrillo, Rocco; Narayan, Ravi S.; Tjin Tham Sjin, Robert; Lee, Kwangho; Ohashi, Kadoaki; Heideman, Daniëlle A.M.; Alfieri, Roberta R.; Heynen, Guus J.; Bernards, René; Smit, Egbert F.; Pao, William; Peters, Godefridus J.; Giovannetti, Elisa

    2015-01-01

    The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations is limited by the emergence of acquired resistance, mostly ascribed to the secondary EGFR-T790M mutation. Selective EGFR-T790M inhibitors have been proposed as a new, extremely relevant therapeutic approach. Here, we demonstrate that the novel irreversible EGFR-TKI CNX-2006, a structural analog of CO-1686, currently tested in a phase-1/2 trial, is active against in vitro and in vivo NSCLC models expressing mutant EGFR, with minimal effect on the wild-type receptor. By integration of genetic and functional analyses in isogenic cell pairs we provide evidence of the crucial role played by NF-κB1 in driving CNX-2006 acquired resistance and show that NF-κB activation may replace the oncogenic EGFR signaling in NSCLC when effective and persistent inhibition of the target is achieved in the presence of the T790M mutation. In this context, we demonstrate that the sole, either genetic or pharmacologic, inhibition of NF-κB is sufficient to reduce the viability of cells that adapted to EGFR-TKIs. Overall, our findings support the rational inhibition of members of the NF-κB pathway as a promising therapeutic option for patients who progress after treatment with novel mutant-selective EGFR-TKIs. PMID:26015408

  18. A novel association of acquired ADAMTS13 inhibitor and acute dengue virus infection

    PubMed Central

    Rossi, Fernanda C.; Angerami, Rodrigo N.; de Paula, Erich V.; Orsi, Fernanda L.; Shang, Dezhi; del Guercio, Vânia M.; Resende, Mariângela R.; Annichino-Bizzacchi, Joyce M.; da Silva, Luiz J.; Zheng, X. Long; Castro, Vagner

    2011-01-01

    BACKGROUND Dengue is a mosquito-borne viral disease with an increasing incidence worldwide. Thrombocytopenia is a common finding in dengue virus (DV) infection; however, the underlying mechanisms remain unknown. CASE REPORT Here we provide the first evidence of a case of antibody formation against ADAMTS13 (ADAMTS13 inhibitor) in the course of a severe acute DV infection resulting in thrombotic microangiopathy (TMA). The patient presented with classical dengue symptoms (positive epidemiology, high fever, myalgia, predominantly in the lower limbs and lumbar region for 1 week) and, after 11 days of initial symptoms, developed TMA. Clinical and laboratorial investigation of dengue and TMA was performed. RESULTS The patient presented with ADAMTS13 inhibitor (IgG) during the acute phase of the disease, without anti-platelet antibodies detectable. Dengue infection had laboratorial confirmation. There were excellent clinical and laboratory responses to 11 serial plasma exchanges. Anti-ADAMTS13 inhibitor disappeared after remission of TMA and dengue resolution. No recurrence of TMA symptoms was observed after 2-year follow-up. CONCLUSIONS Although the real incidence of dengue-related TMA is unknown, this case provides the basis for future epidemiologic studies on acquired ADAMTS13 deficiency in DV infection. The prompt clinical recognition of this complication and early installment of specific therapy with plasma exchange are likely to improve the outcome of severe cases of dengue. PMID:19788513

  19. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy

    PubMed Central

    Kong, Xiangju; Hong, Aayoung; Koya, Richard C.; Moriceau, Gatien; Chodon, Thinle; Guo, Rongqing; Johnson, Douglas B.; Dahlman, Kimberly B.; Kelley, Mark C.; Kefford, Richard F.; Chmielowski, Bartosz; Glaspy, John A.; Sosman, Jeffrey A.; van Baren, Nicolas; Long, Georgina V.; Ribas, Antoni; Lo, Roger S.

    2013-01-01

    BRAF inhibitors elicit rapid anti-tumor responses in the majority of patients with V600BRAF mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that MAPK reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions, in both core drug escape pathways, were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma re-growth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, co-targeting of two core pathways as an essential strategy for durable responses. PMID:24265155

  20. The functional integrity of the serpin domain of C1-inhibitor depends on the unique N-terminal domain, as revealed by a pathological mutant.

    PubMed

    Bos, Ineke G A; Lubbers, Yvonne T P; Roem, Dorina; Abrahams, Jan Pieter; Hack, C Erik; Eldering, Eric

    2003-08-01

    C1-inhibitor (C1-Inh) is a serine protease inhibitor (serpin) with a unique, non-conserved N-terminal domain of unknown function. Genetic deficiency of C1-Inh causes hereditary angioedema. A novel type of mutation (Delta 3) in exon 3 of the C1-Inh gene, resulting in deletion of Asp62-Thr116 in this unique domain, was encountered in a hereditary angioedema pedigree. Because the domain is supposedly not essential for inhibitory activity, the unexpected loss-of-function of this deletion mutant was further investigated. The Delta 3 mutant and three additional mutants starting at Pro76, Gly98, and Ser115, lacking increasing parts of the N-terminal domain, were produced recombinantly. C1-Inh76 and C1-Inh98 retained normal conformation and interaction kinetics with target proteases. In contrast, C1-Inh115 and Delta 3, which both lack the connection between the serpin and the non-serpin domain via two disulfide bridges, were completely non-functional because of a complex-like and multimeric conformation, as demonstrated by several criteria. The Delta 3 mutant also circulated in multimeric form in plasma from affected family members. The C1-Inh mutant reported here is unique in that deletion of an entire amino acid stretch from a domain not shared by other serpins leads to a loss-of-function. The deletion in the unique N-terminal domain results in a "multimerization phenotype" of C1-Inh, because of diminished stability of the central beta-sheet. This phenotype, as well as the location of the disulfide bridges between the serpin and the non-serpin domain of C1-Inh, suggests that the function of the N-terminal region may be similar to one of the effects of heparin in antithrombin III, maintenance of the metastable serpin conformation. PMID:12773530

  1. The Levels of the Lectin Pathway Serine Protease MASP-1 and Its Complex Formation with C1 Inhibitor Are Linked to the Severity of Hereditary Angioedema.

    PubMed

    Hansen, Cecilie Bo; Csuka, Dorottya; Munthe-Fog, Lea; Varga, Lilian; Farkas, Henriette; Hansen, Karin Møller; Koch, Claus; Skjødt, Karsten; Garred, Peter; Skjoedt, Mikkel-Ole

    2015-10-15

    C1 inhibitor (C1-INH) is known to form complexes with the lectin complement pathway serine proteases MASP-1 and MASP-2. Deficiency of C1-INH is associated with hereditary angioedema (HAE), an autosomal inherited disease characterized by swelling attacks caused by elevated levels of bradykinin. MASP-1 was shown to cleave high m.w. kininogen into bradykinin; therefore, we hypothesized that MASP-1 levels and the quantity of MASP-1/C1-INH complexes might be associated with different paraclinical and clinical outcomes of HAE. We measured MASP-1 serum concentrations and endogenous MASP-1/C1-INH complex levels in 128 HAE patients and 100 controls. Relatively high levels of pre-existing MASP-1/C1-INH complexes were observed in normal serum, and we found that both the serum levels of MASP-1 and the complex formation between MASP-1 and C1-INH were significantly reduced in HAE patients compared with matched controls (p < 0.0001). The level of MASP-1 and MASP-1/C1-INH complexes in HE patients correlated with the level of C1-INH (p = 0.0009 and p = 0.0047, respectively), the level of C4 (p = 0.0084 and p < 0.0001, respectively), and the number of attacks in the year of blood sampling (p = 0.0075 and p = 0.0058, respectively). In conclusion, we show that MASP-1/C1-INH complexes circulate in normal human blood. The levels of MASP-1 and MASP-1/C1-INH complexes are reduced in HAE patients compared with controls. Both MASP-1 and MASP-1/C1-INH complexes are related to the degree of complement C4 consumption, as well as the severity of disease. These results suggest that MASP-1 may exert a previously unrecognized role in the pathophysiology of HAE. PMID:26371246

  2. BIIB021, a synthetic Hsp90 inhibitor, has broad application against tumors with acquired multidrug resistance.

    PubMed

    Zhang, Hong; Neely, Laura; Lundgren, Karen; Yang, Yong-Ching; Lough, Rachel; Timple, Noel; Burrows, Francis

    2010-03-01

    17-AAG, the first-generation clinical Hsp90 inhibitor, exhibits promising antitumor activity in clinical studies, but is limited by poor solubility and hepatotoxicity. To pursue compounds with better biopharmaceutical properties, we have developed a series of fully synthetic orally bioavailable inhibitors of Hsp90. Here, we report that 17-AAG and other ansamycin derivatives are inactive in P-gp and/or MRP-1 expressing cell lines and sensitivity could be restored by coadministration of P-gp or MRP inhibitors. In contrast, the synthetic Hsp90 inhibitor, BIIB021 was active in these models. Accordingly, BIIB021 was considerably more active than 17-AAG against adrenocortical carcinoma, a tumor that naturally expresses P-gp, both in vitro and in vivo. This efflux pump-mediated resistance is manifested in both cytotoxicity assays and measurements of target inhibition, such as client protein degradation. Other than this, the cytotoxic activity of BIIB021 was also not influenced by loss of NQO1 or Bcl-2 overexpression, molecular lesions that do not prevent client loss but are nonetheless associated with reduced cell killing by 17-AAG. Our results indicate that the activity of 17-AAG and other ansamycins may be curtailed in tumors that have upregulated efflux pumps or antiapoptotic proteins or other genetic alterations. These data indicate that the new generation of synthetic anti-Hsp90 drugs, exemplified by BIIB021 that is currently undergoing Phase II testing, may have broader application against tumors with acquired multidrug resistance or tumors located in organs protected by MDR proteins, such as the adrenal glands, brain and testis. PMID:19676042

  3. Acquired factor V inhibitor in a patient with mantle cell lymphoma presenting with hematuria followed by thrombosis: a case report

    PubMed Central

    AlJohani, Naif I; Matthews, John H

    2014-01-01

    Acquired factor V inhibitor is a rare hemostatic disorder that presents with hemorrhagic manifestations in the vast majority of patients. Factor V inhibitor may develop through a variety of mechanisms involving development of alloantibodies or autoantibodies specific to Factor V. Autoantibodies, in particular, have been reported in a number of conditions. In this report, we describe a case of acquired factor V inhibitor in a patient with mantle cell lymphoma who presented with hematuria. Seven weeks after diagnosis and successful management, the patient developed deep vein thrombosis in the right lower extremity. The patient’s factor V levels were normalized, and the inhibitor was successfully eradicated using corticosteroids. Here, we discuss this rare disorder, its unusual manifestation, and provide a mini-review of the current literature regarding factor V inhibitors. PMID:24591851

  4. Recent developments in the treatment of acute abdominal and facial attacks of hereditary angioedema: focus on human C1 esterase inhibitor.

    PubMed

    Cardona, Lourdes Pastó; Bellfill, Ramon Lleonart; Caus, Joaquim Marcoval

    2010-01-01

    Hereditary angioedema (HAE) is a potentially fatal genetic disorder typified by a deficiency (type I) or dysfunction (type II) of the C1-inhibitor (C1-INH) and characterized by swelling of the extremities, face, trunk, abdominal viscera, and upper airway. Type III is normal estrogen-sensitive C1-INH HAE. Bradykinin, the main mediator of HAE, binds to endothelial B2 receptors, increasing vascular permeability and resulting in edema. HAE management includes short- and long-term prophylaxis. For treating acute episodes, C1-INH concentrate is recommended with regression of symptoms achieved in 30-90 min. Infusions of 500-1000 U have been used in Europe for years. Two plasma-derived C1-INH concentrates have been licensed recently in the United States: Berinert(®) for treating acute attacks and Cinryze(®) for prophylaxis in adolescent/adult patients. A recombinant C1-INH that is being considered for approval (conestat alfa) exhibited significant superiority versus placebo. Ecallantide (Kalbitor(®)) is a selective kallikrein inhibitor recently licensed in the United States for treating acute attacks in patients aged >16 years. It is administered in three 10-mg subcutaneous injections with the risk of anaphylactic reactions. Icatibant (Firazyr(®)) is a bradykinin B2 receptor competitor. It is administered subcutaneously as a 30-mg injection and approved in Europe but not in the United States. PMID:23776358

  5. Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer.

    PubMed

    Huw, L-Y; O'Brien, C; Pandita, A; Mohan, S; Spoerke, J M; Lu, S; Wang, Y; Hampton, G M; Wilson, T R; Lackner, M R

    2013-01-01

    Agents targeting the PI3K/mTOR signaling axis have shown promise in early-phase clinical trials and are currently being studied in later stages of clinical development in multiple indications. Experience with other targeted agents suggests that clinical responses may be short-lived because of acquired resistance to therapy. Here, we report preclinical modeling of acquired resistance in a HER2-positive, PIK3CA mutant breast cancer cell line, KPL-4. We identified a heretofore-unreported mechanism of resistance, specifically high-level amplification of the mutant allele of PIK3CA, which resulted in a marked upregulation of PI3K signaling, enabling resistant cells to regain proliferative capacity at clinically relevant concentrations of the PI3K inhibitor, GDC-0941. We show that knockdown of the amplified PIK3CA mutant allele in these cells by small interfering RNA restored pathway signaling and sensitivity to PI3K inhibition at levels comparable to parental cells. These novel preclinical findings suggest that, in addition to assessment of other previously reported mechanisms of resistance, evaluation of PI3K copy number variation should be integrated into the exploratory analysis of biopsies obtained at disease progression. PMID:24366379

  6. Pyrazolo[4,3-c][1,2]benzothiazines 5,5-dioxide: a promising new class of Staphylococcus aureus NorA efflux pump inhibitors.

    PubMed

    Sabatini, Stefano; Gosetto, Francesca; Serritella, Serena; Manfroni, Giuseppe; Tabarrini, Oriana; Iraci, Nunzio; Brincat, Jean Pierre; Carosati, Emanuele; Villarini, Milena; Kaatz, Glenn W; Cecchetti, Violetta

    2012-04-12

    The increasing resistance to antibacterials commonly employed in the clinic and the growth of multidrug resistant strains suggest that the development of new therapeutic approaches should be of primary concern. In this context, EPIs may restore life to old drugs. In the present work, the EPI activity of the COX-2 inhibitor celecoxib was confirmed and a new class of pyrazolo[4,3-c][1,2]benzothiazine 5,5-dioxide analogues acting as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump was identified. PMID:22432682

  7. Acquired Factor XIII Inhibitor in Hospitalized and Perioperative Patients: A Systematic Review of Case Reports and Case Series.

    PubMed

    Tone, Kira J; James, Tyler E; Fergusson, Dean A; Tinmouth, Alan; Tay, Jason; Avey, Marc T; Kilty, Shaun; Lalu, Manoj M

    2016-07-01

    Factor XIII (FXIII) cross-links fibrin monomers to support clot stabilization and wound healing. Acquired FXIII deficiency is caused by autoantibodies that inhibit FXIII and can result in bleeding despite normal routine coagulation test results. Given the rarity of this disease, large clinical studies are not feasible. We therefore conducted a systematic review of case reports and case series of acquired FXIII inhibitor to evaluate potential management and treatment strategies for acquired FXIII inhibitor in hospitalized and/or perioperative patients. A systematic search of MEDLINE, Embase, and Web of Science identified reports of hospitalized and perioperative patients with acquired FXIII deficiency. No restrictions were placed on language or publication type. Article screening and data extraction were performed independently by 2 abstractors. Completeness of reporting was evaluated according to modified elements from the CAse REport (CARE) guidelines. A total of 1028 citations were reviewed, with 36 case reports and 3 case series meeting eligibility criteria (63 patients total). The mean age was 60 (range, 9-87) years with balanced sex representation. At presentation, 48 patients (76%) had intramuscular or subcutaneous bleeding, and 34 patients (54%) had external or surgical bleeding. All cases were diagnosed by initially detecting a FXIII deficiency and then identifying the inhibitor. Clinical improvement in bleeding was seen in patients receiving FXIII concentrate (13/17 patients), cryoprecipitate (5/8), and plasma (10/18). Inhibitor reduction was seen in patients who received rituximab (6/6 patients), plasma exchange (2/2), intravenous immunoglobulin (4/5), steroid (15/20), and cyclophosphamide (10/15). Concurrent initiation of multiple therapies and obvious lack of control comparisons made direct association to outcomes difficult to establish. Outcomes were reported for 55 patients, with 25 patients (45%) having complete inhibitor eradication and 15 patients

  8. 26 CFR 1.1082-5 - Basis of property acquired by shareholder upon tax-free distribution under section 1081(c) (1) or...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 11 2010-04-01 2010-04-01 true Basis of property acquired by shareholder upon... Exchanges in Obedience to S.e.c. Orders § 1.1082-5 Basis of property acquired by shareholder upon tax-free... shareholder in a corporation which is a registered holding company or a majority-owned subsidiary...

  9. Expression of the SERPING1 gene is not regulated by promoter hypermethylation in peripheral blood mononuclear cells from patients with hereditary angioedema due to C1-inhibitor deficiency

    PubMed Central

    2014-01-01

    SERPING1 mutations causing Hereditary Angioedema type I (HAE-I) due to C1-Inhibitor (C1-INH) deficiency display a dominant-negative effect usually resulting in protein levels far below the expected 50%. To further investigate mechanisms for its reduced expression, we analyzed the promoter DNA methylation status of SERPING1 and its influence on C1-INH expression. Global epigenetic reactivation correlated with C1-INH mRNA synthesis and protein secretion in Huh7 hepatoma cells. However, PBMCs extracted from controls, HAE-I and HAE-II patients presented identical methylation status of the SERPING1 promoter when analyzed by bisulphite sequencing; the proximal CpG island (exon 2) is constitutively unmethylated, while the most distant one (5.7Kb upstream the transcriptional start site) is fully methylated. These results correlate with the methylation profile observed in Huh7 cells and indicate that there is not a direct epigenetic regulation of C1-INH expression in PBMCs specific for each HAE type. Other indirect modes of epigenetic regulation cannot be excluded. PMID:25053016

  10. A Nationwide Study of Norwegian Patients with Hereditary Angioedema with C1 Inhibitor Deficiency Identified Six Novel Mutations in SERPING1

    PubMed Central

    Johnsrud, Irene; Kulseth, Mari Ann; Rødningen, Olaug Kristin; Landrø, Linn; Helsing, Per; Waage Nielsen, Erik; Heimdal, Ketil

    2015-01-01

    Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is characterized by relapsing, non-pruritic swelling in skin and submucosal tissue. Symptoms can appear in early infancy when diagnosis is more difficult. In the absence of a correct diagnosis, treatment of abdominal attacks often lead to unnecessary surgery, and laryngeal edema can cause asphyxiation. A cohort study of 52 patients from 25 unrelated families in Norway was studied. Diagnosis of C1-INH-HAE was based on international consensus criteria including low functional and/or antigenic C1-INH values and antigenic C4. As SERPING1 mutations in Norwegian patients with C1-INH-HAE are largely undescribed and could help in diagnosis, we aimed to find and describe these mutations. Mutation analysis of the SERPING1 gene was performed by Sanger sequencing of all protein coding exons and exon-intron boundaries. Samples without detected mutation were further analyzed by multiplex ligation-dependent probe amplification to detect deletions and duplications. Novel mutations suspected to lead to splice defects were analyzed on the mRNA level. Fifty-two patients from 25 families were included. Forty-four (84,6%) suffered from C1-INH-HAE type I and eight (15,4%) suffered from C1-INH-HAE type II. Pathogenic or likely pathogenic mutations were found in 22/25 families (88%). Thirteen unique mutations were detected, including six previously undescribed. There were three missense mutations including one mutation affecting the reactive center loop at codon 466, three nonsense mutations, three small deletions/duplications, three gross deletions, and one splice mutation. PMID:26154504

  11. Multi-kinase inhibitor C1 triggers mitotic catastrophe of glioma stem cells mainly through MELK kinase inhibition.

    PubMed

    Minata, Mutsuko; Gu, Chunyu; Joshi, Kaushal; Nakano-Okuno, Mariko; Hong, Christopher; Nguyen, Chi-Hung; Kornblum, Harley I; Molla, Annie; Nakano, Ichiro

    2014-01-01

    Glioblastoma multiforme (GBM) is a highly lethal brain tumor. Due to resistance to current therapies, patient prognosis remains poor and development of novel and effective GBM therapy is crucial. Glioma stem cells (GSCs) have gained attention as a therapeutic target in GBM due to their relative resistance to current therapies and potent tumor-initiating ability. Previously, we identified that the mitotic kinase maternal embryonic leucine-zipper kinase (MELK) is highly expressed in GBM tissues, specifically in GSCs, and its expression is inversely correlated with the post-surgical survival period of GBM patients. In addition, patient-derived GSCs depend on MELK for their survival and growth both in vitro and in vivo. Here, we demonstrate evidence that the role of MELK in the GSC survival is specifically dependent on its kinase activity. With in silico structure-based analysis for protein-compound interaction, we identified the small molecule Compound 1 (C1) is predicted to bind to the kinase-active site of MELK protein. Elimination of MELK kinase activity was confirmed by in vitro kinase assay in nano-molar concentrations. When patient-derived GSCs were treated with C1, they underwent mitotic arrest and subsequent cellular apoptosis in vitro, a phenotype identical to that observed with shRNA-mediated MELK knockdown. In addition, C1 treatment strongly induced tumor cell apoptosis in slice cultures of GBM surgical specimens and attenuated growth of mouse intracranial tumors derived from GSCs in a dose-dependent manner. Lastly, C1 treatment sensitizes GSCs to radiation treatment. Collectively, these data indicate that targeting MELK kinase activity is a promising approach to attenuate GBM growth by eliminating GSCs in tumors. PMID:24739874

  12. Inhibitors of the mitochondrial cytochrome b-c1 complex inhibit the cyanide-insensitive respiration of Trypanosoma brucei.

    PubMed

    Turrens, J F; Bickar, D; Lehninger, A L

    1986-06-01

    The cyanide-insensitive respiration of bloodstream trypomastigote forms of Trypanosoma brucei (75 +/- 8 nmol O2 min-1(mg protein)-1) is completely inhibited by the mitochondrial ubiquinone-like inhibitors 2-hydroxy-3-undecyl-1,4-naphthoquinone (UHNQ) and 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole (UHDBT). The Ki values for UHDBT (30 nM) and UHNQ (2 microM) are much lower than the reported Ki for salicylhydroxamic acid (SHAM) (5 microM), a widely used inhibitor of the cyanide-insensitive oxidase. UHNQ also stimulated the glycerol-3-phosphate-dependent reduction of phenazine methosulfate, demonstrating that the site of UHNQ inhibition is on the terminal oxidase of the cyanide-insensitive respiration of T. brucei. These results suggest that a ubiquinone-like compound may act as an electron carrier between the two enzymatic components of the cyanide-insensitive glycerol-3-phosphate oxidase. PMID:3016533

  13. Two novel ALK mutations mediate acquired resistance to the next generation ALK inhibitor alectinib

    PubMed Central

    Katayama, Ryohei; Friboulet, Luc; Koike, Sumie; Lockerman, Elizabeth L.; Khan, Tahsin M.; Gainor, Justin F.; Iafrate, A. John; Takeuchi, Kengo; Taiji, Makoto; Okuno, Yasushi; Fujita, Naoya; Engelman, Jeffrey A.; Shaw, Alice T.

    2014-01-01

    Purpose The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged NSCLC. Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance. Experimental Design We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure-activity-relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE. Results We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib. Conclusions We have identified two novel ALK mutations arising after alectinib exposure which are sensitive to other next generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs. PMID:25228534

  14. An Acquired Factor VIII Inhibitor in a Patient with HIV and HCV: A Case Presentation and Literature Review

    PubMed Central

    Zeichner, S. B.; Harris, A.; Turner, G.; Francavilla, M.; Lutzky, J.

    2013-01-01

    Introduction. Despite its low incidence, acquired factor VIII inhibitor is the most common autoantibody affecting the clotting cascade. The exact mechanism of acquisition remains unclear, but postpartum patients, those with autoimmune conditions or malignancies, and those with exposure to particular drugs appear most susceptible. There have been several case reports describing acquired FVIII inhibitors in patients receiving interferon alpha for HCV treatment and in patients being treated for HIV. To our knowledge, this is the first case of a patient with HCV and HIV who was not actively receiving treatment for either condition. Case Presentation. A 57-year-old Caucasian male with a history of HIV and HCV was admitted to our hospital for a several day history of progressively worsening right thigh bruising and generalized weakness. CTA of the abdominal arteries revealed large bilateral retroperitoneal hematomas. Laboratory studies revealed the presence of a high titer FVIII inhibitor. Conclusion. Our case of a very rare condition highlights the importance of recognizing and understanding the diagnosis of acquired FVIII inhibitor. Laboratory research and clinical data on the role of newer agents are needed in order to better characterize disease pathogenesis, disease associations, genetic markers, and optimal disease management. PMID:24198984

  15. Hereditary angioedema with normal C1 inhibitor and factor XII mutation: a series of 57 patients from the French National Center of Reference for Angioedema.

    PubMed

    Deroux, A; Boccon-Gibod, I; Fain, O; Pralong, P; Ollivier, Y; Pagnier, A; Djenouhat, K; Du-Thanh, A; Gompel, A; Faisant, C; Launay, D; Bouillet, L

    2016-09-01

    Hereditary angioedema (HAE) is a rare disease associated with either a quantitative or qualitative deficiency in C1-inhibitor (C1-INH) or normal C1-INH. HAE with normal C1-INH is associated in 20% of cases with mutations in the gene for factor XII (FXII) or FXII-HAE. A recent review described 41 families, including 14 German and 15 Spanish families. We have constructed a register of French patients and their characteristics. A national survey was launched through the French National Center of Reference for Angioedema (CREAK) to study the clinical, biological and therapeutic characteristics of patients with HAE linked to a mutation of FXII gene. Fifty-seven patients were identified from 24 different families. In most cases they were young women (mean age at diagnosis: 31 years, mean age at first symptom: 21 years, female/male ratio: 76%). Twenty-one per cent of the patients experienced angioedema attacks only during pregnancy or when on oestrogen contraception. Sixty-three per cent had attacks at all times, but they were more severe during these same periods. Male carriers of the mutation were more frequently asymptomatic than females (P = 0·003). C1-INH concentrate and icatibant were both effective for treating attacks. The prophylactic use of tranexamic acid led to a 64% decrease in the number of attacks. This is one of the largest series reported of HAE patients with FXII mutation. The therapeutic management appeared to be identical to that of HAE with C1-INH deficiency. PMID:27271546

  16. Treatment of hereditary angioedema with nanofiltered C1-esterase inhibitor concentrate (Cetor®): multi-center phase II and III studies to assess pharmacokinetics, clinical efficacy and safety.

    PubMed

    Hofstra, J J; Kleine Budde, I; van Twuyver, E; Choi, G; Levi, M; Leebeek, F W G; de Monchy, J G R; Ypma, P F; Keizer, R J; Huitema, A D R; Strengers, P F W

    2012-03-01

    From 1997, plasma-derived C1-inhibitor concentrate (Cetor®) has been available to HAE and AAE patients. Recently, a virus reducing 15 nm nanofiltration step has been introduced in the production process. A randomized, double-blind controlled cross-over study was performed to compare the pharmacokinetics (PK) of nanofiltered (C1-INH-NF) with conventional C1-inhibitor (C1-INH). Efficacy and safety were investigated in an open-label, on-demand and a prophylactic study. No differences in pharmacokinetic parameters between C1-INH and C1-INH-NF were found (13 non-symptomatic HAE patients). Both C1-inhibitor products equally increased plasma C4 levels. In the on-demand study, 14 acute angioedema attacks in 8 patients were analyzed. In the prophylactic study, 1 AAE and 5 HAE patients experienced in total 31 attacks during 748 observation days. In total 180,000 units of C1-INH-NF were administered. No product-related adverse events occurred, and no anti-C1-antibodies were induced. Nanofiltration in the production process of C1-inhibitor did not affect the pharmacokinetics, efficacy, and safety. PMID:22197071

  17. Unmasking Heavily O-Glycosylated Serum Proteins Using Perchloric Acid: Identification of Serum Proteoglycan 4 and Protease C1 Inhibitor as Molecular Indicators for Screening of Breast Cancer

    PubMed Central

    Lee, Cheng-Siang; Taib, Nur Aishah Mohd; Ashrafzadeh, Ali; Fadzli, Farhana; Harun, Faizah; Rahmat, Kartini; Hoong, See Mee; Abdul-Rahman, Puteri Shafinaz; Hashim, Onn Haji

    2016-01-01

    Heavily glycosylated mucin glycopeptides such as CA 27.29 and CA 15–3 are currently being used as biomarkers for detection and monitoring of breast cancer. However, they are not well detected at the early stages of the cancer. In the present study, perchloric acid (PCA) was used to enhance detection of mucin-type O-glycosylated proteins in the serum in an attempt to identify new biomarkers for early stage breast cancer. Sensitivity and specificity of an earlier developed sandwich enzyme-linked lectin assay were significantly improved with the use of serum PCA isolates. When a pilot case-control study was performed using the serum PCA isolates of normal participants (n = 105) and patients with stage 0 (n = 31) and stage I (n = 48) breast cancer, higher levels of total O-glycosylated proteins in sera of both groups of early stage breast cancer patients compared to the normal control women were demonstrated. Further analysis by gel-based proteomics detected significant inverse altered abundance of proteoglycan 4 and plasma protease C1 inhibitor in both the early stages of breast cancer patients compared to the controls. Our data suggests that the ratio of serum proteoglycan 4 to protease C1 inhibitor may be used for screening of early breast cancer although this requires further validation in clinically representative populations. PMID:26890881

  18. Unmasking Heavily O-Glycosylated Serum Proteins Using Perchloric Acid: Identification of Serum Proteoglycan 4 and Protease C1 Inhibitor as Molecular Indicators for Screening of Breast Cancer.

    PubMed

    Lee, Cheng-Siang; Taib, Nur Aishah Mohd; Ashrafzadeh, Ali; Fadzli, Farhana; Harun, Faizah; Rahmat, Kartini; Hoong, See Mee; Abdul-Rahman, Puteri Shafinaz; Hashim, Onn Haji

    2016-01-01

    Heavily glycosylated mucin glycopeptides such as CA 27.29 and CA 15-3 are currently being used as biomarkers for detection and monitoring of breast cancer. However, they are not well detected at the early stages of the cancer. In the present study, perchloric acid (PCA) was used to enhance detection of mucin-type O-glycosylated proteins in the serum in an attempt to identify new biomarkers for early stage breast cancer. Sensitivity and specificity of an earlier developed sandwich enzyme-linked lectin assay were significantly improved with the use of serum PCA isolates. When a pilot case-control study was performed using the serum PCA isolates of normal participants (n = 105) and patients with stage 0 (n = 31) and stage I (n = 48) breast cancer, higher levels of total O-glycosylated proteins in sera of both groups of early stage breast cancer patients compared to the normal control women were demonstrated. Further analysis by gel-based proteomics detected significant inverse altered abundance of proteoglycan 4 and plasma protease C1 inhibitor in both the early stages of breast cancer patients compared to the controls. Our data suggests that the ratio of serum proteoglycan 4 to protease C1 inhibitor may be used for screening of early breast cancer although this requires further validation in clinically representative populations. PMID:26890881

  19. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients

    PubMed Central

    Wu, Shang-Gin; Liu, Yi-Nan; Tsai, Meng-Feng; Chang, Yih-Leong; Yu, Chong-Jen; Yang, Pan-Chyr; Yang, James Chih-Hsin; Wen, Yueh-Feng; Shih, Jin-Yuan

    2016-01-01

    Introduction Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with favorable response in EGFR mutant lung cancer. Acquired resistance to reversible EGFR TKIs remains a significant barrier, and acquired EGFR T790M-mutation is the major mechanism. Second-generation irreversible EGFR TKI, afatinib, had also been approved for treating EGFR mutant lung cancer patients, but the mechanism of acquired resistance to afatinib has not been well studied. Results Forty-two patients had tissue specimens taken after acquiring resistance to afatinib. The sensitizing EGFR mutation were all consistent between pre- and post-afatinib tissues. Twenty patients (47.6%) had acquired T790M mutation. T790M rate was not different between first-generation EGFR TKI-naïve patients (50%) and first-generation EGFR TKI-treated patients (46.4%) (p = 0.827). No clinical characteristics or EGFR mutation types were associated with the development of acquired T790M. No other second-site EGFR mutations were detected. There were no small cell or squamous cell lung cancer transformation. Other genetic mutations were not identified in PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2. Methods Afatinib-prescription record of our department of pharmacy from January 2007 and December 2014 was retrieved. We investigated patients with tissue specimens available after acquiring resistance to afatinib. Enrolled patients should have partial response or durable stable disease of treatment response to afatinib. Various mechanisms of acquired resistance to first-generation EGFR TKIs were evaluated. Histology and cytology were reviewed. EGFR, PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2 genetic alterations were evaluated by sequencing. Statistical analysis was performed using Chi-square test and Kaplan-Meier method. Conclusions T790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired

  20. Acquired Resistance to EGFR Inhibitors Is Associated with a Manifestation of Stem cell–like Properties in Cancer Cells

    PubMed Central

    Shien, Kazuhiko; Toyooka, Shinichi; Yamamoto, Hiromasa; Soh, Junichi; Jida, Masaru; Thu, Kelsie L.; Hashida, Shinsuke; Maki, Yuho; Ichihara, Eiki; Asano, Hiroaki; Tsukuda, Kazunori; Takigawa, Nagio; Kiura, Katsuyuki; Gazdar, Adi F.; Lam, Wan L.; Miyoshi, Shinichiro

    2015-01-01

    Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) is a critical problem in the treatment of lung cancer. Although several mechanisms have been shown to be responsible for acquired resistance, all mechanisms have not been uncovered. In this study, we investigated the molecular and cellular profiles of the acquired resistant cells to EGFR-TKI in EGFR-mutant lung cancers. Four EGFR-mutant cell lines were exposed to gefitinib by stepwise escalation and high-concentration exposure methods, and resistant sublines to gefitinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Although previously reported, alterations including secondary EGFR T790M mutation, MET amplification, and appearance of epithelial-to-mesenchymal transition (EMT) features were observed, these 2 drug-exposure methods revealed different resistance mechanisms. The resistant cells with EMT features exhibited downregulation of miRNA-200c by DNA methylation. Furthermore, the HCC827-derived subline characterized by the high-concentration exposure method exhibited not only EMT features but also stem cell–like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) overexpression, increase of side-population, and self-renewal capability. Resistant sublines with stem cell–like properties were resistant to conventional chemotherapeutic agents but equally sensitive to histone deacetylase and proteasome inhibitors, compared with their parental cells. ALDH1A1 was upregulated in clinical samples with acquired resistance to gefitinib. In conclusion, our study indicates that the manner of EGFR-TKI exposure influences the mechanism of acquired resistance and the appearance of stem cell–like property with EGFR-TKI treatment. PMID:23542356

  1. Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells.

    PubMed

    Shien, Kazuhiko; Toyooka, Shinichi; Yamamoto, Hiromasa; Soh, Junichi; Jida, Masaru; Thu, Kelsie L; Hashida, Shinsuke; Maki, Yuho; Ichihara, Eiki; Asano, Hiroaki; Tsukuda, Kazunori; Takigawa, Nagio; Kiura, Katsuyuki; Gazdar, Adi F; Lam, Wan L; Miyoshi, Shinichiro

    2013-05-15

    Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) is a critical problem in the treatment of lung cancer. Although several mechanisms have been shown to be responsible for acquired resistance, all mechanisms have not been uncovered. In this study, we investigated the molecular and cellular profiles of the acquired resistant cells to EGFR-TKI in EGFR-mutant lung cancers. Four EGFR-mutant cell lines were exposed to gefitinib by stepwise escalation and high-concentration exposure methods, and resistant sublines to gefitinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Although previously reported, alterations including secondary EGFR T790M mutation, MET amplification, and appearance of epithelial-to-mesenchymal transition (EMT) features were observed, these 2 drug-exposure methods revealed different resistance mechanisms. The resistant cells with EMT features exhibited downregulation of miRNA-200c by DNA methylation. Furthermore, the HCC827-derived subline characterized by the high-concentration exposure method exhibited not only EMT features but also stem cell-like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) overexpression, increase of side-population, and self-renewal capability. Resistant sublines with stem cell-like properties were resistant to conventional chemotherapeutic agents but equally sensitive to histone deacetylase and proteasome inhibitors, compared with their parental cells. ALDH1A1 was upregulated in clinical samples with acquired resistance to gefitinib. In conclusion, our study indicates that the manner of EGFR-TKI exposure influences the mechanism of acquired resistance and the appearance of stem cell-like property with EGFR-TKI treatment. PMID:23542356

  2. The novel ATP-competitive MEK/Aurora kinase inhibitor BI-847325 overcomes acquired BRAF inhibitor resistance through suppression of Mcl-1 and MEK expression

    PubMed Central

    Phadke, Manali S.; Sini, Patrizia; Smalley, Keiran S. M.

    2015-01-01

    Resistance to BRAF inhibitors is a major clinical problem. Here we evaluate BI-847325, an ATP-competitive inhibitor of MEK and Aurora kinases, in treatment-naïve and drug-resistant BRAF-mutant melanoma models. BI-847325 potently inhibited growth and survival of melanoma cell lines that were both BRAF inhibitor naïve and resistant in 2D culture, 3D cell culture conditions and in colony formation assays. Western blot studies showed BI-847325 to reduce expression of phospho-ERK and phospho-histone 3 in multiple models of vemurafenib resistance. Mechanistically, BI-847325 decreased the expression of MEK and Mcl-1 while increasing the expression of the pro-apoptotic protein BIM. Strong suppression of MEK expression was observed after 48 h of treatment, with no recovery following >72 h of washout. siRNA mediated knockdown of Mcl-1 enhanced the effects of BI-847325, whereas Mcl-1 overexpression reversed this in both 2D cell culture and 3D spheroid melanoma models. In vivo, once weekly BI-847325 (70 mg/kg) led to durable regression of BRAF-inhibitor naive xenografts with no regrowth seen (>65 days of treatment). In contrast, treatment with the vemurafenib analog PLX4720 was associated with tumor relapse at >30 days. BI-847325 also suppressed the long-term growth of xenografts with acquired PLX4720 resistance. Analysis of tumor samples revealed BI-847325 to induce apoptosis associated with suppression of phospho-ERK, total MEK, phospho-Histone3 and Mcl-1 expression. Our studies indicate that BI-847325 is effective in overcoming BRAF inhibitor resistance and has long-term inhibitory effects upon BRAF-mutant melanoma in vivo, through a mechanism associated with the decreased expression of both MEK and Mcl-1. PMID:25873592

  3. The Novel ATP-Competitive MEK/Aurora Kinase Inhibitor BI-847325 Overcomes Acquired BRAF Inhibitor Resistance through Suppression of Mcl-1 and MEK Expression.

    PubMed

    Phadke, Manali S; Sini, Patrizia; Smalley, Keiran S M

    2015-06-01

    Resistance to BRAF inhibitors is a major clinical problem. Here, we evaluate BI-847325, an ATP-competitive inhibitor of MEK and Aurora kinases, in treatment-naïve and drug-resistant BRAF-mutant melanoma models. BI-847325 potently inhibited growth and survival of melanoma cell lines that were both BRAF inhibitor naïve and resistant in 2D culture, 3D cell culture conditions, and in colony formation assays. Western blot studies showed BI-847325 to reduce expression of phospho-ERK and phospho-histone 3 in multiple models of vemurafenib resistance. Mechanistically, BI-847325 decreased the expression of MEK and Mcl-1 while increasing the expression of the proapoptotic protein BIM. Strong suppression of MEK expression was observed after 48 hours of treatment, with no recovery following >72 hours of washout. siRNA-mediated knockdown of Mcl-1 enhanced the effects of BI-847325, whereas Mcl-1 overexpression reversed this in both 2D cell culture and 3D spheroid melanoma models. In vivo, once weekly BI-847325 (70 mg/kg) led to durable regression of BRAF-inhibitor naïve xenografts with no regrowth seen (>65 days of treatment). In contrast, treatment with the vemurafenib analog PLX4720 was associated with tumor relapse at >30 days. BI-847325 also suppressed the long-term growth of xenografts with acquired PLX4720 resistance. Analysis of tumor samples revealed BI-847325 to induce apoptosis associated with suppression of phospho-ERK, total MEK, phospho-Histone3, and Mcl-1 expression. Our studies indicate that BI-847325 is effective in overcoming BRAF inhibitor resistance and has long-term inhibitory effects upon BRAF-mutant melanoma in vivo, through a mechanism associated with the decreased expression of both MEK and Mcl-1. PMID:25873592

  4. Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance

    PubMed Central

    Song, Zilan; Wang, Meining; Zhang, Ao

    2015-01-01

    The development of inhibitors for the tyrosine anaplastic lymphoma kinase (ALK) has advanced rapidly, driven by biology and medicinal chemistry. The first generation ALK inhibitor crizotinib was granted US FDA approval with only four years of preclinical and clinical testing. Although this drug offers significant clinical benefit to the ALK-positive patients, resistance has been developed through a variety of mechanisms. In addition to ceritinib, alectinib is another second-generation ALK inhibitor launched in 2014 in Japan. This drug has a unique chemical structure bearing a 5H-benzo[b]carbazol-11(6H)-one structural scaffold with an IC50 value of 1.9 nmol/L, and is highly potent against ALK bearing the gatekeeper mutation L1196M with an IC50 of 1.56 nmol/L. In the clinic, alectinib is highly efficacious in treatment of ALK-positive non-small cell lung cancer (NSCLC), and retains potency to combat crizotinib-resistant ALK mutations L1196M, F1174L, R1275Q and C1156Y. PMID:26579422

  5. Axl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib.

    PubMed

    Giles, Keith M; Kalinowski, Felicity C; Candy, Patrick A; Epis, Michael R; Zhang, Priscilla M; Redfern, Andrew D; Stuart, Lisa M; Goodall, Gregory J; Leedman, Peter J

    2013-11-01

    Elevated expression and activity of the epidermal growth factor receptor (EGFR) is associated with development and progression of head and neck cancer (HNC) and a poor prognosis. Clinical trials with EGFR tyrosine kinase inhibitors (e.g., erlotinib) have been disappointing in HNC. To investigate the mechanisms mediating resistance to these agents, we developed an HNC cell line (HN5-ER) with acquired erlotinib resistance. In contrast to parental HN5 HNC cells, HN5-ER cells exhibited an epithelial-mesenchymal (EMT) phenotype with increased migratory potential, reduced E-cadherin and epithelial-associated microRNAs (miRNA), and elevated vimentin expression. Phosphorylated receptor tyrosine kinase profiling identified Axl activation in HN5-ER cells. Growth and migration of HN5-ER cells were blocked with a specific Axl inhibitor, R428, and R428 resensitized HN5-ER cells to erlotinib. Microarray analysis of HN5-ER cells confirmed the EMT phenotype associated with acquired erlotinib resistance, and identified activation of gene expression associated with cell migration and inflammation pathways. Moreover, increased expression and secretion of interleukin (IL)-6 and IL-8 in HN5-ER cells suggested a role for inflammatory cytokine signaling in EMT and erlotinib resistance. Expression of the tumor suppressor miR-34a was reduced in HN5-ER cells and increasing its expression abrogated Axl expression and reversed erlotinib resistance. Finally, analysis of 302 HNC patients revealed that high tumor Axl mRNA expression was associated with poorer survival (HR = 1.66, P = 0.007). In summary, our results identify Axl as a key mediator of acquired erlotinib resistance in HNC and suggest that therapeutic inhibition of Axl by small molecule drugs or specific miRNAs might overcome anti-EGFR therapy resistance. PMID:24026012

  6. DNA-dependent protein kinase catalytic subunit inhibitor reverses acquired radioresistance in lung adenocarcinoma by suppressing DNA repair.

    PubMed

    Li, Yong; Li, Hang; Peng, Wen; He, Xin-Yun; Huang, Min; Qiu, Dong; Xue, Ying-Bo; Lu, Liang

    2015-07-01

    The mechanisms underlying lung cancer radioresistance remain to be fully elucidated. The DNA repair pathway is a predominant target of radiotherapy, which is considered to be involved in the acquired radioresistance of cancer cells. The present study aimed to establish a radioresistant cell model using the A549 human lung cancer cell line, and to further investigate the potential mechanisms underlying the radioresistance. The A549R radioresistant lung cancer cell variant was established by exposing the parental A549 cells to repeated γ-ray irradiation at a total dose of 60 Gy. Colony formation assays were then used to determine cell survival following γ-ray exposure. The established radioresistant cells were subsequently treated with or without the NU7026 DNA-PKcs inhibitor. The levels of DNA damage were determined by counting the number of fluorescent γ-H2AX foci in the cells. The cellular capacity for DNA repair was assessed using antibodies for the detection of various DNA repair pathway proteins. The radioresistant sub-clones exhibited significantly decreased survival following NU7026 treatment, compared with the parental cells, as determined by colony formation assays (P<0.05), and this finding was found to be dose-dependent. Treatment with the DNA-dependent protein kinase (DNA-PK) inhibitor significantly reduced γ-H2AX foci formation (P<0.05) following acute radiation exposure in the radioresistant sub-clones, compared with the parental control cells. The decreased levels of γ-H2AX were accompanied by an increase in the percentage of apoptotic cells in the radioresistant cell line following post-radiation treatment with the DNA-PKcs inhibitor. The expression levels of proteins associated with the DNA repair pathway were altered markedly in the cells treated with NU7026. The results of the present study suggested that radioresistance may be associated with enhanced DNA repair following exposure to radiation, resulting in reduced apoptosis. Therefore, the

  7. Bortezomib, C1-inhibitor and plasma exchange do not prolong the survival of multi-transgenic GalT-KO pig kidney xenografts in baboons.

    PubMed

    Le Bas-Bernardet, S; Tillou, X; Branchereau, J; Dilek, N; Poirier, N; Châtelais, M; Charreau, B; Minault, D; Hervouet, J; Renaudin, K; Crossan, C; Scobie, L; Takeuchi, Y; Diswall, M; Breimer, M E; Klar, N; Daha, M R; Simioni, P; Robson, S C; Nottle, M B; Salvaris, E J; Cowan, P J; d'Apice, A J F; Sachs, D H; Yamada, K; Lagutina, I; Duchi, R; Perota, A; Lazzari, G; Galli, C; Cozzi, E; Soulillou, J-P; Vanhove, B; Blancho, G

    2015-02-01

    Galactosyl-transferase KO (GalT-KO) pigs represent a potential solution to xenograft rejection, particularly in the context of additional genetic modifications. We have performed life supporting kidney xenotransplantation into baboons utilizing GalT-KO pigs transgenic for human CD55/CD59/CD39/HT. Baboons received tacrolimus, mycophenolate mofetil, corticosteroids and recombinant human C1 inhibitor combined with cyclophosphamide or bortezomib with or without 2-3 plasma exchanges. One baboon received a control GalT-KO xenograft with the latter immunosuppression. All immunosuppressed baboons rejected the xenografts between days 9 and 15 with signs of acute humoral rejection, in contrast to untreated controls (n = 2) that lost their grafts on days 3 and 4. Immunofluorescence analyses showed deposition of IgM, C3, C5b-9 in rejected grafts, without C4d staining, indicating classical complement pathway blockade but alternate pathway activation. Moreover, rejected organs exhibited predominantly monocyte/macrophage infiltration with minimal lymphocyte representation. None of the recipients showed any signs of porcine endogenous retrovirus transmission but some showed evidence of porcine cytomegalovirus (PCMV) replication within the xenografts. Our work indicates that the addition of bortezomib and plasma exchange to the immunosuppressive regimen did not significantly prolong the survival of multi-transgenic GalT-KO renal xenografts. Non-Gal antibodies, the alternative complement pathway, innate mechanisms with monocyte activation and PCMV replication may have contributed to rejection. PMID:25612490

  8. Bortezomib, C1-inhibitor and Plasma Exchange Do Not Prolong the Survival of Multi-transgenic GalT-KO Pig Kidney Xenografts in Baboons

    PubMed Central

    Le, Bas-Bernardet S.; Tillou, X.; Branchereau, J.; Dilek, N.; Poirier, N.; Châtelais, M.; Charreau, B.; Minault, D.; Hervouet, J.; Renaudin, K.; Crossan, C.; Scobie, L.; Takeuchi, Y.; Diswall, M.; Breimer, M.E.; Klar, N.; Daha, M.R.; Simioni, P.; Robson, S.C.; Nottle, M.B.; Salvaris, E.J.; Cowan, P.J.; d’Apice, A.J.F.; Sachs, D.H.; Yamada, K.; Lagutina, I.; Duchi, R.; Perota, A.; Lazzari, G.; Galli, C.; Cozzi, E.; Soulillou, J.-P.; B., Vanhove; Blancho, G.

    2014-01-01

    Galactosyl-transferase knock-out (GalT-KO) pigs represent a potential solution to xenograft rejection, particularly in the context of additional genetic modifications. We have performed life supporting kidney xenotransplantation into baboons utilizing GalT-KO pigs transgenic for human CD55/CD59/CD39/HT. Baboons received tacrolimus, mycophenolate mofetil, corticosteroids and recombinant human C1 Inhibitor combined with cyclophosphamide or bortezomib with or without 2–3 plasma exchanges. One baboon received a control GalT-KO xenograft with the latter immunosuppression. All immunosuppressed baboons rejected the xenografts between days 9 to 15 with signs of acute humoral rejection, in contrast to untreated controls (n=2) which lost their grafts on day 3 and 4. Immunofluorescence analyses showed deposition of IgM, C3, C5b-9 in rejected grafts, without C4d staining, indicating classical complement pathway blockade but alternate pathway activation. Moreover, rejected organs exhibited predominantly monocyte/macrophage infiltration with minimal lymphocyte representation. None of the recipients showed any signs of PERV transmission but some showed evidence of PCMV replication within the xenografts. Our work indicates that the addition of bortezomib and plasma exchange to the immunosuppressive regimen did not significantly prolong the survival of multi-transgenic GalT-KO renal xenografts. Non-Gal antibodies, the alternative complement pathway, innate mechanisms with monocyte activation and PCMV replication may have contributed to rejection. PMID:25612490

  9. Mechanisms of Acquired Resistance to ALK Inhibitors and the Rationale for Treating ALK-positive Lung Cancer.

    PubMed

    Isozaki, Hideko; Takigawa, Nagio; Kiura, Katsuyuki

    2015-01-01

    The discovery of an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene led to improved clinical outcomes in patients with lung cancer after the development of the first ALK-targeting agent, crizotinib. Some second-generation ALK tyrosine kinase inhibitors (TKIs), which might be more potent than crizotinib or effective on crizotinib-resistant patients, have been developed. Although these ALK-TKIs show an excellent response initially, most patients eventually acquire resistance. Therefore, careful consideration of the resistance mechanisms might lead to superior therapeutic strategies. Here, we summarize the history of ALK-TKIs and their underlying resistance mechanisms in both the preclinical and clinical settings. In addition, we discuss potential future treatment strategies in ALK-TKI-naïve and -resistant patients with lung cancer harboring the EML4-ALK fusion gene. PMID:25941796

  10. Mechanisms of Acquired Resistance to ALK Inhibitors and the Rationale for Treating ALK-positive Lung Cancer

    PubMed Central

    Isozaki, Hideko; Takigawa, Nagio; Kiura, Katsuyuki

    2015-01-01

    The discovery of an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene led to improved clinical outcomes in patients with lung cancer after the development of the first ALK-targeting agent, crizotinib. Some second-generation ALK tyrosine kinase inhibitors (TKIs), which might be more potent than crizotinib or effective on crizotinib-resistant patients, have been developed. Although these ALK-TKIs show an excellent response initially, most patients eventually acquire resistance. Therefore, careful consideration of the resistance mechanisms might lead to superior therapeutic strategies. Here, we summarize the history of ALK-TKIs and their underlying resistance mechanisms in both the preclinical and clinical settings. In addition, we discuss potential future treatment strategies in ALK-TKI-naïve and -resistant patients with lung cancer harboring the EML4-ALK fusion gene. PMID:25941796

  11. Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitors

    PubMed Central

    Baker, Theresa; Nerle, Sujata; Pritchard, Justin; Zhao, Boyang; Rivera, Victor M.

    2015-01-01

    Although targeted therapies have revolutionized cancer treatment, overcoming acquired resistance remains a major clinical challenge. EZH2 inhibitors (EZH2i), EPZ-6438 and GSK126, are currently in the early stages of clinical evaluation and the first encouraging signs of efficacy have recently emerged in the clinic. To anticipate mechanisms of resistance to EZH2i, we used a forward genetic platform combining a mutagenesis screen with next generation sequencing technology and identified a hotspot of secondary mutations in the EZH2 D1 domain (Y111 and I109). Y111D mutation within the WT or A677G EZH2 allele conferred robust resistance to both EPZ-6438 and GSK126, but it only drove a partial resistance within the Y641F allele. EZH2 mutants required histone methyltransferase (HMT) catalytic activity and the polycomb repressive complex 2 (PRC2) components, SUZ12 and EED, to drive drug resistance. Furthermore, D1 domain mutations not only blocked the ability of EZH2i to bind to WT and A677G mutant, but also abrogated drug binding to the Y641F mutant. These data provide the first cellular validation of the mechanistic model underpinning the oncogenic function of WT and mutant EZH2. Importantly, our findings suggest that acquired-resistance to EZH2i may arise in WT and mutant EZH2 patients through a single mutation that remains targetable by second generation EZH2i. PMID:26360609

  12. Non-Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases.

    PubMed

    Isozaki, Hideko; Ichihara, Eiki; Takigawa, Nagio; Ohashi, Kadoaki; Ochi, Nobuaki; Yasugi, Masayuki; Ninomiya, Takashi; Yamane, Hiromichi; Hotta, Katsuyuki; Sakai, Katsuya; Matsumoto, Kunio; Hosokawa, Shinobu; Bessho, Akihiro; Sendo, Toshiaki; Tanimoto, Mitsune; Kiura, Katsuyuki

    2016-03-15

    Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult. PMID:26719536

  13. A C1 inhibitor ortholog from rock bream (Oplegnathus fasciatus): molecular perspectives of a central regulator in terms of its genomic arrangement, transcriptional profiles and anti-protease activities of recombinant peptide.

    PubMed

    Umasuthan, Navaneethaiyer; Bathige, S D N K; Revathy, Kasthuri Saranya; Wickramaarachchi, W D N; Wan, Qiang; Whang, Ilson; Kim, Eunmi; Park, Myoung-Ae; Park, Hae-Chul; Lee, Jehee

    2014-02-01

    C1 inhibitor (C1Inh), a member of serpin superfamily, is a crucial regulator of the activation of various plasmatic cascades associated with immunity and inflammation. This study describes the identification and characterization of a C1Inh gene from rock bream Oplegnathus fasciatus (OfC1Inh) at structural, expressional and functional levels. The cDNA-(2245bp) and corresponding gDNA-sequences (5.2kbp) of OfC1Inh were isolated from rock bream transcriptome- and BAC-libraries, respectively. Predicted amino acid sequence of OfC1Inh revealed a two-domain architecture composed of an N-terminal region with two Ig-like domains and a C-terminal region with a serpin domain. Tertiary model of OfC1Inh disclosed its active site topology. In the multi-exonic genomic arrangement of OfC1Inh, it consisted of eleven exons disjoined by ten introns as observed in few other fish homologs. Our comparative analysis indicated that the teleostean C1Inhs were distinct from their non-teleostean vertebrate counterparts in terms of their (1) extended N-terminal domains, (2) evolutionary divergence and (3) exon-intron distribution. The OfC1Inh had a TATA-deficient promoter with a putative initiator element, and two tandemly arranged downstream promoter elements. Several components associated with the immune and inflammatory transcriptional activation were also predicted to exist in 5' flanking region of OfC1Inh. The exclusive mRNA levels in liver and moderate levels in extra-hepatic tissues intimated the diversified importance of OfC1Inh in rock bream physiology. We also provide an evidence for the involvement of OfC1Inh in immune balance, based on its modulated transcription upon different PAMP (lipopolysaccharide and poly I:C)- or pathogen (Streptococcus iniae and rock bream irido virus)-challenges. A recombinantly expressed fusion protein [(r)OfC1Inh] was employed in demonstrating the anti-protease function of OfC1Inh. The (r)OfC1Inh exhibited detectable inhibitory activity against C1

  14. A Nexus Consisting of Beta-Catenin and Stat3 Attenuates BRAF Inhibitor Efficacy and Mediates Acquired Resistance to Vemurafenib.

    PubMed

    Sinnberg, Tobias; Makino, Elena; Krueger, Marcel A; Velic, Ana; Macek, Boris; Rothbauer, Ulrich; Groll, Nicola; Pötz, Oliver; Czemmel, Stefan; Niessner, Heike; Meier, Friedegund; Ikenberg, Kristian; Garbe, Claus; Schittek, Birgit

    2016-06-01

    Acquired resistance to second generation BRAF inhibitors (BRAFis), like vemurafenib is limiting the benefits of long term targeted therapy for patients with malignant melanomas that harbor BRAF V600 mutations. Since many resistance mechanisms have been described, most of them causing a hyperactivation of the MAPK- or PI3K/AKT signaling pathways, one potential strategy to overcome BRAFi resistance in melanoma cells would be to target important common signaling nodes. Known factors that cause secondary resistance include the overexpression of receptor tyrosine kinases (RTKs), alternative splicing of BRAF or the occurrence of novel mutations in MEK1 or NRAS. In this study we show that β-catenin is stabilized and translocated to the nucleus in approximately half of the melanomas that were analyzed and which developed secondary resistance towards BRAFi. We further demonstrate that β-catenin is involved in the mediation of resistance towards vemurafenib in vitro and in vivo. Unexpectedly, β-catenin acts mainly independent of the TCF/LEF dependent canonical Wnt-signaling pathway in resistance development, which partly explains previous contradictory results about the role of β-catenin in melanoma progression and therapy resistance. We further demonstrate that β-catenin interacts with Stat3 after chronic vemurafenib treatment and both together cooperate in the acquisition and maintenance of resistance towards BRAFi. PMID:27428425

  15. [A case report of hereditary angioedema and studies on the serum components of complement, C1-inactivator and proteinase inhibitors during edema attack].

    PubMed

    Mikami, A; Kohno, M

    1987-05-01

    Sixteen years old girl was admitted because of for the past ten years' frequent edema attack and abdominal pain. Laboratory examination revealed hypocomplementemia, marked depletion of the fourth component of complement and low level of C1-inactivator. Familial studies revealed that her mother was also hypocomplementemic and in low level of C1-inactivator. Serial studies performed on the alterlation of components of complement, C1-inactivator, alpha 1-antitrypsin, antithrombin III, and alpha 2-macroglobulin during edema attack. The fourth component of complement and C1-inactivator were markedly depleted in remission and attack. Remarkable depletion was found in antithrombin III and esterase inhibition activity of C1-inactivator during attack. In contrast, alpha 1-antitrypsin and alpha 2-macroglobulin did not change. The present study may explain that Hageman factor fragments, activated by C1s, promotes kinin generation via kalikrein activation. And the condition that complete functional deficiency of C1-inactivator was main role in this circuit. Fibrynolysis and late components of complement was less influence on edema attack. PMID:3610041

  16. Feasibility of home infusion and self-administration of nanofiltered C1 esterase inhibitor for routine prophylaxis in patients with hereditary angioedema and characterization of a training and support program.

    PubMed

    Gregory, Cherylann; Landmesser, Ladonna M; Corrigan, Larry; Mariano, David

    2014-01-01

    Hereditary angioedema (HAE) is a rare, chronic disease of C1 inhibitor deficiency. Study researchers evaluated the prevalence of home and self-administration of nanofiltered, human-derived C1 esterase inhibitor infusions and the implementation of a nursing training and support program. Home administration rate increased from 49.0% to 75.8%. The percentage who self-administered increased from 20.3% to 43.9%. Doses per week averaged 1.85 at home compared with 1.40 in infusion centers and physicians' offices. Patients required an average of 5 visits to be trained. Self-administration is a viable, feasible option in the management of HAE, which is facilitated by a nurse-managed training and support program. PMID:24384882

  17. Successful use of daily intravenous infusion of C1 esterase inhibitor concentrate in the treatment of a hereditary angioedema patient with ascites, hypovolemic shock, sepsis, renal and respiratory failure.

    PubMed

    Pham, Hoang; Santucci, Stephanie; Yang, William H

    2014-01-01

    Hereditary angioedema (HAE) is a rare autosomal dominant disease most commonly associated with defects in C1 esterase inhibitor (C1-INH). HAE manifests as recurrent episodes of edema in various body locations. Atypical symptoms, such as ascites, acute respiratory distress syndrome, and hypovolemic shock, have also been reported. Management of HAE conventionally involves the treatment of acute attacks, as well as short- and long-term prophylaxis. Since attacks can be triggered by several factors, including stress and physical trauma, prophylactic therapy is recommended for patients undergoing surgery. Human plasma-derived C1-INH (pdC1-INH) concentrate is indicated for the treatment of both acute HAE attacks and pre-procedure prevention of HAE episodes in patients undergoing medical, dental, or surgical procedures. We report the first case of a patient with HAE who experienced an abdominal attack precipitated by a retroperitoneal bleed while being converted from warfarin to heparin in preparation for surgery. Subsequently, the patient had a protracted course in hospital with other complications, which included hypovolemic shock, ascites, severe sepsis from nosocomial pneumonia, renal and respiratory failure. Despite intensive interventions, the patient remained in a critical state for months; however, after a trial of daily intravenous infusion of pdC1-INH concentrate (Berinert®, CSL Behring GmbH, Marburg, Germany), clinical status improved, particularly renal function. Therefore, pdC1-INH concentrate may be an effective treatment option to consider for critically-ill patients with HAE. PMID:25520740

  18. Risk of Community-Acquired Pneumonia with Outpatient Proton-Pump Inhibitor Therapy: A Systematic Review and Meta-Analysis

    PubMed Central

    Lambert, Allison A.; Lam, Jennifer O.; Paik, Julie J.; Ugarte-Gil, Cesar; Drummond, M. Bradley; Crowell, Trevor A.

    2015-01-01

    Background Proton-pump inhibitors (PPIs) are among the most frequently prescribed medications. Community-acquired pneumonia (CAP) is a common cause of morbidity, mortality and healthcare spending. Some studies suggest an increased risk of CAP among PPI users. We conducted a systematic review and meta-analysis to determine the association between outpatient PPI therapy and risk of CAP in adults. Methods We conducted systematic searches of MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Scopus and Web of Science on February 3, 2014. Case-control studies, case-crossover, cohort studies and randomized controlled trials reporting outpatient PPI exposure and CAP diagnosis for patients ≥18 years old were eligible. Our primary outcome was the association between CAP and PPI therapy. A secondary outcome examined the risk of hospitalization for CAP and subgroup analyses evaluated the association between PPI use and CAP among patients of different age groups, by different PPI doses, and by different durations of PPI therapy. Results Systematic review of 33 studies was performed, of which 26 studies were included in the meta-analysis. These 26 studies included 226,769 cases of CAP among 6,351,656 participants. We observed a pooled risk of CAP with ambulatory PPI therapy of 1.49 (95% CI 1.16, 1.92; I2 99.2%). This risk was increased during the first month of therapy (OR 2.10; 95% CI 1.39, 3.16), regardless of PPI dose or patient age. PPI therapy also increased risk for hospitalization for CAP (OR 1.61; 95% CI: 1.12, 2.31). Discussion Outpatient PPI use is associated with a 1.5-fold increased risk of CAP, with the highest risk within the first 30 days after initiation of therapy. Providers should be aware of this risk when considering PPI use, especially in cases where alternative regimens may be available or the benefits of PPI use are uncertain. PMID:26042842

  19. Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.

    PubMed

    Suda, Kenichi; Mizuuchi, Hiroshi; Maehara, Yoshihiko; Mitsudomi, Tetsuya

    2012-12-01

    Lung cancers that harbor somatic activating mutations in the gene for the epidermal growth factor receptor (EGFR) depend on mutant EGFR for their proliferation and survival; therefore, lung cancer patients with EGFR mutations often dramatically respond to orally available EGFR tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. To elucidate and overcome this acquired resistance, multidisciplinary basic and clinical investigational approaches have been applied, using in vitro cell line models or samples obtained from lung cancer patients treated with EGFR-TKIs. These efforts have revealed several acquired resistance mechanisms and candidates, including EGFR secondary mutations (T790M and other rare mutations), MET amplification, PTEN downregulation, CRKL amplification, high-level HGF expression, FAS-NFκB pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer. Interestingly, cancer cells harbor potential destiny and ductility together in acquiring resistance to EGFR-TKIs, as shown in in vitro acquired resistance models. Molecular mechanisms of "reversible EGFR-TKI tolerance" that occur in early phase EGFR-TKI exposure have been identified in cell line models. Furthermore, others have reported molecular markers that can predict response to EGFR-TKIs in clinical settings. Deeper understanding of acquired resistance mechanisms to EGFR-TKIs, followed by the development of molecular target drugs that can overcome the resistance, might turn this fatal disease into a chronic disorder. PMID:22736441

  20. Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models.

    PubMed

    Eberlein, Catherine A; Stetson, Daniel; Markovets, Aleksandra A; Al-Kadhimi, Katherine J; Lai, Zhongwu; Fisher, Paul R; Meador, Catherine B; Spitzler, Paula; Ichihara, Eiki; Ross, Sarah J; Ahdesmaki, Miika J; Ahmed, Ambar; Ratcliffe, Laura E; O'Brien, Elizabeth L Christey; Barnes, Claire H; Brown, Henry; Smith, Paul D; Dry, Jonathan R; Beran, Garry; Thress, Kenneth S; Dougherty, Brian; Pao, William; Cross, Darren A E

    2015-06-15

    Resistance to targeted EGFR inhibitors is likely to develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR-mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR tyrosine kinase inhibitors, including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002, or AZD9291. Compared with parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumors in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumors. Furthermore, these findings suggest that NRAS modifications in tumor samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition. PMID:25870145

  1. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1.

    PubMed

    Ohashi, Kadoaki; Sequist, Lecia V; Arcila, Maria E; Moran, Teresa; Chmielecki, Juliann; Lin, Ya-Lun; Pan, Yumei; Wang, Lu; de Stanchina, Elisa; Shien, Kazuhiko; Aoe, Keisuke; Toyooka, Shinichi; Kiura, Katsuyuki; Fernandez-Cuesta, Lynnette; Fidias, Panos; Yang, James Chih-Hsin; Miller, Vincent A; Riely, Gregory J; Kris, Mark G; Engelman, Jeffrey A; Vnencak-Jones, Cindy L; Dias-Santagata, Dora; Ladanyi, Marc; Pao, William

    2012-07-31

    Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment. PMID:22773810

  2. 4,5-Disubstituted 6-Aryloxy-1,3-dihydrobenzo[c][1,2]oxaboroles Are Broad-Spectrum Serine β-Lactamase Inhibitors.

    PubMed

    McKinney, David C; Zhou, Fei; Eyermann, Charles J; Ferguson, Andrew D; Prince, D Bryan; Breen, John; Giacobbe, Robert A; Lahiri, Sushmita; Verheijen, Jeroen C

    2015-07-10

    Bacterially expressed β-lactamases are rapidly eroding the clinical utility of the important β-lactam class of antibacterials, significantly impairing our ability to fight serious bacterial infections. This paper describes a study of oxaborole-derived β-lactamase inhibitors in which crystal structures and computational modeling aided in the rational design of analogues with improved spectrum of activity against class A, C, and D enzymes. Crystal structures of two of these inhibitors covalently bound to two different serine β-lactamases, class C Pseudomonas aeruginosa AmpC and class D OXA-10, are described herein. Improved physicochemical properties as well as increased activity against an array of β-lactamases resulted in substantial restoration of susceptibility to ceftazidime in Escherichia coli and Klebsiella pneumoniae. PMID:27622821

  3. Acquired resistance to mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models

    PubMed Central

    Eberlein, Catherine A.; Stetson, Daniel; Markovets, Aleksandra A.; Al-Kadhimi, Katherine J.; Lai, Zhongwu; Fisher, Paul R.; Meador, Catherine B.; Spitzler, Paula; Ichihara, Eiki; Ross, Sarah J.; Ahdesmaki, Miika J.; Ahmed, Ambar; Ratcliffe, Laura E.; Christey O’Brien, Elizabeth L.; Barnes, Claire H.; Brown, Henry; Smith, Paul D.; Dry, Jonathan R.; Beran, Garry; Thress, Kenneth S.; Dougherty, Brian; Pao, William; Cross, Darren A. E.

    2015-01-01

    Resistance to targeted EGFR inhibitors is likely to develop in EGFR mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR TKIs including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002 or AZD9291. Compared to parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumours in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumours. Further, these findings suggest that NRAS modifications in tumour samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition. PMID:25870145

  4. HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors.

    PubMed

    Sottile, Rosa; Pangigadde, Pradeepa N; Tan, Thomas; Anichini, Andrea; Sabbatino, Francesco; Trecroci, Francesca; Favoino, Elvira; Orgiano, Laura; Roberts, James; Ferrone, Soldano; Kärre, Klas; Colucci, Francesco; Carbone, Ennio

    2016-02-01

    The frequent development of drug resistance to targeted therapies in cancer patients has stimulated interest in strategies counteracting resistance. Combining immunotherapies with targeted therapies is one such strategy. In this context, we asked whether human NK cells can target melanoma cells that have acquired resistance to selective inhibitors targeting activating mutants of the B-Raf kinase (BRAF inhibitors, BRAFi). We generated drug-resistant cell variants in vitro from human BRAF-mutant melanoma cell lines MEL-HO, COLO-38, SK-MEL-37, 1520 and from primary melanoma cells freshly isolated from two patients. All drug-resistant cell variants remained susceptible to lysis by IL-2-activated NK cells; and two BRAFi-resistant lines (BRAFi-R) became significantly more susceptible to NK-cell lysis than their parental lines. This was associated with significant HLA class I antigen downregulation and PD-L1 upregulation on the drug-resistant lines. Although blocking HLA class I enhanced the extent of lysis of both BRAFi-R and parental cells to NK-cell-mediated lysis, antibody-mediated inhibition of PD1-PD-L1 interactions had no detectable effect. HLA class I antigen expression on BRAFi-R melanoma variants thus appears to play a major role in their susceptibility to NK-cell cytotoxicity. These findings suggest that NK-cell-based immunotherapy may be a viable approach to treat melanoma patients with acquired resistance to BRAF inhibitors. PMID:26564811

  5. HLA class I downregulation is associated with enhanced NK‐cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors

    PubMed Central

    Sottile, Rosa; Pangigadde, Pradeepa N.; Tan, Thomas; Anichini, Andrea; Sabbatino, Francesco; Trecroci, Francesca; Favoino, Elvira; Orgiano, Laura; Roberts, James; Ferrone, Soldano; Kärre, Klas; Colucci, Francesco

    2015-01-01

    The frequent development of drug resistance to targeted therapies in cancer patients has stimulated interest in strategies counteracting resistance. Combining immunotherapies with targeted therapies is one such strategy. In this context, we asked whether human NK cells can target melanoma cells that have acquired resistance to selective inhibitors targeting activating mutants of the B‐Raf kinase (BRAF inhibitors, BRAFi). We generated drug‐resistant cell variants in vitro from human BRAF‐mutant melanoma cell lines MEL‐HO, COLO‐38, SK‐MEL‐37, 1520 and from primary melanoma cells freshly isolated from two patients. All drug‐resistant cell variants remained susceptible to lysis by IL‐2‐activated NK cells; and two BRAFi‐resistant lines (BRAFi‐R) became significantly more susceptible to NK‐cell lysis than their parental lines. This was associated with significant HLA class I antigen downregulation and PD‐L1 upregulation on the drug‐resistant lines. Although blocking HLA class I enhanced the extent of lysis of both BRAFi‐R and parental cells to NK‐cell‐mediated lysis, antibody‐mediated inhibition of PD1–PD‐L1 interactions had no detectable effect. HLA class I antigen expression on BRAFi‐R melanoma variants thus appears to play a major role in their susceptibility to NK‐cell cytotoxicity. These findings suggest that NK‐cell‐based immunotherapy may be a viable approach to treat melanoma patients with acquired resistance to BRAF inhibitors. PMID:26564811

  6. Acquired resistance of pancreatic cancer cells to treatment with gemcitabine and HER-inhibitors is accompanied by increased sensitivity to STAT3 inhibition

    PubMed Central

    IOANNOU, NIKOLAOS; SEDDON, ALAN M.; DALGLEISH, ANGUS; MACKINTOSH, DAVID; SOLCA, FLAVIO; MODJTAHEDI, HELMOUT

    2016-01-01

    Drug-resistance is a major contributing factor for the poor prognosis in patients with pancreatic cancer. We have shown previously that the irreversible ErbB family blocker afatinib, is more effective than the reversible EGFR tyrosine kinase inhibitor erlotinib in inhibiting the growth of human pancreatic cancer cells. The aim of this study was to develop human pancreatic cancer cell (BxPc3) variants with acquired resistance to treatment with gemcitabine, afatinib, or erlotinib, and to investigate the molecular changes that accompany the acquisition of a drug-resistant phenotype. We also investigated the therapeutic potential of various agents in the treatment of such drug-resistant variants. Three variant forms of BxPc3 cells with acquired resistance to gemcitabine (BxPc3GEM), afatinib (BxPc3AFR) or erlotinib (BxPc3OSIR) were developed following treatment with increasing doses of such drugs. The expression level, mutational and phosphorylation status of various growth factor receptors and downstream cell signaling molecules were determined by FACS, human phopsho-RTK array, and western blot analysis while the sulforhodamine B assay was used for determining the effect of various agents on the growth of such tumours. We found that all three BxPc3 variants with acquired resistance to gemcitabine (BxPc3GEM), afatinib (BxPc3AFR) or erlotinib (BxPc3OSIR) also become less sensitive to treatment with the two other agents. Acquisition of resistance to these agents was accompanied by upregulation of p-c-MET, p-STAT3, CD44, increased autocrine production of EGFR ligand amphiregulin and differential activation status of EGFR tyrosine residues as well as downregulation of total and p-SRC. Of all therapeutic interventions examined, including the addition of an anti-EGFR antibody ICR62, an anti-CD44 monoclonal antibody, and of STAT3 or c-MET inhibitors, only treatment with the STAT3 inhibitor Stattic produced a higher growth inhibitory effect in all three drug-resistant variants

  7. Acquired resistance to HSP90 inhibitor 17-AAG and increased metastatic potential are associated with MUC1 expression in colon carcinoma cells.

    PubMed

    Liu, Xin; Ban, Li-Li; Luo, Gang; Li, Zhi-Yao; Li, Yun-Feng; Zhou, Yong-Chun; Wang, Xi-Cai; Jin, Cong-Guo; Ye, Jia-Gui; Ma, Ding-Ding; Xie, Qing; Huang, You-Guang

    2016-06-01

    Heat shock protein 90 (HSP90) is a molecular chaperone required for the stability and function of many proteins. The chaperoning of oncoproteins by HSP90 enhances the survival, growth, and invasive potential of cancer cells. HSP90 inhibitors are promising new anticancer agents, in which the benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in clinical evaluation. However, the implications of acquired resistance to this class of drug remain largely unexplored. In the present study, we have generated isogenic human colon cancer cell lines that are resistant to 17-AAG by continued culturing in the compound. Cross-resistance was found with another HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin. The resistant cells showed obvious morphology changes with a metastatic phenotype and significant increases in migration and adhesion to collagens. Western blotting analysis of epithelial-mesenchymal transition molecular markers found that expression of E-cadherin downregulated, whereas expression of N-cadherin and β-catenin upregulated in the resistant cells. Mucin 1 (MUC1) has been reported to mediate metastasis as well as chemical resistance in many cancers. Here, we found that MUC1 expression was significantly elevated in the acquired drug resistance cells. 17-AAG treatment could decrease MUC1 more in parental cells than in acquired 17-AAG-resistant cells. Further study found that knockdown of MUC1 expression by small interfering RNA could obviously re-sensitize the resistant cells to 17-AAG treatment, and decrease the cell migration and adhesion. These were coupled with a downregulation in N-cadherin and β-catenin. The results indicate that HSP90 inhibitor therapies in colon carcinomas could generate resistance and increase metastatic potential that might mediated by upregulation of MUC1 expression. Findings from this study further our understanding of the potential clinical effects of HSP90-directed therapies in

  8. ZEB1 Mediates Acquired Resistance to the Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer

    PubMed Central

    Yoshida, Takeshi; Song, Lanxi; Bai, Yun; Kinose, Fumi; Li, Jiannong; Ohaegbulam, Kim C.; Muñoz-Antonia, Teresita; Qu, Xiaotao; Eschrich, Steven; Uramoto, Hidetaka; Tanaka, Fumihiro; Nasarre, Patrick; Gemmill, Robert M.; Roche, Joëlle; Drabkin, Harry A.; Haura, Eric B.

    2016-01-01

    Epithelial-mesenchymal transition (EMT) is one mechanism of acquired resistance to inhibitors of the epidermal growth factor receptor-tyrosine kinases (EGFR-TKIs) in non-small cell lung cancer (NSCLC). The precise mechanisms of EMT-related acquired resistance to EGFR-TKIs in NSCLC remain unclear. We generated erlotinib-resistant HCC4006 cells (HCC4006ER) by chronic exposure of EGFR-mutant HCC4006 cells to increasing concentrations of erlotinib. HCC4006ER cells acquired an EMT phenotype and activation of the TGF-β/SMAD pathway, while lacking both T790M secondary EGFR mutation and MET gene amplification. We employed gene expression microarrays in HCC4006 and HCC4006ER cells to better understand the mechanism of acquired EGFR-TKI resistance with EMT. At the mRNA level, ZEB1 (TCF8), a known regulator of EMT, was >20-fold higher in HCC4006ER cells than in HCC4006 cells, and increased ZEB1 protein level was also detected. Furthermore, numerous ZEB1 responsive genes, such as CDH1 (E-cadherin), ST14, and vimentin, were coordinately regulated along with increased ZEB1 in HCC4006ER cells. We also identified ZEB1 overexpression and an EMT phenotype in several NSCLC cells and human NSCLC samples with acquired EGFR-TKI resistance. Short-interfering RNA against ZEB1 reversed the EMT phenotype and, importantly, restored erlotinib sensitivity in HCC4006ER cells. The level of micro-RNA-200c, which can negatively regulate ZEB1, was significantly reduced in HCC4006ER cells. Our results suggest that increased ZEB1 can drive EMT-related acquired resistance to EGFR-TKIs in NSCLC. Attempts should be made to explore targeting ZEB1 to resensitize TKI-resistant tumors. PMID:26789630

  9. Acquired C797S Mutation upon Treatment with a T790M-Specific Third-Generation EGFR Inhibitor (HM61713) in Non-Small Cell Lung Cancer.

    PubMed

    Song, Haa-Na; Jung, Ki Sun; Yoo, Kwai Han; Cho, Jinhyun; Lee, Ji Yun; Lim, Sung Hee; Kim, Hae Su; Sun, Jong-Mu; Lee, Se-Hoon; Ahn, Jin Seok; Park, Keunchil; Choi, Yoon-La; Park, Woongyang; Ahn, Myung-Ju

    2016-04-01

    T790M mutation is most common resistant mechanism to epidermal growth factor receptor gene (EGFR) tyrosin kinase inhibitor (TKI). Several third-generation EGFR-mutant selective TKI, such as AZD9291 (AstraZeneca), Rociletinib (Clovis), or HM61713 (Hanmi) have been developed. Acquired resistant C797S mutation was known to be one of the resistance mechanisms of AZD9291, which has not been reported for HM61713 yet. This is the first case report of C797S mutation as resistance mechanism of HM61713. PMID:26749488

  10. Clinical approaches to treat patients with non-small cell lung cancer and epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance.

    PubMed

    Tartarone, Alfredo; Lerose, Rosa

    2015-10-01

    The discovery of epidermal growth factor receptor activating mutations (EGFR Mut+) has determined a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). In several phase III studies, patients with NSCLC EGFR Mut+ achieved a significantly better progression-free survival when treated with a first- (gefitinib, erlotinib) or second-generation (afatinib) EGFR tyrosine kinase inhibitor (TKI) compared with standard chemotherapy. However, despite these impressive results, most patients with NSCLC EGFR Mut+ develop acquired resistance to TKIs. This review will discuss both the mechanisms of resistance to TKIs and the therapeutic strategies to overcome resistance, including emerging data on third-generation TKIs. PMID:26016841

  11. Direct pharmacological assessment of clinically acquired models as a strategy to overcome resistance to tyrosine kinase inhibitors

    PubMed Central

    Benes, Cyril H

    2015-01-01

    We have performed a study using cell lines established from biopsies of clinically resistant non-small cell lung cancers with the aim of discovering therapeutic strategies to overcome acquired resistance. Our results indicate that pharmacological assessment of tumor material might efficiently complement genetic profiling in the future path toward personalized medicine. PMID:27308520

  12. Direct pharmacological assessment of clinically acquired models as a strategy to overcome resistance to tyrosine kinase inhibitors.

    PubMed

    Benes, Cyril H

    2015-01-01

    We have performed a study using cell lines established from biopsies of clinically resistant non-small cell lung cancers with the aim of discovering therapeutic strategies to overcome acquired resistance. Our results indicate that pharmacological assessment of tumor material might efficiently complement genetic profiling in the future path toward personalized medicine. PMID:27308520

  13. mTOR Inhibitors Control the Growth of EGFR Mutant Lung Cancer Even after Acquiring Resistance by HGF

    PubMed Central

    Ishikawa, Daisuke; Takeuchi, Shinji; Nakagawa, Takayuki; Sano, Takako; Nakade, Junya; Nanjo, Shigeki; Yamada, Tadaaki; Ebi, Hiromichi; Zhao, Lu; Yasumoto, Kazuo; Nakamura, Takahiro; Matsumoto, Kunio; Kagamu, Hiroshi; Yoshizawa, Hirohisa; Yano, Seiji

    2013-01-01

    Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is a critical problem in the treatment of EGFR mutant lung cancer. Several mechanisms, including bypass signaling by hepatocyte growth factor (HGF)-triggered Met activation, are implicated as mediators of resistance. The mammalian target of rapamycin (mTOR), is a downstream conduit of EGFR and MET signaling, and is thus considered a therapeutically attractive target in the treatment of various types of cancers. The purpose of this study was to examine whether 2 clinically approved mTOR inhibitors, temsirolimus and everolimus, overcome HGF-dependent resistance to EGFR-TKIs in EGFR mutant lung cancer cells. Both temsirolimus and everolimus inhibited the phosphorylation of p70S6K and 4E-BP1, which are downstream targets of the mTOR pathway, and reduced the viability of EGFR mutant lung cancer cells, PC-9, and HCC827, even in the presence of HGF in vitro. In a xenograft model, temsirolimus suppressed the growth of PC-9 cells overexpressing the HGF-gene; this was associated with suppression of the mTOR signaling pathway and tumor angiogenesis. In contrast, erlotinib did not suppress this signaling pathway or tumor growth. Multiple mechanisms, including the inhibition of vascular endothelial growth factor production by tumor cells and suppression of endothelial cell viability, contribute to the anti-angiogenic effect of temsirolimus. These findings indicate that mTOR inhibitors may be useful for controlling HGF-triggered EGFR-TKI resistance in EGFR mutant lung cancer, and they provide the rationale for clinical trials of mTOR inhibitors in patients stratified by EGFR mutation and HGF expression status. PMID:23690929

  14. Low inducible expression of p21Cip1 confers resistance to paclitaxel in BRAF mutant melanoma cells with acquired resistance to BRAF inhibitor.

    PubMed

    Jang, Gun-Hee; Kim, Na-Yeon; Lee, Michael

    2015-08-01

    The therapeutic efficacy of oncogenic BRAF inhibitor is limited by the onset of acquired resistance. In this study, we investigated the potential therapeutic effects of the mitotic inhibitor paclitaxel on three melanoma cell lines with differing sensitivity to the BRAF inhibitor. Of the two BRAF inhibitor-resistant cell lines, A375P/Mdr cells harboring the BRAF V600E mutant were resistant and the wild-type BRAF SK-MEL-2 cells were sensitive to paclitaxel. In particular, paclitaxel caused the growth inhibition of SK-MEL-2 cells to a much greater extent than it caused growth inhibition of A375P cells. Paclitaxel exhibited no significant effect on the phosphorylation of MEK-ERK in any cell lines tested, regardless of both the BRAF mutation and the drug resistance, implying that paclitaxel activity is independent of MEK-ERK inhibition. In A375P cells, paclitaxel treatment resulted in a marked emergence of apoptotic cells after mitotic arrest, concomitant with a remarkable induction of p21(Cip1). However, paclitaxel only moderately increased the levels of p21(Cip1) in A375P/Mdr cells, which exhibited a strong resistance to paclitaxel. The p21(Cip1) overexpression partially conferred paclitaxel sensitivity to A375P/Mdr cells. Interestingly, we found an extremely low background expression level of p21(Cip1) in SK-MEL-2 cells lacking normal p53 function, which caused much greater G2/M arrest than that seen in A375P cells. Taken together, these results suggest that paclitaxel may be an effective anticancer agent through regulating the expression of p21(Cip1) for the treatment of BRAF mutant melanoma cells resistant to BRAF inhibitors. PMID:25912549

  15. Combined Targeting of JAK2 and Bcl-2/Bcl-xL to Cure Mutant JAK2-Driven Malignancies and Overcome Acquired Resistance to JAK2 Inhibitors

    PubMed Central

    Waibel, Michaela; Solomon, Vanessa S.; Knight, Deborah A.; Ralli, Rachael A.; Kim, Sang-Kyu; Banks, Kellie-Marie; Vidacs, Eva; Virely, Clemence; Sia, Keith C.S.; Bracken, Lauryn S.; Collins-Underwood, Racquel; Drenberg, Christina; Ramsey, Laura B.; Meyer, Sara C.; Takiguchi, Megumi; Dickins, Ross A.; Levine, Ross; Ghysdael, Jacques; Dawson, Mark A.; Lock, Richard B.; Mullighan, Charles G.; Johnstone, Ricky W.

    2013-01-01

    Summary To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2. PMID:24268771

  16. Oncogene swap as a novel mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor in lung cancer.

    PubMed

    Mizuuchi, Hiroshi; Suda, Kenichi; Murakami, Isao; Sakai, Kazuko; Sato, Katsuaki; Kobayashi, Yoshihisa; Shimoji, Masaki; Chiba, Masato; Sesumi, Yuichi; Tomizawa, Kenji; Takemoto, Toshiki; Sekido, Yoshitaka; Nishio, Kazuto; Mitsudomi, Tetsuya

    2016-04-01

    Mutant selective epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as rociletinib and AZD9291, are effective for tumors with T790M secondary mutation that become refractory to first-generation EGFR-TKI. However, acquired resistance to these prospective drugs is anticipated considering the high adaptability of cancer cells and the mechanisms remain largely obscure. Here, CNX-2006 (tool compound of rociletinib) resistant sublines were established by chronic exposure of HCC827EPR cells harboring exon 19 deletion and T790M to CNX-2006. Through the analyses of these resistant subclones, we identified two resistant mechanisms accompanied by MET amplification. One was bypass signaling by MET amplification in addition to T790M, which was inhibited by the combination of CNX-2006 and MET-TKI. Another was loss of amplified EGFR mutant allele including T790M while acquiring MET amplification. Interestingly, MET-TKI alone was able to overcome this resistance, suggesting that oncogenic dependence completely shifted from EGFR to MET. We propose describing this phenomenon as an "oncogene swap." Furthermore, we analyzed multiple lesions from a patient who died of acquired resistance to gefitinib, then found a clinical example of an oncogene swap in which the EGFR mutation was lost and a MET gene copy was gained. In conclusion, an "oncogene swap" from EGFR to MET is a novel resistant mechanism to the EGFR-TKI. This novel mechanism should be considered in order to avoid futile inhibition of the original oncogene. PMID:26845230

  17. Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer

    PubMed Central

    Suda, Kenichi; Murakami, Isao; Sakai, Kazuko; Mizuuchi, Hiroshi; Shimizu, Shigeki; Sato, Katsuaki; Tomizawa, Kenji; Tomida, Shuta; Yatabe, Yasushi; Nishio, Kazuto; Mitsudomi, Tetsuya

    2015-01-01

    Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation. PMID:26400668

  18. Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer.

    PubMed

    Suda, Kenichi; Murakami, Isao; Sakai, Kazuko; Mizuuchi, Hiroshi; Shimizu, Shigeki; Sato, Katsuaki; Tomizawa, Kenji; Tomida, Shuta; Yatabe, Yasushi; Nishio, Kazuto; Mitsudomi, Tetsuya

    2015-01-01

    Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation. PMID:26400668

  19. A platinum-based hybrid drug design approach to circumvent acquired resistance to molecular targeted tyrosine kinase inhibitors

    NASA Astrophysics Data System (ADS)

    Wei, Yuming; Poon, Daniel C.; Fei, Rong; Lam, Amy S. M.; Au-Yeung, Steve C. F.; To, Kenneth K. W.

    2016-05-01

    Three molecular targeted tyrosine kinase inhibitors (TKI) were conjugated to classical platinum-based drugs with an aim to circumvent TKI resistance, predominately mediated by the emergence of secondary mutations on oncogenic kinases. The hybrids were found to maintain specificity towards the same oncogenic kinases as the original TKI. Importantly, they are remarkably less affected by TKI resistance, presumably due to their unique structure and the observed dual mechanism of anticancer activity (kinase inhibition and DNA damage). The study is also the first to report the application of a hybrid drug approach to switch TKIs from being efflux transporter substrates into non-substrates. TKIs cannot penetrate into the brain for treating metastases because of efflux transporters at the blood brain barrier. The hybrids were found to escape drug efflux and they accumulate more than the original TKI in the brain in BALB/c mice. Further development of the hybrid compounds is warranted.

  20. A platinum-based hybrid drug design approach to circumvent acquired resistance to molecular targeted tyrosine kinase inhibitors

    PubMed Central

    Wei, Yuming; Poon, Daniel C.; Fei, Rong; Lam, Amy S. M.; Au-Yeung, Steve C. F.; To, Kenneth K. W.

    2016-01-01

    Three molecular targeted tyrosine kinase inhibitors (TKI) were conjugated to classical platinum-based drugs with an aim to circumvent TKI resistance, predominately mediated by the emergence of secondary mutations on oncogenic kinases. The hybrids were found to maintain specificity towards the same oncogenic kinases as the original TKI. Importantly, they are remarkably less affected by TKI resistance, presumably due to their unique structure and the observed dual mechanism of anticancer activity (kinase inhibition and DNA damage). The study is also the first to report the application of a hybrid drug approach to switch TKIs from being efflux transporter substrates into non-substrates. TKIs cannot penetrate into the brain for treating metastases because of efflux transporters at the blood brain barrier. The hybrids were found to escape drug efflux and they accumulate more than the original TKI in the brain in BALB/c mice. Further development of the hybrid compounds is warranted. PMID:27150583

  1. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR mutant lung cancer: Distinct natural history of patients with tumors harboring the T790M mutation

    PubMed Central

    Oxnard, Geoffrey R.; Arcila, Maria E.; Sima, Camelia S.; Riely, Gregory J.; Chmielecki, Juliann; Kris, Mark G.; Pao, William; Ladanyi, Marc; Miller, Vincent A.

    2010-01-01

    Purpose Patients with EGFR-mutant lung adenocarcinoma develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) after a median of 10–16 months. In half of these cases a second EGFR mutation, T790M, underlies acquired resistance. We undertook this study to examine the clinical course of patients harboring the T790M mutation following progression on TKI. Experimental design EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs were identified as part of a prospective re-biopsy protocol where post-progression tumor specimens were collected for molecular analysis. Post-progression survival and characteristics of disease progression were compared in patients with and without T790M. Results We identified T790M in the initial re-biopsy specimens from 58/93 patients (62%, 95% confidence interval 52%–72%). T790M was more common in biopsies of lung/pleura tissue and lymph nodes than in more distant sites (p=0.014). Median post-progression survival was 16 months (interquartile range 9–29 months); patients with T790M had a significantly longer post-progression survival (p=0.036). Patients without T790M more often progressed in a previously uninvolved organ system (p=0.014) and exhibited a poorer performance status at time of progression (p=0.007). Conclusions Among patients with acquired resistance to EGFR TKIs, the presence of T790M defines a clinical subset with a relatively favorable prognosis and more indolent progression. Knowledge of T790M status is therefore important for the clinical care of these patients as well as for the optimal design and interpretation of clinical trials in this setting. PMID:21135146

  2. FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973

    PubMed Central

    2012-01-01

    Background The BRAF inhibitor, vemurafenib, has recently been approved for the treatment of metastatic melanoma in patients harboring BRAFV600 mutations. Currently, dual BRAF and MEK inhibition are ongoing in clinical trials with the goal of overcoming the acquired resistance that has unfortunately developed in some vemurafenib patients. FDG-PET measures of metabolic activity are increasingly employed as a pharmacodynamic biomarker for guiding single-agent or combination therapies by gauging initial drug response and monitoring disease progression. However, since tumors are inherently heterogeneous, investigating the effects of BRAF and MEK inhibition on FDG uptake in a panel of different melanomas could help interpret imaging outcomes. Methods 18 F-FDG uptake was measured in vitro in cells with wild-type and mutant (V600) BRAF, and in melanoma cells with an acquired resistance to vemurafenib. We treated the cells with vemurafenib alone or in combination with MEK inhibitor GDC-0973. PET imaging was used in mice to measure FDG uptake in A375 melanoma xenografts and in A375 R1, a vemurafenib-resistant derivative. Histological and biochemical studies of glucose transporters, the MAPK and glycolytic pathways were also undertaken. Results We demonstrate that vemurafenib is equally effective at reducing FDG uptake in cell lines harboring either heterozygous or homozygous BRAFV600 but ineffective in cells with acquired resistance or having WT BRAF status. However, combination with GDC-0973 results in a highly significant increase of efficacy and inhibition of FDG uptake across all twenty lines. Drug-induced changes in FDG uptake were associated with altered levels of membrane GLUT-1, and cell lines harboring RAS mutations displayed enhanced FDG uptake upon exposure to vemurafenib. Interestingly, we found that vemurafenib treatment in mice bearing drug-resistant A375 xenografts also induced increased FDG tumor uptake, accompanied by increases in Hif-1α, Sp1 and Ksr

  3. Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro

    PubMed Central

    2014-01-01

    , suggesting the mTOR kinase inhibitor impact was largely ER-independent. The capacity of AZD8055 for ER-independent activity was further evidenced by growth inhibition (IC5018 and 20 nM) of two acquired fulvestrant resistant models lacking ER. Conclusions This is the first report demonstrating dual mTORC1/2 mTOR kinase inhibitors have potential to control acquired endocrine resistant BC, even under conditions where everolimus fails. Such inhibitors may prove of particular benefit when used alongside anti-hormonal treatment as second-line therapy in endocrine resistant disease, and also potentially alongside anti-hormones during the earlier endocrine responsive phase to hinder development of resistance. PMID:24457069

  4. Proteasome inhibitors MG-132 and bortezomib induce AKR1C1, AKR1C3, AKR1B1, and AKR1B10 in human colon cancer cell lines SW-480 and HT-29.

    PubMed

    Ebert, Bettina; Kisiela, Michael; Wsól, Vladimir; Maser, Edmund

    2011-05-30

    Aldo-keto reductases (AKRs) play central roles in the reductive metabolism of endogenous signaling molecules and in the detoxification of xenobiotics. AKRC1-1C3, AKR1B1 and AKR1B10 have been shown to be regulated via nuclear factor-erythroid 2 related factor 2 (Nrf2), a transcription factor that is activated upon oxidative stress. Proteasome inhibitors bortezomib and MG-132 produce mild oxidative stress that activates Nrf2-mediated gene expression that in turn may have cytoprotective effects. Bortezomib is clinically approved to treat haematological malignancies and it has also proven activity in solid tumors such as colon cancer. The present study investigated the effect of bortezomib and MG-132 on the expression of AKR1C1-1C4, AKR1B1, and AKR1B10 in colon cancer cell lines HT-29 and SW-480. Human cancer cell lines derived from different organs (lung, colon, pancreas, skin, liver, ovary) were initially assayed for the expression of the AKRs, showing a very unequal distribution. Even among the colon cell lines HT-29, Caco-2, HCT116 and SW-480, the AKRs were expressed quite non-uniformly. HT-29 cells expressed all AKRs on the mRNA level including liver-specific AKR1C4, but AKR1B1 was almost undetectable. In SW-480 cells, treatment with bortezomib (50 nM, 48 h) dramatically increased mRNA levels of AKR1B10 (32-fold), AKR1B1 (5.5-fold), and, to a lesser extent, AKR1C1 and AKR1C3. Drug-efflux transporter MRP2 (ABCC2) and Cox-2 were induced as well. AKR1C2 mRNA was down-regulated in SW-480 but induced in HT-29 cells. MG-132 increased mRNA amounts of AKR1C1, 1C3, 1B1, and 1B10 in a concentration-dependent manner. AKR1B10 and AKR1B1 protein expression was inducible by bortezomib in HT-29 cells, but not detectable in SW-480 cells. In conclusion, treatment with proteasome inhibitors increased the expression of several AKRs as well as of MRP2. It remains to be investigated whether this enzyme induction may contribute to enhanced cell survival and thereby supporting the

  5. miR-200c/Bmi1 axis and epithelial–mesenchymal transition contribute to acquired resistance to BRAF inhibitor treatment

    PubMed Central

    Liu, Shujing; Tetzlaff, Michael T.; Wang, Tao; Yang, Ruifeng; Xie, Lin; Zhang, Gao; Krepler, Clemens; Xiao, Min; Beqiri, Marilda; Xu, Wei; Karakousis, Giorgos; Schuchter, Lynn; Amaravadi, Ravi K.; Xu, Weiting; Wei, Zhi; Herlyn, Meenhard; Yao, Yuan; Zhang, Litao; Wang, Yingjie; Zhang, Lin; Xu, Xiaowei

    2015-01-01

    Summary Resistance to BRAF inhibitors (BRAFi) is one of the major challenges for targeted therapies for BRAF-mutant melanomas. However, little is known about the role of microRNAs in conferring BRAFi resistance. Herein, we demonstrate that miR-200c expression is significantly reduced whereas miR-200c target genes including Bmi1, Zeb2, Tubb3, ABCG5, and MDR1 are significantly increased in melanomas that acquired BRAFi resistance compared to pretreatment tumor biopsies. Similar changes were observed in BRAFi-resistant melanoma cell lines. Overexpression of miR-200c or knock-down of Bmi1 in resistant melanoma cells restores their sensitivities to BRAFi, leading to deactivation of the PI3K/AKT and MAPK signaling cascades, and acquisition of epithelial– mesenchymal transition-like phenotypes, including upregulation of E-cadherin, downregulation of N-cadherin, and ABCG5 and MDR1 expression. Conversely, knock-down of miR-200c or overexpression of Bmi1 in BRAFi-sensitive melanoma cells activates the PI3K/AKT and MAPK pathways, upregulates N-cadherin, ABCG5, and MDR1 expression, and downregulates E-cadherin expression, leading to BRAFi resistance. Together, our data identify miR-200c as a critical signaling node in BRAFi-resistant melanomas impacting the MAPK and PI3K/AKT pathways, suggesting miR-200c as a potential therapeutic target for overcoming acquired BRAFi resistance. PMID:25903073

  6. Increased CD271 expression by the NF-kB pathway promotes melanoma cell survival and drives acquired resistance to BRAF inhibitor vemurafenib

    PubMed Central

    Lehraiki, Abdelali; Cerezo, Michael; Rouaud, Florian; Abbe, Patricia; Allegra, Marilyne; Kluza, Jerome; Marchetti, Philippe; Imbert, Veronique; Cheli, Yann; Bertolotto, Corine; Ballotti, Robert; Rocchi, Stéphane

    2015-01-01

    Specific BRAFV600E inhibitors (BRAFi) are highly effective in the treatment of melanoma. However, acquired drug resistances invariably develop after the initial response. Therefore, the identification of new mechanisms of acquired resistance gives important clues towards the development of therapies that could elicit long lasting responses. Here we report that CD271 confers resistance to BRAFi in melanoma cells. The expression of CD271 is increased by BRAFi through a stimulation of tumor necrosis factor-alpha (TNFα) secretion that leads to NF-κB signaling pathway activation. CD271 is upregulated in a subset of BRAFi-resistant melanoma cells. The inhibition of TNFα/NF-κB pathway and CD271 silencing restore the BRAFi sensitivity of resistant melanoma cells. Finally, increase of CD271 expression is validated in BRAFi-resistant xenografts tumors and also in tumors from the patients who relapsed under BRAFi. In summary, these results reveal a novel TNFα/NF-κB/CD271 axis whose activation contributes to the acquisition of resistance to BRAFi and therefore may represent a novel therapeutic target to improve the efficacy of therapy in melanoma.

  7. Acquired resistance to EGFR tyrosine kinase inhibitors alters the metabolism of human head and neck squamous carcinoma cells and xenograft tumours

    PubMed Central

    Beloueche-Babari, M; Box, C; Arunan, V; Parkes, H G; Valenti, M; De Haven Brandon, A; Jackson, L E; Eccles, S A; Leach, M O

    2015-01-01

    Background: Acquired resistance to molecularly targeted therapeutics is a key challenge in personalised cancer medicine, highlighting the need for identifying the underlying mechanisms and early biomarkers of relapse, in order to guide subsequent patient management. Methods: Here we use human head and neck squamous cell carcinoma (HNSCC) models and nuclear magnetic resonance (NMR) spectroscopy to assess the metabolic changes that follow acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), and which could serve as potential metabolic biomarkers of drug resistance. Results: Comparison of NMR metabolite profiles obtained from control (CALS) and EGFR TKI-resistant (CALR) cells grown as 2D monolayers, 3D spheroids or xenograft tumours in athymic mice revealed a number of differences between the sensitive and drug-resistant models. In particular, we observed elevated levels of glycerophosphocholine (GPC) in CALR relative to CALS monolayers, spheroids and tumours, independent of the growth rate or environment. In addition, there was an increase in alanine, aspartate and creatine+phosphocreatine in resistant spheroids and xenografts, and increased levels of lactate, branched-chain amino acids and a fall in phosphoethanolamine only in xenografts. The xenograft lactate build-up was associated with an increased expression of the glucose transporter GLUT-1, whereas the rise in GPC was attributed to inhibition of GPC phosphodiesterase. Reduced glycerophosphocholine (GPC) and phosphocholine were observed in a second HNSCC model probably indicative of a different drug resistance mechanism. Conclusions: Our studies reveal metabolic signatures associated not only with acquired EGFR TKI resistance but also growth pattern, microenvironment and contributing mechanisms in HNSCC models. These findings warrant further investigation as metabolic biomarkers of disease relapse in the clinic. PMID:25742484

  8. Targeting AKT with the allosteric AKT inhibitor MK-2206 in non-small cell lung cancer cells with acquired resistance to cetuximab.

    PubMed

    Iida, Mari; Brand, Toni M; Campbell, David A; Starr, Megan M; Luthar, Neha; Traynor, Anne M; Wheeler, Deric L

    2013-06-01

    The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for use in oncology. Despite clinical success the majority of patients do not respond to cetuximab and those who initially respond frequently acquire resistance. To understand how tumor cells acquire resistance to cetuximab we developed a model of resistance using the non-small cell lung cancer line NCI-H226. We found that cetuximab-resistant (Ctx (R) ) clones manifested strong activation of EGFR, PI3K/AKT and MAPK. To investigate the role of AKT signaling in cetuximab resistance we analyzed the activation of the AKT pathway effector molecules using a human AKT phospho-antibody array. Strong activation was observed in Ctx (R) clones for several key AKT substrates including c-jun, GSK3β, eIF4E, rpS6, IKKα, IRS-1 and Raf1. Inhibition of AKT signaling by siAKT1/2 or by the allosteric AKT inhibitor MK-2206 resulted in robust inhibition of cell proliferation in all Ctx (R) clones. Moreover, the combinational treatment of cetuximab and MK-2206 resulted in further decreases in proliferation than either drug alone. This combinatorial treatment resulted in decreased activity of both AKT and MAPK thus highlighting the importance of simultaneous pathway inhibition to maximally affect the growth of Ctx (R) cells. Collectively, our findings demonstrate that AKT activation is an important pathway in acquired resistance to cetuximab and suggests that combinatorial therapy directed at both the AKT and EGFR/MAPK pathways may be beneficial in this setting. PMID:23760490

  9. Targeting AKT with the allosteric AKT inhibitor MK-2206 in non-small cell lung cancer cells with acquired resistance to cetuximab

    PubMed Central

    Iida, Mari; Brand, Toni M.; Campbell, David A.; Starr, Megan M.; Luthar, Neha; Traynor, Anne M.; Wheeler, Deric L.

    2013-01-01

    The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for use in oncology. Despite clinical success the majority of patients do not respond to cetuximab and those who initially respond frequently acquire resistance. To understand how tumor cells acquire resistance to cetuximab we developed a model of resistance using the non-small cell lung cancer line NCI-H226. We found that cetuximab-resistant (CtxR) clones manifested strong activation of EGFR, PI3K/AKT and MAPK. To investigate the role of AKT signaling in cetuximab resistance we analyzed the activation of the AKT pathway effector molecules using a human AKT phospho-antibody array. Strong activation was observed in CtxR clones for several key AKT substrates including c-jun, GSK3β, eIF4E, rpS6, IKKα, IRS-1 and Raf1. Inhibition of AKT signaling by siAKT1/2 or by the allosteric AKT inhibitor MK-2206 resulted in robust inhibition of cell proliferation in all CtxR clones. Moreover, the combinational treatment of cetuximab and MK-2206 resulted in further decreases in proliferation than either drug alone. This combinatorial treatment resulted in decreased activity of both AKT and MAPK thus highlighting the importance of simultaneous pathway inhibition to maximally affect the growth of CtxR cells. Collectively, our findings demonstrate that AKT activation is an important pathway in acquired resistance to cetuximab and suggests that combinatorial therapy directed at both the AKT and EGFR/MAPK pathways may be beneficial in this setting. PMID:23760490

  10. Valproic acid, an inhibitor of class I histone deacetylases, reverses acquired Erlotinib-resistance of lung adenocarcinoma cells: a Connectivity Mapping analysis and an experimental study.

    PubMed

    Zhuo, Wenlei; Zhang, Liang; Zhu, Yi; Xie, Qichao; Zhu, Bo; Chen, Zhengtang

    2015-01-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been used as a powerful targeting therapeutic agent for treatment of lung adenocarcinoma for years. Nevertheless, the efficacy of TKI was hampered by the appearance of acquired TKI-resistance. In the present study, we aimed to search, predict, and screen the agents that can overcome the acquired TKI-resistance of lung adenocarcinoma by using the expression profiles of differentially expressed genes (DEGs) and Connectivity map (CMAP). The profiles of DEGs were obtained by searching GEO microarray database, and then, they were submitted to CMAP for analysis in order to predict and screen the agent that might reverse the TKI-resistance of lung cancer cells. Next, the effects of the selected agent on TKI-resistant cancer cells were tested and the possible signaling pathways were also evaluated. As a result, valproic acid (VPA) was selected. Then, we used a low-concentration of VPA that has little effect on the cell growth for analysis. Interestingly, the results showed that treatment with a combination of VPA and Erlotinib significantly led to a decrease in cell viability and an increase in cell apoptosis for TKI-resistant HCC827-ER cells, relative to those treated with VPA or Erlotinib alone. Further experiments confirmed that inhibition of MAPK and AKT might be involved in this process. Analyzing the DEGs through the CMAP is a good strategy for exploitation of anti-tumor agents. VPA might markedly increase the sensitivity of TKI-resistant lung adenocarcinoma cells to Erlotinib, thus reversing the acquired TKI-resistance of cancer cells and raising VPA as a potential agent for TKI-resistant lung cancer therapy. PMID:26328250

  11. Inhibitors

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  12. Significant Differences in the Development of Acquired Resistance to the MDM2 Inhibitor SAR405838 between In Vitro and In Vivo Drug Treatment

    PubMed Central

    Hoffman-Luca, C. Gianna; Yang, Chao-Yie; Lu, Jianfeng; Ziazadeh, Daniel; McEachern, Donna; Debussche, Laurent; Wang, Shaomeng

    2015-01-01

    SAR405838 is a potent and specific MDM2 inhibitor currently being evaluated in Phase I clinical trials for the treatment of human cancer. Using the SJSA-1 osteosarcoma cell line which harbors an amplified MDM2 gene and wild-type p53, we have investigated the acquired resistance mechanisms both in vitro and in vivo to SAR405838. Treatment of SJSA-1 cells with SAR405838 in vitro leads to dose-dependent cell growth inhibition, cell cycle arrest and robust apoptosis. However, prolonged treatment of SJSA-1 cells in vitro with SAR405838 results in profound acquired resistance to the drug. Analysis of in vitro-derived resistant cell lines showed that p53 is mutated in the DNA binding domain and can no longer be activated by SAR405838. Treatment of the parental SJSA-1 xenograft tumors with SAR405838 in mice yields rapid tumor regression but the tumors eventually regrow. Culturing the regrown tumors established a number of sublines, which showed only modest (3–5 times) loss of sensitivity to SAR405838 in vitro. Sequencing of the p53 showed that it retains its wild-type status in these in vivo sublines, with the exception of one subline, which harbors a single heterozygous C176F p53 mutation. Using xenograft models of two in vivo derived sublines, which has either wild-type p53 or p53 containing a single heterozygous C176F mutation, we showed that while SAR405838 effectively achieves partial tumor regression in these models, it no longer induces complete tumor regression and tumors resume growth once the treatment is stopped. Harvesting and culturing tumors obtained from a prolonged treatment with SAR405838 in mice established additional in vivo sublines, which all contain a single heterozygous C176F mutation with no additional p53 mutation detected. Interestingly, SAR405838 can still effectively activate p53 in all sublines containing a single heterozygous C176F mutation, with a moderately reduced potency as compared to that in the parental cell line. Consistently, SAR

  13. C1q protein binds to the apoptotic nucleolus and causes C1 protease degradation of nucleolar proteins.

    PubMed

    Cai, Yitian; Teo, Boon Heng Dennis; Yeo, Joo Guan; Lu, Jinhua

    2015-09-11

    In infection, complement C1q recognizes pathogen-congregated antibodies and elicits complement activation. Among endogenous ligands, C1q binds to DNA and apoptotic cells, but whether C1q binds to nuclear DNA in apoptotic cells remains to be investigated. With UV irradiation-induced apoptosis, C1q initially bound to peripheral cellular regions in early apoptotic cells. By 6 h, binding concentrated in the nuclei to the nucleolus but not the chromatins. When nucleoli were isolated from non-apoptotic cells, C1q also bound to these structures. In vivo, C1q exists as the C1 complex (C1qC1r2C1s2), and C1q binding to ligands activates the C1r/C1s proteases. Incubation of nucleoli with C1 caused degradation of the nucleolar proteins nucleolin and nucleophosmin 1. This was inhibited by the C1 inhibitor. The nucleoli are abundant with autoantigens. C1q binding and C1r/C1s degradation of nucleolar antigens during cell apoptosis potentially reduces autoimmunity. These findings help us to understand why genetic C1q and C1r/C1s deficiencies cause systemic lupus erythematosus. PMID:26231209

  14. Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD-transformed hematopoietic cells.

    PubMed

    Bagrintseva, Ksenia; Schwab, Ruth; Kohl, Tobias M; Schnittger, Susanne; Eichenlaub, Sabine; Ellwart, Joachim W; Hiddemann, Wolfgang; Spiekermann, Karsten

    2004-03-15

    Activating mutations in the juxtamembrane domain (FLT3-length mutations, FLT3-LM) and in the protein tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD) represent the most frequent genetic alterations in acute myeloid leukemia (AML) and define a molecular target for therapeutic interventions by protein tyrosine kinase (PTK) inhibitors. We could show that distinct activating FLT3-TKD mutations at position D835 mediate primary resistance to FLT3 PTK inhibitors in FLT3-transformed cell lines. In the presence of increasing concentrations of the FLT3 PTK inhibitor SU5614, we generated inhibitor resistant Ba/F3 FLT3-internal tandem duplication (ITD) cell lines (Ba/F3 FLT3-ITD-R1-R4) that were characterized by a 7- to 26-fold higher IC50 (concentration that inhibits 50%) to SU5614 compared with the parental ITD cells. The molecular characterization of ITD-R1-4 cells demonstrated that specific TKD mutations (D835N and Y842H) on the ITD background were acquired during selection with SU5614. Introduction of these dual ITD-TKD, but not single D835N or Y842H FLT3 mutants, in Ba/F3 cells restored the FLT3 inhibitor resistant phenotype. Our data show that preexisting or acquired mutations in the PTK domain of FLT3 can induce drug resistance to FLT3 PTK inhibitors in vitro. These findings provide a molecular basis for the evaluation of clinical resistance to FLT3 PTK inhibitors in patients with AML. PMID:14604974

  15. Phase I/II Study of HSP90 Inhibitor AUY922 and Erlotinib for EGFR-Mutant Lung Cancer With Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

    PubMed Central

    Johnson, Melissa L.; Yu, Helena A.; Hart, Eric M.; Weitner, Bing Bing; Rademaker, Alfred W.; Patel, Jyoti D.; Kris, Mark G.; Riely, Gregory J.

    2015-01-01

    Purpose AUY922 is an HSP90 inhibitor that causes degradation of HSP chaperones and their client proteins, including epidermal growth factor receptor. We conducted a phase I/II trial to evaluate AUY922 and erlotinib for patients with EGFR-mutant lung cancer and disease progression during erlotinib treatment. Patients and Methods All patients had developed acquired resistance after treatment with erlotinib and underwent repeat tumor biopsies before study entry to assess for EGFR T790M. In phase I, 18 patients were treated with AUY922 intravenously once per week and erlotinib once per day in 28-day cycles using a 3 + 3 dose-escalation design. In phase II, 19 additional patients were treated at the maximum-tolerated dose. The primary end point of the phase II trial was complete plus partial response rate. Results In phase I (n = 18), three patients were treated in each cohort, except the highest-dose cohort (AUY922 70 mg and erlotinib 150 mg), which expanded to six patients because of a dose-limiting toxicity (ie, junctional cardiac rhythm). Common drug-related adverse events were diarrhea, skin rash, hyperglycemia, and night blindness. All patients treated at maximum-tolerated dose (n = 25) were evaluable for response. The partial response rate was 16% (four of 25 patients; 95% CI, 5% to 36%) and was independent of tumor T790M status. Conclusion Partial responses were observed, but the duration of treatment with AUY922 and erlotinib was limited by toxicities, especially night blindness. This phase II study of AUY922 and erlotinib did not meet its primary end point. PMID:25870087

  16. Activation of the IGF1R pathway potentially mediates acquired resistance to mutant-selective 3rd-generation EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer.

    PubMed

    Park, Ji Hyun; Choi, Yun Jung; Kim, Seon Ye; Lee, Jung-Eun; Sung, Ki Jung; Park, Sojung; Kim, Woo Sung; Song, Joon Seon; Choi, Chang-Min; Sung, Young Hoon; Rho, Jin Kyung; Lee, Jae Cheol

    2016-04-19

    Mutant-selective, 3rd-generation EGFR-TKIs were recently developed to control lung cancer cells harboring T790M-mediated resistance. However, the development of resistance to these novel drugs seems inevitable. Thus, we investigated the mechanism of acquired resistance to the mutant-selective EGFR-TKI WZ4002. We established five WZ4002-resistant cells, derived from cells harboring both EGFR and T790M mutations by long-term exposure to increasing doses of WZ4002. Compared with the parental cells, all resistant cells showed 10-100-folds higher resistance to WZ4002, as well as cross-resistance to other mutant-selective inhibitors. Among them, three resistant cells (HCC827/WR, PC-9/WR and H1975/WR) showed dependency on EGFR signaling, but two other cells (PC-9/GR/WR and PC-9/ER/WR) were not. Notably, insulin-like growth factor-1 receptor (IGF1R) was aberrantly activated in PC-9/GR/WR cells in phospho-receptor tyrosine kinase array, consistently accompanied by loss of IGF binding protein-3 (IGFBP3). Down-regulation of IGF1R by shRNA, as well as inhibition of IGF1R activity either by AG-1024 (a small molecule IGF1R inhibitor) or BI 836845 (a monoclonal anti-IGF1/2 blocking antibody), restored the sensitivity to WZ4002 both in vitro and xenograft. Taken together, these results suggest that activation of the IGF1R pathway associated with IGFBP3 loss can induce an acquired resistance to the mutant-selective EGFR-TKI, WZ4002. Therefore, a combined therapy of IGF1R inhibitors and mutant-selective EGFR-TKIs might be a viable treatment strategy for overcoming acquired resistance. PMID:26980747

  17. Activation of the IGF1R pathway potentially mediates acquired resistance to mutant-selective 3rd-generation EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer

    PubMed Central

    Park, Ji Hyun; Choi, Yun Jung; Kim, Seon Ye; Lee, Jung-Eun; Sung, Ki Jung; Park, Sojung; Kim, Woo Sung; Song, Joon Seon; Choi, Chang-Min; Sung, Young Hoon; Rho, Jin Kyung; Lee, Jae Cheol

    2016-01-01

    Mutant-selective, 3rd-generation EGFR-TKIs were recently developed to control lung cancer cells harboring T790M-mediated resistance. However, the development of resistance to these novel drugs seems inevitable. Thus, we investigated the mechanism of acquired resistance to the mutant-selective EGFR-TKI WZ4002. We established five WZ4002-resistant cells, derived from cells harboring both EGFR and T790M mutations by long-term exposure to increasing doses of WZ4002. Compared with the parental cells, all resistant cells showed 10–100-folds higher resistance to WZ4002, as well as cross-resistance to other mutant-selective inhibitors. Among them, three resistant cells (HCC827/WR, PC-9/WR and H1975/WR) showed dependency on EGFR signaling, but two other cells (PC-9/GR/WR and PC-9/ER/WR) were not. Notably, insulin-like growth factor-1 receptor (IGF1R) was aberrantly activated in PC-9/GR/WR cells in phospho-receptor tyrosine kinase array, consistently accompanied by loss of IGF binding protein-3 (IGFBP3). Down-regulation of IGF1R by shRNA, as well as inhibition of IGF1R activity either by AG-1024 (a small molecule IGF1R inhibitor) or BI 836845 (a monoclonal anti-IGF1/2 blocking antibody), restored the sensitivity to WZ4002 both in vitro and xenograft. Taken together, these results suggest that activation of the IGF1R pathway associated with IGFBP3 loss can induce an acquired resistance to the mutant-selective EGFR-TKI, WZ4002. Therefore, a combined therapy of IGF1R inhibitors and mutant-selective EGFR-TKIs might be a viable treatment strategy for overcoming acquired resistance. PMID:26980747

  18. Overexpression of PI3K p110α contributes to acquired resistance to MET inhibitor, in MET-amplified SNU-5 gastric xenografts

    PubMed Central

    Ji, Fujian; Liu, Xuanwen; Wu, Yuanyu; Fang, Xuedong; Huang, Guomin

    2015-01-01

    Gastric cancer is one of the most virulent malignant diseases and is the second leading cause of cancer mortality in the world. The receptor tyrosine kinase MET is constitutively activated in many gastric cancers and its expression is strictly required for survival of some gastric cancer cells. Targeting gastric cancers with amplified or abnormally activated MET may have therapeutic benefit based on nonclinical and emerging clinical findings. However, one of the major problems of therapies targeting tyrosine kinases is that many tumors are not responsive to treatment or eventually develop resistance to the drugs. This study aims to understand the mechanisms of MET resistance in gastric SNU-5 xenografts which developed resistance to PHA665752, a MET inhibitor, through long-period tyrosine kinase inhibitor exposure. In the current study, we found that PI3K p110α is overexpressed in PHA665752-resistant SNU-5 xenografts. These findings showed that high PI3K p110α expression contributes to tyrosine kinase inhibitor resistance. In addition, we reported the development of a carcinogen-induced gastric cancer model that recapitulates PI3K p110α expression in human disease, which will serve as a useful model to study PI3K p110α’s biology and its effectiveness as a novel biomarker and a molecular target for gastric cancer. Ultimately, PI3K p110α represents a novel target for gastric cancer. PMID:26543351

  19. Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor.

    PubMed

    Caporali, Simona; Alvino, Ester; Lacal, Pedro Miguel; Levati, Lauretta; Giurato, Giorgio; Memoli, Domenico; Caprini, Elisabetta; Antonini Cappellini, Gian Carlo; D'Atri, Stefania

    2016-09-01

    BRAF inhibitors (BRAFi) have proven clinical benefits in patients with BRAF-mutant melanoma. However, acquired resistance eventually arises. The effects of BRAFi on melanoma cell proliferation and survival have been extensively studied, and several mechanisms involved in acquired resistance to the growth suppressive activity of these drugs have been identified. Much less is known about the impact of BRAFi, and in particular of dabrafenib, on the invasive potential of melanoma cells. In the present study, the BRAF-mutant human melanoma cell line A375 and its dabrafenib-resistant subline A375R were analyzed for invasive capacity, expression of vascular endothelial growth factor receptor (VEGFR)-2, and secretion of VEGF-A and matrix metalloproteinase (MMP)-9, under basal conditions or in response to dabrafenib. The consequences of inhibiting the PI3K/AKT/mTOR pathway on A375R cell responses to dabrafenib were also evaluated. We found that A375R cells were more invasive and secreted higher levels of VEGF-A and MMP-9 as compared with A375 cells. Dabrafenib reduced invasiveness, VEGFR-2 expression and VEGF-A secretion in A375 cells, whereas it increased invasiveness, VEGF-A and MMP-9 release in A375R cells. In these latter cells, the stimulating effects of dabrafenib on the invasive capacity were markedly impaired by the anti-VEGF‑A antibody bevacizumab, or by AKT1 silencing. A375R cells were not cross-resistant to the PI3K/mTOR inhibitor GSK2126458A. Moreover, this inhibitor given in combination with dabrafenib efficiently counteracted the stimulating effects of the BRAFi on invasiveness and VEGF-A and MMP-9 secretion. Our data demonstrate that melanoma cells with acquired resistance to dabrafenib possess a more invasive phenotype which is further stimulated by exposure to the drug. Substantial evidence indicates that continuing BRAFi therapy beyond progression produces a clinical benefit. Our results suggest that after the development of resistance, a regimen

  20. Acquired hyperpigmentations*

    PubMed Central

    Cestari, Tania Ferreira; Dantas, Lia Pinheiro; Boza, Juliana Catucci

    2014-01-01

    Cutaneous hyperpigmentations are frequent complaints, motivating around 8.5% of all dermatological consultations in our country. They can be congenital, with different patterns of inheritance, or acquired in consequence of skin problems, systemic diseases or secondary to environmental factors. The vast majority of them are linked to alterations on the pigment melanin, induced by different mechanisms. This review will focus on the major acquired hyperpigmentations associated with increased melanin, reviewing their mechanisms of action and possible preventive measures. Particularly prominent aspects of diagnosis and therapy will be emphasized, with focus on melasma, post-inflammatory hyperpigmentation, periorbital pigmentation, dermatosis papulosa nigra, phytophotodermatoses, flagellate dermatosis, erythema dyschromicum perstans, cervical poikiloderma (Poikiloderma of Civatte), acanthosis nigricans, cutaneous amyloidosis and reticulated confluent dermatitis PMID:24626644

  1. Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines.

    PubMed Central

    Jackman, A. L.; Kelland, L. R.; Kimbell, R.; Brown, M.; Gibson, W.; Aherne, G. W.; Hardcastle, A.; Boyle, F. T.

    1995-01-01

    Four cell lines, the mouse L1210 leukaemia, the human W1L2 lymphoblastoid and two human ovarian (CH1 and 41M) cell lines, were made resistant to ZD1694 (Tomudex) by continual exposure to incremental doses of the drug. A 500-fold increase in thymidylate synthase (TS) activity is the primary mechanism of resistance to ZD1694 in the W1L2:RD1694 cell line, which is consequently highly cross-resistant to other folate-based TS inhibitors, including BW1843U89, LY231514 and AG337, but sensitive to antifolates with other enzyme targets. The CH1:RD1694 cell line is 14-fold resistant to ZD1694, largely accounted for by the 4.2-fold increase in TS activity. Cross-resistance was observed to other TS inhibitors, including 5-fluorodeoxyuridine (FdUrd). 41M:RD1694 cells, when exposed to 0.1 microM [3H]ZD1694, accumulated approximately 20-fold less 3H-labelled material over 24 h than the parental line. Data are consistent with this being the result of impaired transport of the drug via the reduced folate/methotrexate carrier. Resistance was therefore observed to methotrexate but not to CB3717, a compound known to use this transport mechanism poorly. The mouse L1210:RD1694 cell line does not accumulate ZD1694 or Methotrexate (MTX) polyglutamates. Folylpolyglutamate synthetase substrate activity (using ZD1694 as the substrate) was decreased to approximately 13% of that observed in the parental line. Cross-resistance was found to those compounds known to be active through polyglutamation. PMID:7537518

  2. Discovery of Methyl 4′-Methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1′-biphenyl]-3-carboxylate, an Improved Small-Molecule Inhibitor of c-Myc–Max Dimerization

    PubMed Central

    Yap, Jeremy L.; Sabato, Philip E.; Hu, Angela; Prochownik, Edward V.; Fletcher, Steven

    2014-01-01

    c-Myc is a bHLH-ZIP transcription factor that is responsible for the transcription of a wide range of target genes involved in many cancer-related cellular processes, such as proliferation, differentiation, apoptosis and metabolism. Over-expression of c-Myc has been observed in, and directly contributes to, a variety of human cancers including those of the hematopoietic system, lung, prostate and colon. To become transcriptionally active, c-Myc must first dimerize with Max via its own bHLH-ZIP domain. A proven strategy towards the inhibition of c-Myc oncogenic activity is to interfere with the structural integrity of the c-Myc–Max heterodimer. The small-molecule 10074-G5 is an inhibitor of c-Myc–Max dimerization (IC50 = 146 μM) that operates by binding and stabilizing c-Myc in its monomeric form. Herein, we report on our on-going efforts to optimize the c-Myc–Max inhibitory activity of 10074-G5-related molecules in vitro and in cancer cells that over-express c-Myc. Specifically, we have identified a congener of 10074-G5, termed 3jc48-3, that is about five times as potent (IC50 = 34 μM) at inhibiting c-Myc–Max dimerization as the parent compound. In addition, 3jc48-3 exhibited an approximate two-fold selectivity for c-Myc–Max heterodimers over Max–Max dimers, suggesting that, like its predecessor, its mode of action is through binding c-Myc. 3jc48-3 inhibited the proliferation of c-Myc-over-expressing HL60 and Daudi cells with single-digit micromolar IC50 values by causing growth arrest at the G0/G1 phase. Furthermore, co-immunoprecipitation studies indicated that 3jc48-3 inhibits c-Myc–Max dimerization in cells, which was further substantiated by the specific silencing of a c-Myc-driven luciferase reporter gene. Finally, unlike previously described 10074-G5 analogues, which are rapidly released and/or metabolized by cells following their uptake, 3jc48-3’s intracellular half-life was >17 h. Collectively, these data demonstrate 3jc48-3 to be one of

  3. Fundamental role of C1q in autoimmunity and inflammation

    PubMed Central

    Son, Myoungsun; Santiago-Schwarz, Frances

    2016-01-01

    C1q, historically viewed as the initiating component of the classical complement pathway, also exhibits a variety of complement-independent activities in both innate and acquired immunity. Recent studies focusing on C1q’s suppressive role in the immune system have provided new insight into how abnormal C1q expression and bioactivity may contribute to autoimmunity. In particular, molecular networks involving C1q interactions with cell surface receptors and other ligands are emerging as mechanisms involved in C1q’s modulation of immunity. Here, we discuss the role of C1q in controlling immune cell function, including recently elucidated mechanisms of action, and suggest how these processes are critical for maintaining tissue homeostasis under steady-state conditions and in preventing autoimmunity. PMID:26410546

  4. The Niemann-Pick C1 like 1 (NPC1L1) inhibitor ezetimibe improves metabolic disease via decreased liver X receptor (LXR) activity in liver of obese male mice.

    PubMed

    Sugizaki, Taichi; Watanabe, Mitsuhiro; Horai, Yasushi; Kaneko-Iwasaki, Nao; Arita, Eri; Miyazaki, Teruo; Morimoto, Kohkichi; Honda, Akira; Irie, Junichiro; Itoh, Hiroshi

    2014-08-01

    Dyslipidemic patients with diabetes mellitus, including metabolic syndrome, are at increased risk of coronary heart disease. It has been reported that ezetimibe, a cholesterol absorption inhibitor, improves metabolic diseases in mice and humans. However, the underlying mechanism has been unclear. Here we explored the effects of ezetimibe on lipid and glucose homeostasis. Male KK-A(y) mice were fed a high-fat diet, which is the mouse model of metabolic syndrome, with or without ezetimibe for 14 weeks. Ezetimibe improved dyslipidemia, steatosis, and insulin resistance. Ezetimibe decreased hepatic oxysterols, which are endogenous agonists of liver X receptor (LXR), to decrease hepatic lipogenic gene expressions, especially in stearoyl-CoA desaturase-1 (SCD1), leading to a remarkable reduction of hepatic oleate content that would contribute to the improvement of steatosis by reducing triglycerides and cholesterol esters. Simultaneously, hepatic β-oxidation, NADPH oxidase and cytochrome P450 2E1 (CYP2E1) were reduced, and thus reactive oxygen species (ROS) and inflammatory cytokines were also decreased. Consistent with these changes, ezetimibe diminished c-Jun N-terminal kinase (JNK) phosphorylation and improved insulin signaling in the liver. In vitro study using primary hepatocytes obtained from male SD rats, treated with oleate and LXR agonist, showed excess lipid accumulation, increased oxidative stress and impaired insulin signaling. Therefore, in obese subjects, ezetimibe reduces hepatic LXR activity by reducing hepatic oxysterols to lower hepatic oleate content. This improves steatosis and reduces oxidative stress, and this reduction improves insulin signaling in the liver. These results provide insight into pathogenesis and strategies for treatment of the metabolic syndrome. PMID:24773344

  5. Hereditary angioedema with normal C1-INH (HAE type III).

    PubMed

    Riedl, Marc A

    2013-01-01

    Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH), also known as HAE type III, is a familial condition only clinically recognized within the past three decades. Similar to HAE from C1-INH deficiency (HAE types I and II), affected individuals experience unpredictable angioedema episodes of the skin, gastrointestinal tract, and airway. Unique clinical features of HAE with normal C1-INH include the predominance of affected women, frequent exacerbation by estrogen, and a prominence of angioedema that involves the face and oropharynx. The underlying pathophysiology of HAE with normal C1-INH is poorly understood, but indirect evidence points to contact pathway dysregulation with bradykinin-mediated angioedema. Currently, evaluation is complicated by a lack of confirmatory laboratory testing such that clinical criteria must often be used to make the diagnosis of HAE with normal C1-INH. Factor XII mutations have been identified in only a minority of persons affected by HAE with normal C1-INH, limiting the utility of such analysis. To date, no controlled clinical studies have examined the efficacy of therapeutic agents for HAE with normal C1-INH, although published evidence supports frequent clinical benefit with medications shown effective in HAE due to C1-INH deficiency. PMID:24565612

  6. Studies on human plasma C1 inactivator-enzyme interactions. I. Mechanisms of interaction with C1s, plasmin, and trypsin.

    PubMed Central

    Harpel, P C; Cooper, N R

    1975-01-01

    This study has explored the nature of the molecular events which occur when C1 inactivator, a human plasma inhibitor of the complement, kinin-forming, coagulation, and fibrinolytic enzyme systems, interacts with C1s, plasmin, and trypsin. Purified inhibitor preparations demonstrated two bands, when examined by acrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS). The molecular weights of the major and minor bands were 105,000 and 96,000 daltons, respectively. The minor component appeared to be immunologically and functionally identical to the main C1 inactivator component. Loss of C1s and plasmin functional activity was associated with the formation of a 1:1 molar complex between the inhibitor and each enzyme. These complexes were stable in the presence of SDS and urea. The light chain of both these enzymes provided the binding site for C1 inactivator. Complex formation and enzyme inhibition occurred only with native and not with an inhibitor preparation denatured by acid treatment, thereby demonstrating the importance of conformational factors in the enzyme-inhibitor reaction. Although peptide bond cleavage of the C1 inactivator molecule by C1s was not documented, plasmin was found to degrade the inhibitor with the production of several characteristic derivatives. At least one of these products retained the ability to complex with C1s and plasmin. Trypsin, which failed to form a complex with C1 inactivator, degraded the inhibitor in a limited and sequential manner with the production of nonfunctional derivatives one of which appeared structurally similar to a plasmin-induced product. These studies therefore, provide new information concerning the molecular interactions between C1 inactivator and several of the proteases which it inhibits. Images PMID:123251

  7. 26 CFR 1.381(c)(1)-1 - Net operating loss carryovers in certain corporate acquisitions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... corporate acquisitions. 1.381(c)(1)-1 Section 1.381(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE... Reorganizations § 1.381(c)(1)-1 Net operating loss carryovers in certain corporate acquisitions. (a) Carryover requirement. (1) Section 381(c)(1) requires the acquiring corporation to succeed to, and take into......

  8. 26 CFR 1.381(c)(1)-1 - Net operating loss carryovers in certain corporate acquisitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... corporate acquisitions. 1.381(c)(1)-1 Section 1.381(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE... Reorganizations § 1.381(c)(1)-1 Net operating loss carryovers in certain corporate acquisitions. (a) Carryover requirement. (1) Section 381(c)(1) requires the acquiring corporation to succeed to, and take into......

  9. 26 CFR 1.381(c)(1)-1 - Net operating loss carryovers in certain corporate acquisitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... corporate acquisitions. 1.381(c)(1)-1 Section 1.381(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE... Reorganizations § 1.381(c)(1)-1 Net operating loss carryovers in certain corporate acquisitions. (a) Carryover requirement. (1) Section 381(c)(1) requires the acquiring corporation to succeed to, and take into......

  10. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by co-targeting MEK and IGF-1R/PI3K

    PubMed Central

    Villanueva, Jessie; Vultur, Adina; Lee, John T.; Somasundaram, Rajasekharan; Fukunaga-Kalabis, Mizuho; Cipolla, Angela K.; Wubbenhorst, Bradley; Xu, Xiaowei; Gimotty, Phyllis A.; Kee, Damien; Santiago-Walker, Ademi E.; Letrero, Richard; D’Andrea, Kurt; Pushparajan, Anitha; Hayden, James E.; Brown, Kimberly Dahlman; Laquerre, Sylvie; McArthur, Grant A.; Sosman, Jeffrey A.; Nathanson, Katherine L.; Herlyn, Meenhard

    2010-01-01

    Summary BRAF is an attractive target for melanoma drug development. However, resistance to BRAF inhibitors is a significant clinical challenge. We describe a model of resistance to BRAF inhibitors developed by chronic treatment of BRAFV600E melanoma cells with the BRAF inhibitor SB-590885; these cells are cross resistant to other BRAF-selective inhibitors. Resistance involves flexible switching among the three RAF isoforms, underscoring the ability of melanoma cells to adapt to pharmacological challenges. IGF-1R/PI3K signaling was enhanced in resistant melanomas, and combined treatment with IGF-1R/PI3K and MEK inhibitors induced death of BRAF inhibitor-resistant cells. Increased IGFR-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF-1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors. PMID:21156289

  11. Update on laboratory tests for the diagnosis and differentiation of hereditary angioedema and acquired angioedema.

    PubMed

    Frazer-Abel, Ashley; Giclas, Patricia C

    2011-01-01

    The importance of laboratory testing in the diagnosis of hereditary angioedema (HAE) has increased with the advent of new treatment options in recent years. It has been 50 years since HAE was linked to a decrease of C1INH (the inhibitor of complement enzyme, C1 esterase), a link that provided for the first laboratory test available for this disorder. HAE is subdivided into types that can be differentiated only by laboratory testing. The Type I form is characterized by low levels and function of C1INH in the circulation. The Type II form is characterized by normal levels of C1INH, but low function. Sample collection and handling is critical for the functional assays. The serum samples for the functional analysis must be collected, separated, and frozen at less than -60°C within 2 hours of the blood draw. Additionally some suspected Type II patients may benefit from looking closely at what method is used for the functional testing. The acquired forms of angioedema (AAE) can benefit from the same clinical testing, because most are ultimately due to decreased C1INH. Measurement of C1q levels and testing for anti-C1INH autoantibodies can help differentiate AAE from HAE. Diagnostic testing for the third hereditary form, alternately called estrogen-dependent HAE, HAE with Normal C1INH or HAE Type III, still presents challenges, and definitive testing may have to wait until there is a more complete understanding of this mixed group of patients. The next steps will include genetic analysis of C1INH and other proteins involved in HAE. PMID:22195757

  12. Hospital-acquired pneumonia

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000146.htm Hospital-acquired pneumonia To use the sharing features on this page, please enable JavaScript. Hospital-acquired pneumonia is an infection of the lungs ...

  13. Clinical presentation, pathophysiology, diagnosis, and treatment of acquired and hereditary angioedema: Exploring state-of-the-art therapies in RI.

    PubMed

    Guo, Canting; Settipane, Russell A

    2016-01-01

    Hereditary and acquired angioedema are potentially life-threatening diseases characterized by spontaneous episodes of subcutaneous and submucosal swelling of face, lips, oral cavity, larynx, and GI tract. Hereditary angioedema (HAE) usually presents within the first and second decades of life, whereas acquired angioedema presents in adults after 40 years of age. These clinical symptoms together with reduced C1 inhibitor levels and/or activity can usually confirm the diagnosis. In recent years, multiple novel therapies for treating hereditary angioedema have emerged including C1 inhibitor concentrates, ecallantide/kallikrein inhibitor, and icatibant/bradykinin receptor antagonist. This article reviews the clinical presentation, diagnosis, treatment, and prophylaxis of HAE. Lastly, this article takes into consideration that, in reality, acute care treatment can often be limited by each hospital's formulary, included is a review of HAE treatments available at the nine major hospitals in Rhode Island. [Full article available at http://rimed.org/rimedicaljournal-2016-06.asp, free with no login]. PMID:27247973

  14. C1q and systemic lupus erythematosus.

    PubMed

    Walport, M J; Davies, K A; Botto, M

    1998-08-01

    In this chapter we review the association between SLE and C1q. In the first part of the chapter we discuss the clinical associations of C1q deficiency, and tabulate the available information in the literature relating to C1q deficiency and autoimmune disease. Other clinical associations of C1q deficiency are then considered, and we mention briefly the association between other genetically determined complement deficiencies and lupus. In the review we explore the relationship between C1q consumption and lupus and we discuss the occurrence of low molecular weight (7S) C1q in lupus, which raises the possibility that increased C1q turnover in the disease may result in unbalanced chain synthesis of the molecule. Anti-C1q antibodies are also strongly associated with severe SLE affecting the kidney, and with hypocomplementaemic urticarial vasculitis, and these associations are also examined. We address the question of how C1q deficiency may cause SLE, discussing the possibility that this may be due to abnormalities of immune complex processing, which have been well characterised in a umber of different human models. There is clear evidence that immune complex processing is abnormal in patients with hypocomplementaemia, and this is compatible with the hypothesis that ineffective immune complex clearance could cause tissue injury, and this may in turn stimulate an autoantibody response. We have also considered the possibility that C1q-C1q receptor interactions are critical in the regulation of apoptosis, and we explore the hypothesis that dysregulation of apoptosis could explain important features in the development of autoimmune disease associated with C1q deficiency. An abnormally high rate of apoptosis, or defective clearance of apoptotic cells, could promote the accumulation of abnormal cellular products that might drive an autoimmune response. Anti-C1q antibodies have been described in a number of murine models of lupus, and these are also briefly discussed. We focus

  15. Autoantibodies against complement C1q specifically target C1q bound on early apoptotic cells.

    PubMed

    Bigler, Cornelia; Schaller, Monica; Perahud, Iryna; Osthoff, Michael; Trendelenburg, Marten

    2009-09-01

    Autoantibodies against complement C1q (anti-C1q) are frequently found in patients with systemic lupus erythematosus (SLE). They strongly correlate with the occurrence of severe lupus nephritis, suggesting a pathogenic role in SLE. Because anti-C1q are known to recognize a neoepitope on bound C1q, but not on fluid-phase C1q, the aim of this study was to clarify the origin of anti-C1q by determining the mechanism that renders C1q antigenic. We investigated anti-C1q from serum and purified total IgG of patients with SLE and hypocomplementemic urticarial vasculitis as well as two monoclonal human anti-C1q Fab from a SLE patient generated by phage display. Binding characteristics, such as their ability to recognize C1q bound on different classes of Igs, on immune complexes, and on cells undergoing apoptosis, were analyzed. Interestingly, anti-C1q did not bind to C1q bound on Igs or immune complexes. Neither did we observe specific binding of anti-C1q to C1q bound on late apoptotic/necrotic cells when compared with binding in the absence of C1q. However, as shown by FACS analysis and confocal microscopy, anti-C1q specifically targeted C1q bound on early apoptotic cells. Anti-C1q were found to specifically target C1q bound on cells undergoing apoptosis. Our observations suggest that early apoptotic cells are a major target of the autoimmune response in SLE and provide a direct link between human SLE, apoptosis, and C1q. PMID:19648280

  16. Acquired hemophilia masked by warfarin therapy.

    PubMed

    Kantor, R; Mayan, H; Puritz, L; Varon, D; Farfel, Z

    2000-03-01

    People without hemophilia but with autoantibodies specifically directed against the procoagulant activity of factor VIII are known to have acquired hemophilia. The bleeding diathesis in these patients is often severe and life-threatening. The definite laboratory diagnosis of this disorder includes demonstration of low factor VIII levels in plasma with a high titer of factor VIII inhibitors, but the initial suspicion for its presence should rise in view of a prolonged partial thromboblastin time (PTT) and a normal prothrombin time associated with an acquired bleeding disorder. Oral anticoagulant treatment is known to prolong PTT as well, and the merger of these 2 situations may cause delayed diagnosis of acquired hemophilia with devastating consequences. We describe here the first reported case of acquired hemophilia diagnosed in a patient treated with warfarin. In such patients prolonged PTT may be ascribed to warfarin therapy rather than to acquired hemophilia, thus causing a dangerous delay in diagnosis. PMID:10746834

  17. C1 neurons: the body's EMTs.

    PubMed

    Guyenet, Patrice G; Stornetta, Ruth L; Bochorishvili, Genrieta; Depuy, Seth D; Burke, Peter G R; Abbott, Stephen B G

    2013-08-01

    The C1 neurons reside in the rostral and intermediate portions of the ventrolateral medulla (RVLM, IVLM). They use glutamate as a fast transmitter and synthesize catecholamines plus various neuropeptides. These neurons regulate the hypothalamic pituitary axis via direct projections to the paraventricular nucleus and regulate the autonomic nervous system via projections to sympathetic and parasympathetic preganglionic neurons. The presympathetic C1 cells, located in the RVLM, are probably organized in a roughly viscerotopic manner and most of them regulate the circulation. C1 cells are variously activated by hypoglycemia, infection or inflammation, hypoxia, nociception, and hypotension and contribute to most glucoprivic responses. C1 cells also stimulate breathing and activate brain stem noradrenergic neurons including the locus coeruleus. Based on the various effects attributed to the C1 cells, their axonal projections and what is currently known of their synaptic inputs, subsets of C1 cells appear to be differentially recruited by pain, hypoxia, infection/inflammation, hemorrhage, and hypoglycemia to produce a repertoire of stereotyped autonomic, metabolic, and neuroendocrine responses that help the organism survive physical injury and its associated cohort of acute infection, hypoxia, hypotension, and blood loss. C1 cells may also contribute to glucose and cardiovascular homeostasis in the absence of such physical stresses, and C1 cell hyperactivity may contribute to the increase in sympathetic nerve activity associated with diseases such as hypertension. PMID:23697799

  18. 42 CFR 52c.1 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Applicability. 52c.1 Section 52c.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS MINORITY BIOMEDICAL RESEARCH... Biomedical Research Support Program) awarded in accordance with section 301(a)(3) of the Public...

  19. 42 CFR 52c.1 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Applicability. 52c.1 Section 52c.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS MINORITY BIOMEDICAL RESEARCH... Biomedical Research Support Program) awarded in accordance with section 301(a)(3) of the Public...

  20. C1 neurons: the body's EMTs

    PubMed Central

    Stornetta, Ruth L.; Bochorishvili, Genrieta; DePuy, Seth D.; Burke, Peter G. R.; Abbott, Stephen B. G.

    2013-01-01

    The C1 neurons reside in the rostral and intermediate portions of the ventrolateral medulla (RVLM, IVLM). They use glutamate as a fast transmitter and synthesize catecholamines plus various neuropeptides. These neurons regulate the hypothalamic pituitary axis via direct projections to the paraventricular nucleus and regulate the autonomic nervous system via projections to sympathetic and parasympathetic preganglionic neurons. The presympathetic C1 cells, located in the RVLM, are probably organized in a roughly viscerotopic manner and most of them regulate the circulation. C1 cells are variously activated by hypoglycemia, infection or inflammation, hypoxia, nociception, and hypotension and contribute to most glucoprivic responses. C1 cells also stimulate breathing and activate brain stem noradrenergic neurons including the locus coeruleus. Based on the various effects attributed to the C1 cells, their axonal projections and what is currently known of their synaptic inputs, subsets of C1 cells appear to be differentially recruited by pain, hypoxia, infection/inflammation, hemorrhage, and hypoglycemia to produce a repertoire of stereotyped autonomic, metabolic, and neuroendocrine responses that help the organism survive physical injury and its associated cohort of acute infection, hypoxia, hypotension, and blood loss. C1 cells may also contribute to glucose and cardiovascular homeostasis in the absence of such physical stresses, and C1 cell hyperactivity may contribute to the increase in sympathetic nerve activity associated with diseases such as hypertension. PMID:23697799

  1. Molecular Determinants of the Substrate Specificity of the Complement-initiating Protease, C1r*

    PubMed Central

    Wijeyewickrema, Lakshmi C.; Yongqing, Tang; Tran, Thuy P.; Thompson, Phillip E.; Viljoen, Jacqueline E.; Coetzer, Theresa H.; Duncan, Renee C.; Kass, Itamar; Buckle, Ashley M.; Pike, Robert N.

    2013-01-01

    The serine protease, C1r, initiates activation of the classical pathway of complement, which is a crucial innate defense mechanism against pathogens and altered-self cells. C1r both autoactivates and subsequently cleaves and activates C1s. Because complement is implicated in many inflammatory diseases, an understanding of the interaction between C1r and its target substrates is required for the design of effective inhibitors of complement activation. Examination of the active site specificity of C1r using phage library technology revealed clear specificity for Gln at P2 and Ile at P1′, which are found in these positions in physiological substrates of C1r. Removal of one or both of the Gln at P2 and Ile at P1′ in the C1s substrate reduced the rate of C1r activation. Substituting a Gln residue into the P2 of the activation site of MASP-3, a protein with similar domain structure to C1s that is not normally cleaved by C1r, enabled efficient activation of this enzyme. Molecular dynamics simulations and structural modeling of the interaction of the C1s activation peptide with the active site of C1r revealed the molecular mechanisms that particularly underpin the specificity of the enzyme for the P2 Gln residue. The complement control protein domains of C1r also made important contributions to efficient activation of C1s by this enzyme, indicating that exosite interactions were also important. These data show that C1r specificity is well suited to its cleavage targets and that efficient cleavage of C1s is achieved through both active site and exosite contributions. PMID:23589288

  2. Procyanidin C1 Causes Vasorelaxation Through Activation of the Endothelial NO/cGMP Pathway in Thoracic Aortic Rings

    PubMed Central

    Byun, Eui-Baek; Sung, Nak-Yun; Yang, Mi-So; Song, Du-Sup; Byun, Eui-Hong; Kim, Jae-Kyung; Park, Jong-Heum; Song, Beom-Seok; Lee, Ju-Woon; Park, Sang-Hyun; Byun, Myung-Woo

    2014-01-01

    Abstract The aim of this study was to clarify the efficacy of procyanidin C1 (Pro C1) for modulating vascular tone. Pro C1 induced a potent vasorelaxant effect on phenylephrine-constricted endothelium-intact thoracic aortic rings, but had no effect on denuded thoracic aortic rings. Moreover, Pro C1 caused a significant increase in nitric oxide (NO) production in endothelial cells. Pro C1-induced vasorelaxation and Pro C1-induced NO production were significantly decreased in the presence of a nonspecific potassium channel blocker (tetraethylammonium chloride [TEA]), an endothelial NO synthase inhibitor (NG-monomethyl-L-arginine [L-NMMA]), and a store-operated calcium entry inhibitor (2-aminoethyl diphenylborinate [2-APB]). Pro C1-induced vasorelaxation was also completely abolished by an inhibitor of soluble guanyl cyclase, which suggests that the Pro C1 effects observed involved cyclic guanosine monophosphate (cGMP) production. Interestingly, Pro C1 significantly enhanced basal cGMP levels. Taken together, these results indicate that Pro C1-induced vasorelaxation is associated with the activation of the calcium-dependent NO/cGMP pathway, involving potassium channel activation. Thus, Pro C1 may represent a novel and potentially therapeutically relevant compound for the treatment of cardiovascular diseases. PMID:24971771

  3. Procyanidin C1 causes vasorelaxation through activation of the endothelial NO/cGMP pathway in thoracic aortic rings.

    PubMed

    Byun, Eui-Baek; Sung, Nak-Yun; Yang, Mi-So; Song, Du-Sup; Byun, Eui-Hong; Kim, Jae-Kyung; Park, Jong-Heum; Song, Beom-Seok; Lee, Ju-Woon; Park, Sang-Hyun; Byun, Myung-Woo; Kim, Jae-Hun

    2014-07-01

    The aim of this study was to clarify the efficacy of procyanidin C1 (Pro C1) for modulating vascular tone. Pro C1 induced a potent vasorelaxant effect on phenylephrine-constricted endothelium-intact thoracic aortic rings, but had no effect on denuded thoracic aortic rings. Moreover, Pro C1 caused a significant increase in nitric oxide (NO) production in endothelial cells. Pro C1-induced vasorelaxation and Pro C1-induced NO production were significantly decreased in the presence of a nonspecific potassium channel blocker (tetraethylammonium chloride [TEA]), an endothelial NO synthase inhibitor (N(G)-monomethyl-L-arginine [L-NMMA]), and a store-operated calcium entry inhibitor (2-aminoethyl diphenylborinate [2-APB]). Pro C1-induced vasorelaxation was also completely abolished by an inhibitor of soluble guanyl cyclase, which suggests that the Pro C1 effects observed involved cyclic guanosine monophosphate (cGMP) production. Interestingly, Pro C1 significantly enhanced basal cGMP levels. Taken together, these results indicate that Pro C1-induced vasorelaxation is associated with the activation of the calcium-dependent NO/cGMP pathway, involving potassium channel activation. Thus, Pro C1 may represent a novel and potentially therapeutically relevant compound for the treatment of cardiovascular diseases. PMID:24971771

  4. Posterior osseous bridging of C1.

    PubMed

    Simsek, Serkan; Yigitkanli, Kazim; Comert, Ayhan; Acar, Halil I; Seckin, Hakan; Er, Uygur; Belen, Deniz; Tekdemir, Ibrahim; Elhan, Alaittin

    2008-06-01

    The sulcus of the vertebral artery is located behind the lateral mass of the atlas and in some cases is converted into a foramen by anomalous ossification known as the posterior ponticulus (osseous bridge). This study involved anatomical observations of 158 isolated anatomical specimens of dry C1 vertebrae. The incidence and types of posterior osseous bridging were identified for the 158 dry samples of atlas vertebrae. In nine (5.6%) dry C1 vertebrae, partial osseous bridging was detected (bilaterally in eight vertebrae and unilaterally on the left in one). Complete osseous bridging (arcuate foramen) was observed in six (3.8%) dry C1 vertebrae (bilaterally in one vertebra, unilaterally on the left in three, and on the right in two). Awareness of the types of posterior osseous bridging of C1 in craniocervical junction surgery is essential, and may be helpful in surgical interventions in this region. PMID:18378457

  5. Anti-C1q autoantibodies.

    PubMed

    Kallenberg, Cees G M

    2008-09-01

    Autoantibodies to complement components are associated with various diseases. Anti-C1q antibodies are present in all patients with hypocomplementemic urticarial vasculitis, but also, with varying prevalence, in other conditions. In SLE, these antibodies are neither sensitive nor specific for this condition. They occur, however, more frequently in (proliferative) lupus nephritis, particularly during active disease. Furthermore, levels of anti-C1q rise, in many cases, prior to a relapse of lupus nephritis, suggesting a pathogenic role for the autoantibodies. Indeed, experimental studies strongly support a pathogenic role for anti-C1q in immune complex-mediated renal disease. In addition, anti-C1q may interfere with the clearance of apoptotic cells, so influencing induction and expression of autoimmunity. PMID:18606253

  6. Acquired reactive perforating collagenosis.

    PubMed

    Basak, P Y; Turkmen, C

    2001-01-01

    Acquired perforating disorder has been recognized as an uncommon distinct dermatosis in which altered collagen is eliminated through the epidermis. Several disorders accompanied by itching and scratching were reported to be associated with reactive perforating collagenosis. A 67-year-old white woman diagnosed as acquired reactive perforating collagenosis with poorly controlled diabetes mellitus and congestive cardiac failure is presented. PMID:11525959

  7. 21 CFR 866.5250 - Complement C2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  8. 21 CFR 866.5250 - Complement C2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  9. 21 CFR 866.5250 - Complement C 2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  10. 21 CFR 866.5250 - Complement C 2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  11. Acquired Cystic Kidney Disease

    MedlinePlus

    ... a kidney transplant or blood-filtering treatments called dialysis. The cysts are more likely to develop in people who are on kidney dialysis. The chance of developing acquired cystic kidney disease ...

  12. Hospital-acquired pneumonia

    MedlinePlus

    ... tends to be more serious than other lung infections because: People in the hospital are often very sick and cannot fight off ... prevent pneumonia. Most hospitals have programs to prevent hospital-acquired infections.

  13. Complimentary action: C1q increases ganglion cell survival in an in vitro model of retinal degeneration.

    PubMed

    Taylor, Linnéa; Arnér, Karin; Blom, Anna M; Ghosh, Fredrik

    2016-09-15

    Using a previously described retinal explant culture system as an acute injury model, we here explore the role of C1q, the initiator of the classical complement pathway, in neuronal cell survival and retinal homeostasis. Full-thickness adult rat retinal explants were divided into four groups, receiving the following supplementation: C1q (50nM), C1-inhibitor (C1-inh; Berinert; 500mg/l), C1q+C1-inh, and no supplementation (culture controls). Explants were kept for 12h or 2days after which they were examined morphologically and with a panel of immunohistochemical markers. C1q supplementation protects ganglion cells from degeneration within the explant in vitro system. This effect is correlated to an attenuated endogenous production of C1q, and a quiesced gliotic response. PMID:27609284

  14. Acquired coagulation factor XIII deficiency: a case report.

    PubMed

    Jia, Yongqing; Hu, Huixian; Wei, Bin

    2016-06-01

    The main objective of the study is to summarize the clinical characteristics of acquired factor XIII (FXIII) deficiency caused by a spontaneous FXIII inhibitor. Here we report a new case of acquired FXIII deficiency caused by FXIII inhibitor and review the medical literature regarding the characteristics and treatment of this disorder. FXIII deficiency caused by FXIII inhibitors is rare and of uncertain pathogenesis. Experience with therapeutic measures is limited to data from case reports. Immunosuppressive drugs may reduce autoantibodies or inhibit the cell clone generating the antibodies and may have been of benefit in our patient. The impact of such therapy on patient prognosis is incompletely known. PMID:26588447

  15. Isolation and function of a human endothelial cell C1q receptor

    PubMed Central

    Dunn, L.; Berg, R. van den; Lange, Y. Muizert-de; Gerritsen, A.; Es, L. A. van

    1993-01-01

    It has been shown previously that cultured human venous and arterial endothelial cells (EC) bind C1q in a time- and dose-dependent manner. Cultured human endothelial cells express an average number of 5.2 × 105 binding sites/cell. In the present study the putative receptor for C1q (C1qR) was isolated from the membranes of 1–5 × 109 human umbilical cord EC by affinity chromatography on C1q–Sepharose. During isolation, C1qR was detected by its capacity to inhibit the lysis of EAC1q in C1q-deficient serum. The eluate from C1q–Sepharose was concentrated, dialysed and subjected to QAE-A50 chromatography and subsequently to gel filtration on HPLC–TSK 3000. C1qR filtered at an apparent molecular weight of 60 kDa. Purified C1qR exhibited an apparent molecular weight of 55–62 kDa in the unreduced state and a molecular weight of 64–68 kDa in reduced form. Two IgM monoclonal antibodies (mAb) D3 and D5 were raised following immunization of mice with purified receptor preparations. Both monoclonal antibodies increased the binding of 125I-C1q to endothelial cells but F(ab')2 anti-C1qR mAb inhibited the binding of a125I-C1q to EC in a dosedependent manner. The D3 mAb recognized a band of 54–60 kDa in Western blots of membranes of human EC and polymorphonuclear leukocytes. Previously, the authors showed that C1q induces the binding of IgM-containing immune complexes to EC. Therefore, it was hypothesized that during a primary immune response generation of IgM-IC may occur, resulting in binding and activation of C1, dissociation of activated C1 by C1 inhibitor and subsequent interaction of IgM-IC bearing C1q with EC–C1qR. PMID:18475561

  16. Cooperative Research in C1 Chemistry

    SciTech Connect

    Gerald P. Huffman

    2000-10-27

    C1 chemistry refers to the conversion of simple carbon-containing materials that contain one carbon atom per molecule into valuable products. The feedstocks for C1 chemistry include natural gas, carbon dioxide, carbon monoxide, methanol and synthesis gas (a mixture of carbon monoxide and hydrogen). Synthesis gas, or syngas, is produced primarily by the reaction of natural gas, which is principally methane, with steam. It can also be produced by gasification of coal, petroleum coke, or biomass. The availability of syngas from coal gasification is expected to increase significantly in the future because of increasing development of integrated gasification combined cycle (IGCC) power generation. Because of the abundance of remote natural gas, the advent of IGCC, and environmental advantages, C1 chemistry is expected to become a major area of interest for the transportation fuel and chemical industries in the relatively near future. The CFFLS will therefore perform a valuable national service by providing science and engineering graduates that are trained in this important area. Syngas is the source of most hydrogen. Approximately 10 trillion standard cubic feet (SCF) of hydrogen are manufactured annually in the world. Most of this hydrogen is currently used for the production of ammonia and in a variety of refining and chemical operations. However, utilization of hydrogen in fuel cells is expected to grow significantly in the next century. Syngas is also the feedstock for all methanol and Fischer-Tropsch plants. Currently, world consumption of methanol is over 25 million tons per year. There are many methanol plants in the U.S. and throughout the world. Methanol and oxygenated transportation fuel products play a significant role in the CFFLS C1 program. Currently, the only commercial Fischer-Tropsch plants are overseas, principally in South Africa (SASOL). However, new plants are being built or planned for a number of locations. One possible location for future F

  17. Community-acquired pneumonia.

    PubMed

    Falguera, M; Ramírez, M F

    2015-11-01

    This article not only reviews the essential aspects of community-acquired pneumonia for daily clinical practice, but also highlights the controversial issues and provides the newest available information. Community-acquired pneumonia is considered in a broad sense, without excluding certain variants that, in recent years, a number of authors have managed to delineate, such as healthcare-associated pneumonia. The latter form is nothing more than the same disease that affects more frail patients, with a greater number of risk factors, both sharing an overall common approach. PMID:26186969

  18. Acquired Brain Injury Program.

    ERIC Educational Resources Information Center

    Schwartz, Stacey Hunter

    This paper reviews the Acquired Brain Injury (ABI) Program at Coastline Community College (California). The ABI Program is a two-year, for-credit educational curriculum designed to provide structured cognitive retraining for adults who have sustained an ABI due to traumatic (such as motor vehicle accident or fall) or non-traumatic(such as…

  19. Acquired von Willebrand disease.

    PubMed

    Petrini, P

    1999-05-01

    Acquired von Willebrand disease (AvWD) is a syndrome that has clinical and laboratory features similar to hereditary vWD. In contrast to the latter it occurs in patients without a family history of previous bleeding tendency. PMID:23401904

  20. COOPERATIVE RESEARCH IN C1 CHEMISTRY

    SciTech Connect

    Gerald P. Huffman

    2001-04-30

    Faculty and students from five universities (Kentucky, West Virginia, Utah, Pittsburgh and Auburn) are collaborating on a basic research program to develop novel C1 chemistry processes for the production of clean, high quality transportation fuel. An Industrial Advisory Board (IAB) with members from Chevron, Eastman Chemical, Energy International, Teir Associates, and the Department of Defense has been formed to provide practical guidance to the program. The program has two principal objectives. (1) Develop technology for conversion of C1 source materials (natural gas, synthesis gas, carbon dioxide and monoxide, and methanol) into clean, high efficiency transportation fuel. (2) Develop novel processes for producing hydrogen from natural gas and other hydrocarbons. Some of the principal accomplishments of the program in its first two years are: (1) The addition of acetylenic compounds in Fischer-Tropsch synthesis is found to produce significant amounts of oxygenated products in FT diesel fuels. Such oxygenated products should decrease particulate matter (PM) emissions. (2) Nanoscale, binary, Fe-based catalysts supported on alumina have been shown to have significant activity for the decomposition of methane into pure hydrogen and potentially valuable multi-walled carbon nanotubes. (3) Catalytic synthesis processes have been developed for synthesis of diethyl carbonate, higher ethers, and higher alcohols from C1 source materials. Testing of the effect of adding these oxygenates to diesel fuel on PM emissions has begun using a well-equipped small diesel engine test facility. (4) Supercritical fluid (SCF) FT synthesis has been conducted under SCF hexane using both Fe and Co catalysts. There is a marked effect on the hydrocarbon product distribution, with a shift to higher carbon number products. These and other results are summarized.

  1. Microbial growth on C1 compounds

    PubMed Central

    Kemp, M. B.; Quayle, J. R.

    1967-01-01

    1. A study has been made of the incorporation of carbon from [14C]formaldehyde and [14C]formate by cultures of Pseudomonas methanica growing on methane. 2. The distribution of radioactivity within the non-volatile constituents of the ethanol-soluble fractions of the cells, after incubation with labelled compounds for periods of up to 1min., has been analysed by chromatography and radioautography. 3. Radioactivity was fixed from [14C]formaldehyde mainly into the phosphates of the sugars, glucose, fructose, sedoheptulose and allulose. 4. Very little radioactivity was fixed from [14C]formate; after 1min. the only products identified were serine and malate. 5. The distribution of radioactivity within the carbon skeleton of glucose, obtained from short-term incubations with [14C]methanol of Pseudomonas methanica growing on methane, has been investigated. At the earliest time of sampling over 70% of the radioactivity was located in C-1; as the time increased the radioactivity spread throughout the molecule. 6. The results have been interpreted in terms of a variant of the pentose phosphate cycle, involving the condensation of formaldehyde with C-1 of ribose 5-phosphate to give allulose phosphate. PMID:6030306

  2. Acquired von Willebrand disease.

    PubMed

    Kumar, Shaji; Pruthi, Rajiv K; Nichols, William L

    2002-02-01

    Acquired von Willebrand disease (AvWD) is a relatively rare acquired bleeding disorder that usually occurs in elderly patients, in whom its recognition may be delayed. Patients usually present predominantly with mucocutaneous bleeding, with no previous history of bleeding abnormalities and no clinically meaningful family history. Various underlying diseases have been associated with AvWD, most commonly hematoproliferative disorders, including monoclonal gammopathies, lymphoproliferative disorders, and myeloproliferative disorders. The pathogenesis of AvWD remains incompletely understood but includes autoantibodies directed against the von Willebrand factor (vWF), leading to a more rapid clearance from the circulation or interference with its function, adsorption of vWF by tumor cells, and nonimmunologic mechanisms of destruction. Laboratory evaluation usually reveals a pattern of prolonged bleeding time and decreased levels of vWF antigen, ristocetin cofactor activity, and factor VIII coagulant activity consistent with a diagnosis of vWD. Acquired vWD is distinguished from the congenital form by age at presentation, absence of a personal and family history of bleeding disorders, and, often, presence of a hematoproliferative or autoimmune disorder. The severity of the bleeding varies considerably among patients. Therapeutic options include desmopressin and certain factor VIII concentrates that also contain vWF. Successful treatment of the associated illness can reverse the clinical and laboratory manifestations. Intravenous immunoglobulins have also shown some efficacy in the management of AvWD, especially cases associated with monoclonal gammopathies. Awareness of AvWD is essential for diagnosis and appropriate management. PMID:11838652

  3. [Acquired von Willebrand syndrome].

    PubMed

    Franchini, Massimo

    2006-01-01

    Acquired von Willebrand syndrome (aVWS) is a rare, but probably underestimated, bleeding disorder that mimics the congenital form of von Willebrand disease (VWD) in terms of laboratory findings and clinical presentation. However, unlike congenital VWD, it arises in individuals with no personal or family history of bleeding. AVWS occurs in association with a variety of underlying disorders, including lymphoproliferative disorders, myeloproliferative disorders and cardiovascular diseases. The main pathogenic, clinical, laboratory and therapeutic aspects of this syndrome are concisely reported in this review. PMID:16913181

  4. Acquired hemophilia A in a patient with systemic lupus erythematosus.

    PubMed

    Ishikawa, T; Tsukamoto, N; Suto, M; Uchiumi, H; Mitsuhashi, H; Yokohama, A; Maesawa, A; Nojima, Y; Naruse, T

    2001-06-01

    A patient with systemic lupus erythematosus (SLE) developed acquired hemophilia A. The patient, a 24-year-old Japanese woman, was referred to our hospital because of uncontrollable bleeding following a tooth extraction. Laboratory examination revealed prolonged APTT (116 seconds), reduced factor VIII activity (2.8 %) and the presence of factor VIII inhibitor at a titer of 46.5 Bethesda units/ml. Transfusion of prothrombin complex concentrate and activated prothrombin complex concentrate followed by administration of prednisolone and cyclophosphamide successfully arrested bleeding and reduced the factor VIII inhibitor level. Acquired hemophilia A is a rare but lethal condition. Rapid diagnosis and introduction of adequate therapies are critical. PMID:11446683

  5. Acquired hemophilia A: A rare cause of gross hematuria

    PubMed Central

    Hosier, Gregory W.; Mason, Ross J.; Sue Robinson, K.; Bailly, Gregory G.

    2015-01-01

    Acquired hemophilia A is a rare condition caused by spontaneous development of factor VIII inhibitor. This condition most commonly presents with multiple hemorrhagic symptoms and isolated hematuria is exceedingly rare. Early diagnosis is important, as this condition carries a high mortality rate (13–22%). We present a case of an 82-year-old man with isolated hematuria caused by a factor VIII inhibitor who was successfully treated with recombinant activated factor VII concentrate, as well as prednisone and cyclophosphamide. PMID:26834904

  6. Complete cDNA sequence of human complement C1s and close physical linkage of the homologous genes C1s and C1r

    SciTech Connect

    Tosi, M.; Duponchel, C.; Meo, T.; Julier, C.

    1987-12-29

    Overlapping molecular clones encoding the complement subcomponent C1s were isolated from a human liver cDNA library. The nucleotide sequence reconstructed from these clones spans about 85% of the length of the liver C1s messenger RNAs, which occur in three distinct size classes around 3 kilobases in length. Comparisons with the sequence of C1r, the other enzymatic subcomponent of C1, reveal 40% amino acid identity and conservation of all the cysteine residues. Beside the serine protease domain, the following sequence motifs, previously described in C1r, were also found in C1s: (a) two repeats of the type found in the Ba fragment of complement factor B and in several other complement but also noncomplement proteins, (b) a cysteine-rich segment homologous to the repeats of epidermal growth factor precursor, and (c) a duplicated segment found only in C1r and C1s. Differences in each of these structural motifs provide significant clues for the interpretation of the functional divergence of these interacting serine protease zymogens. Hybridizations of C1r and C1s probes to restriction endonuclease fragments of genomic DNA demonstrate close physical linkage of the corresponding genes. The implications of this finding are discussed with respect to the evolution of C1r and C1s after their origin by tandem gene duplication and to the previously observed combined hereditary deficiencies of Clr and Cls.

  7. Acquired Localized Hypertrichosis Induced by Rivastigmine

    PubMed Central

    Imbernón-Moya, Adrian; Podlipnik, Sebastian; Burgos, Fernando; Vargas-Laguna, Elena; Aguilar-Martínez, Antonio; Fernández-Cogolludo, Eva; Gallego-Valdes, Miguel Angel

    2016-01-01

    Hypertrichosis is the excessive hair growth in any area of the skin surface. Acquired localized hypertrichosis may be secondary to multiple causes and there is a secondary form due to several drugs, which is usually reversible with discontinuation of the causative agent. Rivastigmine is a reversible and competitive inhibitor of acetylcholinesterase and butyrylcholinesterase used for symptomatic treatment of Alzheimer dementia and Parkinson's disease. It has an adequate safety profile and cutaneous side effects are unusual. Irritant contact dermatitis, allergic dermatitis, baboon syndrome, and cutaneous rash due to rivastigmine have been reported. We report on a Caucasian 80-year-old male with personal history of Alzheimer's disease. The patient started therapy with oral rivastigmine one month prior to clinical presentation of localized hypertrichosis on both forearms. Norgalanthamine has been shown to promote hair growth activity via the proliferation of dermal papilla. Acetylcholinesterase inhibitors can induce hair growth. PMID:27073702

  8. AIDS: acquired immunodeficiency syndrome *

    PubMed Central

    Gilmore, N.J.; Beaulieu, R.; Steben, M.; Laverdière, M.

    1992-01-01

    Acquired immunodeficiency syndrome, or AIDS, is a new illness that occurs in previously healthy individuals. It is characterized by immunodeficiency, opportunistic infections and unusual malignant diseases. Life-threatening single or multiple infections with viruses, mycobacteria, fungi or protozoa are common. A rare neoplasm, Kaposi's sarcoma, has developed in approximately one third of patients with AIDS. More than 800 cases of AIDS have been reported in North America, over 24 of them in Canada. The majority of patients are male homosexuals, although AIDS has also developed in abusers of intravenously administered drugs, Haitian immigrants, individuals with hemophilia, recipients of blood transfusions, prostitutes, and infants, spouses and partners of patients with AIDS. The cause of AIDS is unknown, but the features are consistent with an infectious process. Early diagnosis can be difficult owing to the nonspecific symptoms and signs of the infections and malignant diseases. Therefore, vigilance by physicians is of the utmost importance. PMID:1544049

  9. Community-acquired pneumonia.

    PubMed

    Polverino, E; Torres Marti, A

    2011-02-01

    Despite the remarkable advances in antibiotic therapies, diagnostic tools, prevention campaigns and intensive care, community-acquired pneumonia (CAP) is still among the primary causes of death worldwide, and there have been no significant changes in mortality in the last decades. The clinical and economic burden of CAP makes it a major public health problem, particularly for children and the elderly. This issue provides a clinical overview of CAP, focusing on epidemiology, economic burden, diagnosis, risk stratification, treatment, clinical management, and prevention. Particular attention is given to some aspects related to the clinical management of CAP, such as the microbial etiology and the available tools to achieve it, the usefulness of new and old biomarkers, and antimicrobial and other non-antibiotic adjunctive therapies. Possible scenarios in which pneumonia does not respond to treatment are also analyzed to improve clinical outcomes of CAP. PMID:21242952

  10. Acquired Porphyria Cutanea Tarda

    PubMed Central

    Koval, Andrew; Danby, C. W. E.; Petermann, H.

    1965-01-01

    Currently, the porphyrias are classified in four main groups: congenital porphyria, acute intermittent porphyria, porphyria cutanea tarda hereditaria, and porphyria cutanea tarda symptomatica. The acquired form of porphyria (porphyria cutanea tarda symptomatica) occurs in older males and is nearly always associated with chronic alcoholism and hepatic cirrhosis. The main clinical changes are dermatological, with excessive skin fragility and photosensitivity resulting in erosions and bullae. Biochemically, high levels of uroporphyrin are found in the urine and stools. Treatment to date has been symptomatic and usually unsuccessful. A case of porphyria cutanea tarda symptomatica is presented showing dramatic improvement of both the skin lesions and porphyrin levels in urine and blood following repeated phlebotomy. Possible mechanisms of action of phlebotomy on porphyria cutanea tarda symptomatica are discussed. ImagesFig. 1Fig. 2 PMID:14341652

  11. [ICU acquired neuromyopathy].

    PubMed

    Gueret, G; Guillouet, M; Vermeersch, V; Guillard, E; Talarmin, H; Nguyen, B-V; Rannou, F; Giroux-Metges, M-A; Pennec, J-P; Ozier, Y

    2013-09-01

    ICU acquired neuromyopathy (IANM) is the most frequent neurological pathology observed in ICU. Nerve and muscle defects are merged with neuromuscular junction abnormalities. Its physiopathology is complex. The aim is probably the redistribution of nutriments and metabolism towards defense against sepsis. The main risk factors are sepsis, its severity and its duration of evolution. IANM is usually diagnosed in view of difficulties in weaning from mechanical ventilation, but electrophysiology may allow an earlier diagnosis. There is no curative therapy, but early treatment of sepsis, glycemic control as well as early physiotherapy may decrease its incidence. The outcomes of IANM are an increase in morbi-mortality and possibly long-lasting neuromuscular abnormalities as far as tetraplegia. PMID:23958176

  12. Molecular analysis of the maize anthocyanin regulatory locus C1.

    PubMed Central

    Cone, K C; Burr, F A; Burr, B

    1986-01-01

    The C1 gene of maize plays a regulatory role in the production of anthocyanin pigments in the aleurone layer of the endosperm. As an initial step toward understanding the molecular details of how C1 controls pigment biosynthesis, we cloned the C1 gene. This was accomplished by first cloning a mutable allele of C1, c1-m5, which contains the transposable element Spm. A combination of molecular and genetic analysis was used to identify the Spm at the C1 locus. Individual genomic DNAs from a population in which the c1-mutable phenotype was segregating with the recessive c1 phenotype were digested with methyl-sensitive restriction enzymes and probed with a small DNA fragment derived from a defective Spm. One Sal I restriction fragment complementary to the Spm probe was shown to be present in the DNA of individuals with the c1-m5 phenotype but absent from DNA of individuals with a recessive c1 phenotype. Subsequent cloning and restriction analysis of this fragment revealed sequences flanking the Spm that proved to be C1-specific. A DNA fragment derived from the flanking sequences was then used as a probe to clone the wild-type C1 gene and several additional alleles of C1, including one stable recessive, two mutations caused by Ds insertions, one mutation induced by insertion of a defective Spm, and two dominant mutations, C1-S and C1-I. RNA blot hybridization analysis of three C1 alleles indicates that C1 regulation of the Bz1 and A1 structural genes in the anthocyanin biosynthetic pathway is at the transcriptional level. Images PMID:3025847

  13. The genome of the anaerobic fungus Orpinomyces sp. strain C1A reveals the unique evolutionary history of a remarkable plant biomass degrader.

    PubMed

    Youssef, Noha H; Couger, M B; Struchtemeyer, Christopher G; Liggenstoffer, Audra S; Prade, Rolf A; Najar, Fares Z; Atiyeh, Hasan K; Wilkins, Mark R; Elshahed, Mostafa S

    2013-08-01

    Anaerobic gut fungi represent a distinct early-branching fungal phylum (Neocallimastigomycota) and reside in the rumen, hindgut, and feces of ruminant and nonruminant herbivores. The genome of an anaerobic fungal isolate, Orpinomyces sp. strain C1A, was sequenced using a combination of Illumina and PacBio single-molecule real-time (SMRT) technologies. The large genome (100.95 Mb, 16,347 genes) displayed extremely low G+C content (17.0%), large noncoding intergenic regions (73.1%), proliferation of microsatellite repeats (4.9%), and multiple gene duplications. Comparative genomic analysis identified multiple genes and pathways that are absent in Dikarya genomes but present in early-branching fungal lineages and/or nonfungal Opisthokonta. These included genes for posttranslational fucosylation, the production of specific intramembrane proteases and extracellular protease inhibitors, the formation of a complete axoneme and intraflagellar trafficking machinery, and a near-complete focal adhesion machinery. Analysis of the lignocellulolytic machinery in the C1A genome revealed an extremely rich repertoire, with evidence of horizontal gene acquisition from multiple bacterial lineages. Experimental analysis indicated that strain C1A is a remarkable biomass degrader, capable of simultaneous saccharification and fermentation of the cellulosic and hemicellulosic fractions in multiple untreated grasses and crop residues examined, with the process significantly enhanced by mild pretreatments. This capability, acquired during its separate evolutionary trajectory in the rumen, along with its resilience and invasiveness compared to prokaryotic anaerobes, renders anaerobic fungi promising agents for consolidated bioprocessing schemes in biofuels production. PMID:23709508

  14. The Genome of the Anaerobic Fungus Orpinomyces sp. Strain C1A Reveals the Unique Evolutionary History of a Remarkable Plant Biomass Degrader

    PubMed Central

    Youssef, Noha H.; Couger, M. B.; Struchtemeyer, Christopher G.; Liggenstoffer, Audra S.; Prade, Rolf A.; Najar, Fares Z.; Atiyeh, Hasan K.; Wilkins, Mark R.

    2013-01-01

    Anaerobic gut fungi represent a distinct early-branching fungal phylum (Neocallimastigomycota) and reside in the rumen, hindgut, and feces of ruminant and nonruminant herbivores. The genome of an anaerobic fungal isolate, Orpinomyces sp. strain C1A, was sequenced using a combination of Illumina and PacBio single-molecule real-time (SMRT) technologies. The large genome (100.95 Mb, 16,347 genes) displayed extremely low G+C content (17.0%), large noncoding intergenic regions (73.1%), proliferation of microsatellite repeats (4.9%), and multiple gene duplications. Comparative genomic analysis identified multiple genes and pathways that are absent in Dikarya genomes but present in early-branching fungal lineages and/or nonfungal Opisthokonta. These included genes for posttranslational fucosylation, the production of specific intramembrane proteases and extracellular protease inhibitors, the formation of a complete axoneme and intraflagellar trafficking machinery, and a near-complete focal adhesion machinery. Analysis of the lignocellulolytic machinery in the C1A genome revealed an extremely rich repertoire, with evidence of horizontal gene acquisition from multiple bacterial lineages. Experimental analysis indicated that strain C1A is a remarkable biomass degrader, capable of simultaneous saccharification and fermentation of the cellulosic and hemicellulosic fractions in multiple untreated grasses and crop residues examined, with the process significantly enhanced by mild pretreatments. This capability, acquired during its separate evolutionary trajectory in the rumen, along with its resilience and invasiveness compared to prokaryotic anaerobes, renders anaerobic fungi promising agents for consolidated bioprocessing schemes in biofuels production. PMID:23709508

  15. Acute Acquired Concomitant Esotropia

    PubMed Central

    Chen, Jingchang; Deng, Daming; Sun, Yuan; Shen, Tao; Cao, Guobin; Yan, Jianhua; Chen, Qiwen; Ye, Xuelian

    2015-01-01

    Abstract Acute acquired concomitant esotropia (AACE) is a rare, distinct subtype of esotropia. The purpose of this retrospective study was to describe the clinical characteristics and discuss the classification and etiology of AACE. Charts from 47 patients with AACE referred to our institute between October 2010 and November 2014 were reviewed. All participants underwent a complete medical history, ophthalmologic and orthoptic examinations, and brain and orbital imaging. Mean age at onset was 26.6 ± 12.2 years. Of the 18 cases with deviations ≤ 20 PD, 16 presented with diplopia at distance and fusion at near vision at the onset of deviation; differences between distance and near deviations were < 8 PD; all cases except one were treated with prism and diplopia resolved. Of the 29 cases with deviations > 20 PD, 5 were mild hypermetropic with age at onset between 5 and 19 years, 16 were myopic, and 8 were emmetropic with age at onset > 12 years; 24 were surgically treated and 5 cases remained under observation; all 24 cases achieved normal retinal correspondence or fusion or stereopsis on postoperative day 1 in synoptophore; in 23 cases diplopia or visual confusion resolved postoperatively. Of the 47 cases, brain and orbital imaging in 2 cases revealed a tumor in the cerebellopontine angle and 1 case involved spinocerebellar ataxia as revealed by genetic testing. AACE in this study was characterized by a sudden onset of concomitant nonaccommodative esotropia with diplopia or visual confusion at 5 years of age or older and the potential for normal binocular vision. We suggest that AACE can be divided into 2 subgroups consisting of patients with relatively small versus large angle deviations. Coexisting or underlying neurological diseases were infrequent in AACE. PMID:26705210

  16. Interaction between complement subcomponent C1q and bacterial lipopolysaccharides.

    PubMed

    Zohair, A; Chesne, S; Wade, R H; Colomb, M G

    1989-02-01

    The heptose-less mutant of Escherichia coli, D31m4, bound complement subcomponent C1q and its collagen-like fragments (C1qCLF) with Ka values of 1.4 x 10(8) and 2.0 x 10(8) M-1 respectively. This binding was suppressed by chemical modification of C1q and C1qCLF using diethyl pyrocarbonate (DEPC). To investigate the role of lipopolysaccharides (LPS) in this binding, biosynthetically labelled [14C]LPS were purified from E. coli D31m4 and incorporated into liposomes prepared from phosphatidylcholine (PC) and phosphatidylethanolamine (PE) [PC/PE/LPS, 2:2:1, by wt.]. Binding of C1q or its collagen-like fragments to the liposomes was estimated via a flotation test. These liposomes bound C1q and C1qCLF with Ka values of 8.0 x 10(7) and 2.0 x 10(7) M-1; this binding was totally inhibited after chemical modification of C1q and C1qCLF by DEPC. Liposomes containing LPS purified from the wild-strain E. coli K-12 S also bound C1q and C1qCLF, whereas direct binding of C1q or C1qCLF to the bacteria was negligible. Diamines at concentrations which dissociate C1 into C1q and (C1r, C1s)2, strongly inhibited the interaction of C1q or C1qCLF with LPS. Removal of 3-deoxy-D-manno-octulosonic acid (2-keto-3-deoxyoctonic acid; KDO) from E. coli D31m4 LPS decreases the binding of C1qCLF to the bacteria by 65%. When this purified and modified LPS was incorporated into liposomes, the C1qCLF binding was completely abolished. These results show: (i) the essential role of the collagen-like moiety and probably its histidine residues in the interaction between C1q and the mutant D31m4; (ii) the contribution of LPS, particularly the anionic charges of KDO, to this interaction. PMID:2649081

  17. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... confer control of X and therefore will file as an acquiring person. Because A held the plant prior to the... within two persons, “A” and “B.” Under this section, if V is to acquire corporation X, both “A” and “B... person. Examples: 1. Assume that person “Q” will acquire voting securities of corporation X held by...

  18. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... confer control of X and therefore will file as an acquiring person. Because A held the plant prior to the... within two persons, “A” and “B.” Under this section, if V is to acquire corporation X, both “A” and “B... person. Examples: 1. Assume that person “Q” will acquire voting securities of corporation X held by...

  19. 26 CFR 1.1092(c)-1 - Qualified covered calls.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 11 2010-04-01 2010-04-01 true Qualified covered calls. 1.1092(c)-1 Section 1.1092(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Wash Sales of Stock Or Securities § 1.1092(c)-1 Qualified covered calls. (a)...

  20. 26 CFR 49.4262(c)-1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Definitions. 49.4262(c)-1 Section 49.4262(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4262(c)-1 Definitions. (a) The continental United States. For purposes...

  1. 26 CFR 31.3401(c)-1 - Employee.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Employee. 31.3401(c)-1 Section 31.3401(c)-1... Income Tax at Source § 31.3401(c)-1 Employee. (a) The term employee includes every individual performing... relationship of employer and employee. The term includes officers and employees, whether elected or...

  2. 26 CFR 1.1092(c)-1 - Qualified covered calls.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 11 2012-04-01 2012-04-01 false Qualified covered calls. 1.1092(c)-1 Section 1.1092(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Wash Sales of Stock Or Securities § 1.1092(c)-1 Qualified covered...

  3. Revisiting the mechanism of the autoactivation of the complement protease C1r in the C1 complex: structure of the active catalytic region of C1r.

    PubMed

    Kardos, József; Harmat, Veronika; Palló, Anna; Barabás, Orsolya; Szilágyi, Katalin; Gráf, László; Náray-Szabó, Gábor; Goto, Yuji; Závodszky, Péter; Gál, Péter

    2008-03-01

    C1r is a modular serine protease which is the autoactivating component of the C1 complex of the classical pathway of the complement system. We have determined the first crystal structure of the entire active catalytic region of human C1r. This fragment contains the C-terminal serine protease (SP) domain and the preceding two complement control protein (CCP) modules. The activated CCP1-CCP2-SP fragment makes up a dimer in a head-to-tail fashion similarly to the previously characterized zymogen. The present structure shows an increased number of stabilizing interactions. Moreover, in the crystal lattice there is an enzyme-product relationship between the C1r molecules of neighboring dimers. This enzyme-product complex exhibits the crucial S1-P1 salt bridge between Asp631 and Arg446 residues, and intermolecular interaction between the CCP2 module and the SP domain. Based on these novel structural information we propose a new split-and-reassembly model for the autoactivation of the C1r. This model is consistent with experimental results that have not been explained adequately by previous models. It allows autoactivation of C1r without large-scale, directed movement of C1q arms. The model is concordant with the stability of the C1 complex during activation of the next complement components. PMID:17996945

  4. Proteasome inhibitors.

    PubMed

    Teicher, Beverly A; Tomaszewski, Joseph E

    2015-07-01

    Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment, moved rapidly through development from bench in 1994 to first approval in 2003. Bortezomib is a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. All of the agents are potent cytotoxics. The disease focus for all the proteasome inhibitors is multiple myeloma. This focus arose from clinical observations made in bortezomib early clinical trials. Later preclinical studies confirmed that multiple myeloma cells were indeed more sensitive to proteasome inhibitors than other tumor cell types. The discovery and development of the proteasome inhibitor class of anticancer agents has progressed through a classic route of serendipity and scientific investigation. These agents are continuing to have a major impact in their treatment of hematologic malignancies and are beginning to be explored as potential treatment agent for non-cancer indications. PMID:25935605

  5. 16 CFR 801.2 - Acquiring and acquired persons.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... acquired person is the pre-acquisition ultimate parent entity of the entity. (ii) The value of an... directors of B. A is deemed to be acquiring all of the assets of B as a result. (g) Transfers of patent... transfer of patent rights covered by this paragraph constitutes an asset acquisition; and (3) Patent...

  6. Cellular response to antitumor cis-Dichlorido platinum(II) complexes of CDK inhibitor Bohemine and its analogues.

    PubMed

    Liskova, Barbora; Zerzankova, Lenka; Novakova, Olga; Kostrhunova, Hana; Travnicek, Zdenek; Brabec, Viktor

    2012-02-20

    The cellular and molecular pharmacology of the new class of anticancer drugs, in which the CDK inhibitor bohemine and its analogues are coordinated to Pt(II) to form cisplatin derivatives, was investigated. The results revealed the unique anticancer profile of a cisplatin-derived platinum(II) dichlorido complex involving N(7)-coordinated bohemine (C1). Although the IC(50) values were ∼6-fold higher for C1 than for cisplatin in cisplatin-sensitive tumor cells, the tumor cells in which C1 was also active are those which acquired resistance to cisplatin. In addition, among the novel conjugates of bohemine and its analogues with cisplatin, marked selectivity of C1 for tumor cells relative to the nontumorigenic, normal cells was observed. However, coordination of bohemine to platinum in C1 considerably reduced one of the dual functionalities anticipated to be effective after C1 reaches the nucleus. Further studies performed in the cells with wt p53 status show differences between cisplatin and C1 at the level of cell cycle regulation. Impedance-based real-time monitoring of the effects of C1 and cisplatin on cell growth supported the thesis that critical differences exist in the rate and mechanisms of cell kill caused by the two agents and that C1 was a more potent inducer of apoptosis and/or necrosis than cisplatin. The results also showed that the distinct differences in cell killing observed for C1 and cisplatin might be associated with processes at the DNA level. The DNA binding experiments carried out in a cell-free medium demonstrated that modification reactions resulting in the irreversible coordination of C1 to DNA were slower than that of cisplatin. Transcription mapping experiments and determination of interstrand cross-linking efficiency of C1 suggested that several aspects of DNA binding mode of C1 and cisplatin were similar. It was concluded that C1 remains a promising prototype of compounds for the generation of novel drug candidates with cytotoxicity

  7. Transcriptional activator elements for curtovirus C1 expression reside in the 3' coding region of ORF C1.

    PubMed

    Hur, Jingyung; Buckley, Kenneth; Lee, Sukchan; Davis, Keith

    2007-02-28

    Beet curly top virus (BCTV) and Beet severe curly top virus (BSCTV), members of curtoviruses, encode seven open reading frames (ORFs) within a approximately 3 kb genome. One of these viral ORFs, C1, is known to play an important role in the early stage of viral infection in plants during initiation of viral DNA replication. We used promoter:: reporter (beta-glucuronidase) gene fusions in transgenic Ara-bidopsis to identify the putative promoter region of BCTV ORF C1. Unlike other geminiviruses, the intergenic region of BCTV was not sufficient to promote C1 expression in transgenic plants. When sequences extending into the coding region of C1 were tested, strong expression of the reporter protein was observed in vascular tissues of transgenic plants. This expression was not dependent on the presence of the intergenic regions or proximal 5' portions of the C1 coding region. Transgenic plants expressing a reporter gene under control of the putative complete C1 promoter were inoculated with virus to determine if any viral transcript affected C1 expression. Virus inoculated plants did not show any altered pattern or change in of reporter gene expression level. These results suggest that (1) important transcriptional activator elements for C1 expression reside in the 3' portion of C1 coding area itself, (2) C1 protein does not auto-regulate its own expression and (3) C1 expression of two curtoviruses is controlled differently compared to other geminiviruses. PMID:17464215

  8. Children Acquire Emotion Categories Gradually

    ERIC Educational Resources Information Center

    Widen, Sherri C.; Russell, James A.

    2008-01-01

    Some accounts imply that basic-level emotion categories are acquired early and quickly, whereas others imply that they are acquired later and more gradually. Our study examined this question for fear, happiness, sadness, and anger in the context of children's categorization of emotional facial expressions. Children (N=168, 2-5 years) first labeled…

  9. 21 CFR 866.5250 - Complement C2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... component of complement (a group of serum proteins which destroy infectious agents). Measurement of complement C1 inhibitor aids in the diagnosis of hereditary angioneurotic edema (increased blood...

  10. In vivo 13 carbon metabolic imaging at 3T with hyperpolarized 13C-1-pyruvate.

    PubMed

    Kohler, S J; Yen, Y; Wolber, J; Chen, A P; Albers, M J; Bok, R; Zhang, V; Tropp, J; Nelson, S; Vigneron, D B; Kurhanewicz, J; Hurd, R E

    2007-07-01

    We present for the first time dynamic spectra and spectroscopic images acquired in normal rats at 3T following the injection of (13)C-1-pyruvate that was hyperpolarized by the dynamic nuclear polarization (DNP) method. Spectroscopic sampling was optimized for signal-to-noise ratio (SNR) and for spectral resolution of (13)C-1-pyruvate and its metabolic products (13)C-1-alanine, (13)C-1-lactate, and (13)C-bicarbonate. Dynamic spectra in rats were collected with a temporal resolution of 3 s from a 90-mm axial slab using a dual (1)H-(13)C quadrature birdcage coil to observe the combined effects of metabolism, flow, and T(1) relaxation. In separate experiments, spectroscopic imaging data were obtained during a 17-s acquisition of a 20-mm axial slice centered on the rat kidney region to provide information on the spatial distribution of the metabolites. Conversion of pyruvate to lactate, alanine, and bicarbonate occurred within a minute of injection. Alanine was observed primarily in skeletal muscle and liver, while pyruvate, lactate, and bicarbonate concentrations were relatively high in the vasculature and kidneys. In contrast to earlier work at 1.5 T, bicarbonate was routinely observed in skeletal muscle as well as the kidney and vasculature. PMID:17659629

  11. 26 CFR 1.661(c)-1 - Limitation on deduction.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Limitation on deduction. 1.661(c)-1 Section 1... Corpus § 1.661(c)-1 Limitation on deduction. An estate or trust is not allowed a deduction under section..., a trust, which reports on the calendar year basis, has distributable net income of $20,000, which...

  12. 26 CFR 31.6413(c)-1 - Special refunds.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Special refunds. 31.6413(c)-1 Section 31.6413(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES... Administrative Provisions of Special Application to Employment Taxes (Selected Provisions of Subtitle F,...

  13. 26 CFR 1.652(c)-1 - Different taxable years.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Different taxable years. 1.652(c)-1 Section 1... (CONTINUED) INCOME TAXES Trusts Which Distribute Current Income Only § 1.652(c)-1 Different taxable years. If a beneficiary has a different taxable year (as defined in section 441 or 442) from the taxable...

  14. 26 CFR 1.662(c)-1 - Different taxable years.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Different taxable years. 1.662(c)-1 Section 1... Corpus § 1.662(c)-1 Different taxable years. If a beneficiary has a different taxable year (as defined in section 441 or 442) from the taxable year of an estate or trust, the amount he is required to include...

  15. Anti-C1q in systemic lupus erythematosus.

    PubMed

    Stojan, G; Petri, M

    2016-07-01

    C1q is the first component of the classical complement pathway. Both clinically validated in-house ELISA assays as well as commercial ELISA kits are used for detection of anti-C1q antibodies. Anti-C1q autoantibodies can be detected in a wide range of autoimmune diseases and are highly sensitive for hypocomplementemic uticarial vasculitis. In SLE, anti-C1q are strongly associated with proliferative lupus nephritis, and their absence carries a negative predictive value for development of lupus nephritis of close to 100%. Anti-C1q in combination with anti-dsDNA and low complement has the strongest serological association with renal involvement. The anti-C1q titers correlate with global disease activity scores in patients with renal involvement, and higher titers seem to precede renal flares. After the successful treatment of a renal flare, anti-C1q has the tendency to decrease or even become undetectable. The main obstacle to the inclusion of anti-C1q in the classification criteria and clinical management of SLE is the lack of standardized laboratory assays. PMID:27252264

  16. 17 CFR 240.14c-1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Definitions. 240.14c-1 Section 240.14c-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL... Exchange Act of 1934 Regulation 14c: Distribution of Information Pursuant to Section 14(c) §...

  17. 17 CFR 240.14c-1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Definitions. 240.14c-1 Section 240.14c-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL... Exchange Act of 1934 Regulation 14c: Distribution of Information Pursuant to Section 14(c) §...

  18. 17 CFR 240.14c-1 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Definitions. 240.14c-1 Section 240.14c-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL... Exchange Act of 1934 Regulation 14c: Distribution of Information Pursuant to Section 14(c) §...

  19. 17 CFR 240.14c-1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Definitions. 240.14c-1 Section 240.14c-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL... Exchange Act of 1934 Regulation 14c: Distribution of Information Pursuant to Section 14(c) §...

  20. 17 CFR 240.14c-1 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Definitions. 240.14c-1 Section 240.14c-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL... Exchange Act of 1934 Regulation 14c: Distribution of Information Pursuant to Section 14(c) §...

  1. 26 CFR 1.662(c)-1 - Different taxable years.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Different taxable years. 1.662(c)-1 Section 1... Corpus § 1.662(c)-1 Different taxable years. If a beneficiary has a different taxable year (as defined in section 441 or 442) from the taxable year of an estate or trust, the amount he is required to include...

  2. 26 CFR 1.662(c)-1 - Different taxable years.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Different taxable years. 1.662(c)-1 Section 1... Corpus § 1.662(c)-1 Different taxable years. If a beneficiary has a different taxable year (as defined in section 441 or 442) from the taxable year of an estate or trust, the amount he is required to include...

  3. Overcoming acquired resistance to kinase inhibition: the cases of EGFR, ALK and BRAF.

    PubMed

    Giroux, Simon

    2013-01-15

    In the past decade, several kinase inhibitors have been approved based on their clinical benefit for cancer patients. Unfortunately, in many cases, patients develop resistance to these agents via secondary mutations and alternative mechanisms. This review will focus on the cases of acquired resistance to EGFR and ALK inhibitors for non-small cell lung cancer patients and BRAF inhibitors for melanoma patients. I will overview the main causes of acquired resistance, and explore the chemical scaffolds as well as combination of drugs, used to tackle these major causes of resistance. PMID:23245516

  4. Acquired antiprothrombin antibodies: an unusual cause of bleeding.

    PubMed

    Carvalho, Cristiana; Viveiro, Carolina; Maia, Paulo; Rezende, Teresa

    2013-01-01

    Acquired inhibitors of coagulation causing bleeding manifestations are rare in children. They emerge, normally in the context of autoimmune diseases or drug ingestion, but transient and self-limiting cases can occur after viral infection. We describe, an otherwise healthy, 7-year-old girl who had gingival bleeding after a tooth extraction. The prothrombin time (PT) and the activated partial thromboplastin time (APTT) were both prolonged with evidence of an immediate acting inhibitor (lupic anticoagulant). Further coagulation studies demonstrated prothrombin (FII) deficiency and prothrombin directed (FII) antibodies. The serological tests to detect an underlying autoimmune disease were all negative. The coagulation studies normalised alongside the disappearance of the antibody. This article presents lupus anticoagulant hypoprothrombinaemia syndrome (LAHS) as a rare case of acquired bleeding diathesis in childhood. PMID:23299692

  5. CFTR Inhibitors

    PubMed Central

    Verkman, Alan S.; Synder, David; Tradtrantip, Lukmanee; Thiagarajah, Jay R.; Anderson, Marc O.

    2014-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cAMP-regulated Cl− channel whose major function is to facilitate epithelial fluid secretion. Loss-of-function mutations in CFTR cause the genetic disease cystic fibrosis. CFTR is required for transepithelial fluid transport in certain secretory diarrheas, such as cholera, and for cyst expansion in autosomal dominant polycystic kidney disease. High-throughput screening has yielded CFTR inhibitors of the thiazolidinone, glycine hydrazide and quinoxalinedione chemical classes. The glycine hydrazides target the extracellular CFTR pore, whereas the thiazolidinones and quinoxalinediones act at the cytoplasmic surface. These inhibitors have been widely used in cystic fibrosis research to study CFTR function at the cell and organ levels. The most potent CFTR inhibitor has IC50 of approximately 4 nM. Studies in animal models support the development of CFTR inhibitors for antisecretory therapy of enterotoxin-mediated diarrheas and polycystic kidney disease. PMID:23331030

  6. SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis.

    PubMed

    Ferreira, Viviana P; Fazito Vale, Vladimir; Pangburn, Michael K; Abdeladhim, Maha; Mendes-Sousa, Antonio Ferreira; Coutinho-Abreu, Iliano V; Rasouli, Manoochehr; Brandt, Elizabeth A; Meneses, Claudio; Lima, Kolyvan Ferreira; Nascimento Araújo, Ricardo; Pereira, Marcos Horácio; Kotsyfakis, Michalis; Oliveira, Fabiano; Kamhawi, Shaden; Ribeiro, Jose M C; Gontijo, Nelder F; Collin, Nicolas; Valenzuela, Jesus G

    2016-01-01

    Blood-feeding insects inject potent salivary components including complement inhibitors into their host's skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases. PMID:26758086

  7. SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis

    PubMed Central

    Ferreira, Viviana P.; Fazito Vale, Vladimir; Pangburn, Michael K.; Abdeladhim, Maha; Ferreira Mendes-Sousa, Antonio; Coutinho-Abreu, Iliano V.; Rasouli, Manoochehr; Brandt, Elizabeth A.; Meneses, Claudio; Lima, Kolyvan Ferreira; Nascimento Araújo, Ricardo; Horácio Pereira, Marcos; Kotsyfakis, Michalis; Oliveira, Fabiano; Kamhawi, Shaden; Ribeiro, Jose M. C.; Gontijo, Nelder F.; Collin, Nicolas; Valenzuela, Jesus G.

    2016-01-01

    Blood-feeding insects inject potent salivary components including complement inhibitors into their host’s skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases. PMID:26758086

  8. Vein formation in the C1 carbonaceous chondrites

    NASA Technical Reports Server (NTRS)

    Richardson, S. M.

    1978-01-01

    Veins in the C1 chondrites Orgueil, Alais, and Ivuna have been deposited during an extended period of impact brecciation and leaching. At least three generations of mineralization, dominated successively by carbonates, calcium sulfate, and magnesium sulfate, can be recognized. Vein minerals are derived locally by closed-system reactions between matrix phyllosilicates and an aqueous fluid, with the result that few, if any, primitive mineral phases still exist in the C1s.

  9. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...)-7, inclusive, the term “trade or business”, for the purpose of the tax on self-employment income... 26 Internal Revenue 12 2010-04-01 2010-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for...

  10. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 12 2013-04-01 2013-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or...

  11. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 12 2014-04-01 2014-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or...

  12. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 12 2011-04-01 2011-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or...

  13. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 12 2012-04-01 2012-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or...

  14. Acquired Equivalence Changes Stimulus Representations

    ERIC Educational Resources Information Center

    Meeter, M.; Shohamy, D.; Myers, C. E.

    2009-01-01

    Acquired equivalence is a paradigm in which generalization is increased between two superficially dissimilar stimuli (or antecedents) that have previously been associated with similar outcomes (or consequents). Several possible mechanisms have been proposed, including changes in stimulus representations, either in the form of added associations or…

  15. Mapping Surface Accessibility of the C1r/C1s Tetramer by Chemical Modification and Mass Spectrometry Provides New Insights into Assembly of the Human C1 Complex*

    PubMed Central

    Brier, Sébastien; Pflieger, Delphine; Le Mignon, Maxime; Bally, Isabelle; Gaboriaud, Christine; Arlaud, Gérard J.; Daniel, Régis

    2010-01-01

    C1, the complex that triggers the classic pathway of complement, is a 790-kDa assembly resulting from association of a recognition protein C1q with a Ca2+-dependent tetramer comprising two copies of the proteases C1r and C1s. Early structural investigations have shown that the extended C1s-C1r-C1r-C1s tetramer folds into a compact conformation in C1. Recent site-directed mutagenesis studies have identified the C1q-binding sites in C1r and C1s and led to a three-dimensional model of the C1 complex (Bally, I., Rossi, V., Lunardi, T., Thielens, N. M., Gaboriaud, C., and Arlaud, G. J. (2009) J. Biol. Chem. 284, 19340–19348). In this study, we have used a mass spectrometry-based strategy involving a label-free semi-quantitative analysis of protein samples to gain new structural insights into C1 assembly. Using a stable chemical modification, we have compared the accessibility of the lysine residues in the isolated tetramer and in C1. The labeling data account for 51 of the 73 lysine residues of C1r and C1s. They strongly support the hypothesis that both C1s CUB1-EGF-CUB2 interaction domains, which are distant in the free tetramer, associate with each other in the C1 complex. This analysis also provides the first experimental evidence that, in the proenzyme form of C1, the C1s serine protease domain is partly positioned inside the C1q cone and yields precise information about its orientation in the complex. These results provide further structural insights into the architecture of the C1 complex, allowing significant improvement of our current C1 model. PMID:20592021

  16. The Crystal Structure Analysis of Group B Streptococcus Sortase C1: A Model for the ;Lid; Movement upon Substrate Binding

    SciTech Connect

    Khare, Baldeep; Fu, Zheng-Qing; Huang, I-Hsiu; Ton-That, Hung; Narayana, Sthanam V.L.

    2012-02-07

    A unique feature of the class-C-type sortases, enzymes essential for Gram-positive pilus biogenesis, is the presence of a flexible 'lid' anchored in the active site. However, the mechanistic details of the 'lid' displacement, suggested to be a critical prelude for enzyme catalysis, are not yet known. This is partly due to the absence of enzyme-substrate and enzyme-inhibitor complex crystal structures. We have recently described the crystal structures of the Streptococcus agalactiae SAG2603 V/R sortase SrtC1 in two space groups (type II and type III) and that of its 'lid' mutant and proposed a role of the 'lid' as a protector of the active-site hydrophobic environment. Here, we report the crystal structures of SAG2603 V/R sortase C1 in a different space group (type I) and that of its complex with a small-molecule cysteine protease inhibitor. We observe that the catalytic Cys residue is covalently linked to the small-molecule inhibitor without lid displacement. However, the type I structure provides a view of the sortase SrtC1 lid displacement while having structural elements similar to a substrate sorting motif suitably positioned in the active site. We propose that these major conformational changes seen in the presence of a substrate mimic in the active site may represent universal features of class C sortase substrate recognition and enzyme activation.

  17. In silico structural characteristics and α-amylase inhibitory properties of Ric c 1 and Ric c 3, allergenic 2S albumins from Ricinus communis seeds.

    PubMed

    Do Nascimento, Viviane Veiga; Castro, Helena Carla; Abreu, Paula Alvarez; Oliveira, Antônia Elenir Amâncio; Fernandez, Jorge Hernandez; Araújo, Jucélia Da Silva; Machado, Olga Lima Tavares

    2011-05-11

    The major Ricinus communis allergens are the 2S albumins, Ric c 1 and Ric c 3. These proteins contain a trypsin/α-amylase inhibitor family domain, suggesting that they have a role in insect resistance. In this study, we verified that Ric c 1 and Ric c 3 inhibited the α-amylase activity of Callosobruchus maculatus, Zabrotes subfasciatus, and Tenebrio molitor (TMA) larvae as well as mammalian α-amylase. The toxicity of 2S albumin was determined through its incorporation in C. maculatus larvae as part of an artificial diet. Bioassays revealed that 2S albumin reduced larval growth by 20%. We also analyzed the tridimensional structures of Ric c 1 and Ric c 3 by (a) constructing a comparative model of Ric c 1 based on Ric c 3 NMR structure and (b) constructing the theoretical structure of the Ric c 1-TMA and Ric c 3-TMA complexes. Our biological and theoretical results revealed that Ric c 1 and Ric c 3 are a new class of α-amylase inhibitors. They could potentially be used to help design inhibitors that would be useful in diverse fields, ranging from diabetes treatment to crop protection. PMID:21425874

  18. Emerging and Novel Functions of Complement Protein C1q

    PubMed Central

    Kouser, Lubna; Madhukaran, Shanmuga Priyaa; Shastri, Abhishek; Saraon, Anuvinder; Ferluga, Janez; Al-Mozaini, Maha; Kishore, Uday

    2015-01-01

    Complement protein C1q, the recognition molecule of the classical pathway, performs a diverse range of complement and non-complement functions. It can bind various ligands derived from self, non-self, and altered self and modulate the functions of immune and non-immune cells including dendritic cells and microglia. C1q involvement in the clearance of apoptotic cells and subsequent B cell tolerance is more established now. Recent evidence appears to suggest that C1q plays an important role in pregnancy where its deficiency and dysregulation can have adverse effects, leading to preeclampsia, missed abortion, miscarriage or spontaneous loss, and various infections. C1q is also produced locally in the central nervous system, and has a protective role against pathogens and possible inflammatory functions while interacting with aggregated proteins leading to neurodegenerative diseases. C1q role in synaptic pruning, and thus CNS development, its anti-cancer effects as an immune surveillance molecule, and possibly in aging are currently areas of extensive research. PMID:26175731

  19. Acquired Hemophilia A: A Frequently Overlooked Autoimmune Hemorrhagic Disorder

    PubMed Central

    Takeda, Tomohiro

    2014-01-01

    Acquired hemophilia A (AHA) is a rare hemorrhagic disease in which autoantibodies against coagulation factor VIII- (FVIII-) neutralizing antibodies (inhibitors) impair the intrinsic coagulation system. As the inhibitors developed in AHA are autoantibodies, the disease may have an autoimmune cause and is often associated with autoimmune disease. Although acute hemorrhage associated with AHA may be fatal and is costly to treat, AHA is often unrecognized or misdiagnosed. AHA should thus be considered in the differential diagnosis particularly in postpartum women and the elderly with bleeding tendency or prolonged activated partial thromboplastin time. Cross-mixing tests and measurement of FVIII-binding antibodies are useful to confirm AHA diagnosis. For treatment of acute hemorrhage, hemostatic therapy with bypassing agents should be provided. Unlike in congenital hemophilia A with inhibitors, in which immune tolerance induction therapy using repetitive infusions of high-dose FVIII concentrates is effective for inhibitor eradication, immune tolerance induction therapy has shown poor efficacy in treating AHA. Immunosuppressive treatment should thus be initiated to eradicate inhibitors as soon as the diagnosis of AHA is confirmed. PMID:24741588

  20. Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex.

    PubMed

    Garcia, Brandon L; Zhi, Hui; Wager, Beau; Höök, Magnus; Skare, Jon T

    2016-01-01

    Pathogens that traffic in blood, lymphatics, or interstitial fluids must adopt strategies to evade innate immune defenses, notably the complement system. Through recruitment of host regulators of complement to their surface, many pathogens are able to escape complement-mediated attack. The Lyme disease spirochete, Borrelia burgdorferi, produces a number of surface proteins that bind to factor H related molecules, which function as the dominant negative regulator of the alternative pathway of complement. Relatively less is known about how B. burgdorferi evades the classical pathway of complement despite the observation that some sensu lato strains are sensitive to classical pathway activation. Here we report that the borrelial lipoprotein BBK32 potently and specifically inhibits the classical pathway by binding with high affinity to the initiating C1 complex of complement. In addition, B. burgdorferi cells that produce BBK32 on their surface bind to both C1 and C1r and a serum sensitive derivative of B. burgdorferi is protected from killing via the classical pathway in a BBK32-dependent manner. Subsequent biochemical and biophysical approaches localized the anti-complement activity of BBK32 to its globular C-terminal domain. Mechanistic studies reveal that BBK32 acts by entrapping C1 in its zymogen form by binding and inhibiting the C1 subcomponent, C1r, which serves as the initiating serine protease of the classical pathway. To our knowledge this is the first report of a spirochetal protein acting as a direct inhibitor of the classical pathway and is the only example of a biomolecule capable of specifically and noncovalently inhibiting C1/C1r. By identifying a unique mode of complement evasion this study greatly enhances our understanding of how pathogens subvert and potentially manipulate host innate immune systems. PMID:26808924

  1. Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex

    PubMed Central

    Wager, Beau; Höök, Magnus; Skare, Jon T.

    2016-01-01

    Pathogens that traffic in blood, lymphatics, or interstitial fluids must adopt strategies to evade innate immune defenses, notably the complement system. Through recruitment of host regulators of complement to their surface, many pathogens are able to escape complement-mediated attack. The Lyme disease spirochete, Borrelia burgdorferi, produces a number of surface proteins that bind to factor H related molecules, which function as the dominant negative regulator of the alternative pathway of complement. Relatively less is known about how B. burgdorferi evades the classical pathway of complement despite the observation that some sensu lato strains are sensitive to classical pathway activation. Here we report that the borrelial lipoprotein BBK32 potently and specifically inhibits the classical pathway by binding with high affinity to the initiating C1 complex of complement. In addition, B. burgdorferi cells that produce BBK32 on their surface bind to both C1 and C1r and a serum sensitive derivative of B. burgdorferi is protected from killing via the classical pathway in a BBK32-dependent manner. Subsequent biochemical and biophysical approaches localized the anti-complement activity of BBK32 to its globular C-terminal domain. Mechanistic studies reveal that BBK32 acts by entrapping C1 in its zymogen form by binding and inhibiting the C1 subcomponent, C1r, which serves as the initiating serine protease of the classical pathway. To our knowledge this is the first report of a spirochetal protein acting as a direct inhibitor of the classical pathway and is the only example of a biomolecule capable of specifically and noncovalently inhibiting C1/C1r. By identifying a unique mode of complement evasion this study greatly enhances our understanding of how pathogens subvert and potentially manipulate host innate immune systems. PMID:26808924

  2. Kinetic modeling of hyperpolarized 13C 1-pyruvate metabolism in normal rats and TRAMP mice

    NASA Astrophysics Data System (ADS)

    Zierhut, Matthew L.; Yen, Yi-Fen; Chen, Albert P.; Bok, Robert; Albers, Mark J.; Zhang, Vickie; Tropp, Jim; Park, Ilwoo; Vigneron, Daniel B.; Kurhanewicz, John; Hurd, Ralph E.; Nelson, Sarah J.

    2010-01-01

    PurposeTo investigate metabolic exchange between 13C 1-pyruvate, 13C 1-lactate, and 13C 1-alanine in pre-clinical model systems using kinetic modeling of dynamic hyperpolarized 13C spectroscopic data and to examine the relationship between fitted parameters and dose-response. Materials and methodsDynamic 13C spectroscopy data were acquired in normal rats, wild type mice, and mice with transgenic prostate tumors (TRAMP) either within a single slice or using a one-dimensional echo-planar spectroscopic imaging (1D-EPSI) encoding technique. Rate constants were estimated by fitting a set of exponential equations to the dynamic data. Variations in fitted parameters were used to determine model robustness in 15 mm slices centered on normal rat kidneys. Parameter values were used to investigate differences in metabolism between and within TRAMP and wild type mice. ResultsThe kinetic model was shown here to be robust when fitting data from a rat given similar doses. In normal rats, Michaelis-Menten kinetics were able to describe the dose-response of the fitted exchange rate constants with a 13.65% and 16.75% scaled fitting error (SFE) for kpyr→lac and kpyr→ala, respectively. In TRAMP mice, kpyr→lac increased an average of 94% after up to 23 days of disease progression, whether the mice were untreated or treated with casodex. Parameters estimated from dynamic 13C 1D-EPSI data were able to differentiate anatomical structures within both wild type and TRAMP mice. ConclusionsThe metabolic parameters estimated using this approach may be useful for in vivo monitoring of tumor progression and treatment efficacy, as well as to distinguish between various tissues based on metabolic activity.

  3. Acquired causes of intestinal malabsorption.

    PubMed

    van der Heide, F

    2016-04-01

    This review focuses on the acquired causes, diagnosis, and treatment of intestinal malabsorption. Intestinal absorption is a complex process that depends on many variables, including the digestion of nutrients within the intestinal lumen, the absorptive surface of the small intestine, the membrane transport systems, and the epithelial absorptive enzymes. Acquired causes of malabsorption are classified by focussing on the three phases of digestion and absorption: 1) luminal/digestive phase, 2) mucosal/absorptive phase, and 3) transport phase. Most acquired diseases affect the luminal/digestive phase. These include short bowel syndrome, extensive small bowel inflammation, motility disorders, and deficiencies of digestive enzymes or bile salts. Diagnosis depends on symptoms, physical examination, and blood and stool tests. There is no gold standard for the diagnosis of malabsorption. Further testing should be based on the specific clinical context and the suspected underlying disease. Therapy is directed at nutritional support by enteral or parenteral feeding and screening for and supplementation of deficiencies in vitamins and minerals. Early enteral feeding is important for intestinal adaptation in short bowel syndrome. Medicinal treatment options for diarrhoea in malabsorption include loperamide, codeine, cholestyramine, or antibiotics. PMID:27086886

  4. Biomechanical characteristics of C1-2 cable fixations.

    PubMed

    Dickman, C A; Crawford, N R; Paramore, C G

    1996-08-01

    The biomechanical characteristics of four different methods of C1-2 cable fixation were studied to assess the effectiveness of each technique in restoring atlantoaxial stability. Biomechanical testing was performed on the upper cervical spines of four human cadaveric specimens. Physiological range loading was applied to the atlantoaxial specimens and three-dimensional motion was analyzed with stereophotogrammetry. The load-deformation relationships and kinematics were measured, including the stiffness, the angular ranges of motion, the linear ranges of motion, and the axes of rotation. Specimens were nondestructively tested in the intact state, after surgical destabilization, and after each of four different methods of cable fixation. Cable fixation techniques included the interspinous technique, the Brooks technique, and two variants of the Gallie technique. All specimens were tested immediately after fixation and again after the specimen was fatigued with 6000 cycles of physiological range torsional loading. All four cable fixation methods were moderately flexible immediately; the different cable fixations allowed between 5 degrees and 40 degrees of rotational motion and between 0.6 and 7 mm of translational motion to occur at C1-2. The Brooks and interspinous methods controlled C1-2 motion significantly better than both of the Gallie techniques. The motion allowed by one of the Gallie techniques did not differ significantly from the motion of the unfixed destabilized specimens. All cable fixation techniques loosened after cyclic loading and demonstrated significant increases in C1-2 rotational and translational motions. The bone grafts shifted during cyclic loading, which reduced the effectiveness of the fixation. The locations of the axes of rotation, which were unconstrained and mobile in the destabilized specimens, became altered with cable fixation. The C1-2 cables constrained motion by shifting the axes of rotation so that C-1 rotated around the fixed cable

  5. Acquired Hemophilia A Successfully Treated with Rituximab

    PubMed Central

    D’Arena, Giovanni; Grandone, Elvira; Di Minno, Matteo Nicola Dario; Musto, Pellegrino; Di Minno, Giovanni

    2015-01-01

    Acquired hemophilia A (AHA) is a rare bleeding disorder due to the development of specific autoantibodies against factor VIII. The anti-CD20 monoclonal antibody Rituximab has been proven to be effective in obtaining a long-term suppression of inhibitors of AHA, besides other immunosuppressive standard treatments. Here we describe a case of idiopathic AHA in a 60-year old man successfully treated with rituximab. He showed a complete clinical response with a normalization of clotting parameters after 5 weekly courses of rituximab given at a dose of 375 mg/sqm., but after stopping rituximab, an initial worsening of coagulation parameters induced the addition of 3 further courses. At present, the patient is in complete clinical and hematological remission after 200 days. This case confirms that Rituximab may be a safe and useful tool to treat AHA and, a prolonged administration can overcome the initial resistance. However, the precise position of this drug in the therapeutic strategy (first or second-line, alone or in combination with other drugs) remains to be established and warrants further investigation. PMID:25745551

  6. 75 FR 57846 - Airworthiness Directives; Robert E. Rust, Jr. Model DeHavilland DH.C1 Chipmunk 21, DH.C1 Chipmunk...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-23

    ....gov . SUPPLEMENTARY INFORMATION: Airworthiness Directive 2010-18-12, amendment 39-16426 (75 FR 53861.... Model DeHavilland DH.C1 Chipmunk 21, DH.C1 Chipmunk 22, and DH.C1 Chipmunk 22A Airplanes AGENCY: Federal...Havilland DH.C1 Chipmunk 21, DH.C1 Chipmunk 22, and DH.C1 Chipmunk 22A airplanes. As published, the...

  7. [Proteasome inhibitor].

    PubMed

    Yagi, Hideo

    2014-06-01

    The ubiquitin-proteasome system plays an essential role in degradation of eukaryotic intracellular protein, including cell cycle regulation, cell growth and proliferation, and survival. Cancer cells generally have higher level of proteasome activity compared with normal cells, suggesting proteasome inhibition could be therapeutic target in oncology. Bortezomib, the first proteasome inhibitor introduced into the clinic, is approved for the treatment of patients with multiple myeloma (MM). Although it was approved as single agent in the relapsed setting, bortezomib is now predominantly used in combination with conventional and novel targeted agents because bortezomib has demonstrated additive and synergistic activity in preclinical studies. Recently, several second-generation proteasome inhibitors, such as carfilzomib and MLN9708, have been developed and entered into clinical trials. These agents were investigated in frontline MM in combination with lenalidomide and low-dose dexamethasone. These studies demonstrated positive efficacy and safety, and it is expected that they will be approved in near future. PMID:25016815

  8. 26 CFR 1.662(c)-1 - Different taxable years.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Different taxable years. 1.662(c)-1 Section 1...)-1 Different taxable years. If a beneficiary has a different taxable year (as defined in section 441 or 442) from the taxable year of an estate or trust, the amount he is required to include in...

  9. 26 CFR 1.652(c)-1 - Different taxable years.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Different taxable years. 1.652(c)-1 Section 1... taxable years. If a beneficiary has a different taxable year (as defined in section 441 or 442) from the taxable year of the trust, the amount he is required to include in gross income in accordance with...

  10. C1q Nephropathy: The Unique Underrecognized Pathological Entity.

    PubMed

    Devasahayam, Joe; Erode-Singaravelu, Gowrishankar; Bhat, Zeenat; Oliver, Tony; Chandran, Arul; Zeng, Xu; Dakshinesh, Paramesh; Pillai, Unni

    2015-01-01

    C1q nephropathy is a rare glomerular disease with characteristic mesangial C1q deposition noted on immunofluorescence microscopy. It is histologically defined and poorly understood. Light microscopic features are heterogeneous and comprise minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and proliferative glomerulonephritis. Clinical presentation is also diverse, and ranges from asymptomatic hematuria or proteinuria to frank nephritic or nephrotic syndrome in both children and adults. Hypertension and renal insufficiency at the time of diagnosis are common findings. Optimal treatment is not clear and is usually guided by the underlying light microscopic lesion. Corticosteroids are the mainstay of treatment, with immunosuppressive agents reserved for steroid resistant cases. The presence of nephrotic syndrome and FSGS appear to predict adverse outcomes as opposed to favorable outcomes in those with MCD. Further research is needed to establish C1q nephropathy as a universally recognized distinct clinical entity. In this paper, we discuss the current understanding of pathogenesis, histopathology, clinical features, therapeutic options, and outcomes of C1q nephropathy. PMID:26640759

  11. 26 CFR 1.514(c)-1 - Acquisition indebtedness.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of Certain Exempt Organizations § 1.514(c)-1... where State law provides that a tax lien attaches to property prior to the time when such lien becomes... and payable and the organization has had an opportunity to pay such lien in accordance with State...

  12. 26 CFR 53.4941(c)-1 - Special rules.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... of private foundation X, lend one of the foundation's paintings to G, a disqualified person, for... EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(c)-1 Special...) (relating to tax on foundation managers). An initial tax is imposed on both A and B with respect to the...

  13. 26 CFR 53.4941(c)-1 - Special rules.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... of private foundation X, lend one of the foundation's paintings to G, a disqualified person, for... EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(c)-1 Special...) (relating to tax on foundation managers). An initial tax is imposed on both A and B with respect to the...

  14. 26 CFR 53.4941(c)-1 - Special rules.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... of private foundation X, lend one of the foundation's paintings to G, a disqualified person, for... EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(c)-1 Special...) (relating to tax on foundation managers). An initial tax is imposed on both A and B with respect to the...

  15. 26 CFR 53.4941(c)-1 - Special rules.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... of private foundation X, lend one of the foundation's paintings to G, a disqualified person, for... EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(c)-1 Special...) (relating to tax on foundation managers). An initial tax is imposed on both A and B with respect to the...

  16. 26 CFR 53.4941(c)-1 - Special rules.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... of private foundation X, lend one of the foundation's paintings to G, a disqualified person, for... EXCISE TAXES (CONTINUED) FOUNDATION AND SIMILAR EXCISE TAXES Taxes on Self-Dealing § 53.4941(c)-1 Special...) (relating to tax on foundation managers). An initial tax is imposed on both A and B with respect to the...

  17. 26 CFR 1.652(c)-1 - Different taxable years.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Different taxable years. 1.652(c)-1 Section 1... taxable years. If a beneficiary has a different taxable year (as defined in section 441 or 442) from the taxable year of the trust, the amount he is required to include in gross income in accordance with...

  18. 26 CFR 1.652(c)-1 - Different taxable years.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Different taxable years. 1.652(c)-1 Section 1... taxable years. If a beneficiary has a different taxable year (as defined in section 441 or 442) from the taxable year of the trust, the amount he is required to include in gross income in accordance with...

  19. Isolation and mode of action of bacteriocin BacC1 produced by nonpathogenic Enterococcus faecium C1.

    PubMed

    Goh, H F; Philip, K

    2015-08-01

    Lactic acid bacteria are present in fermented food products and help to improve shelf life and enhance the flavor of the food. They also produce metabolites such as bacteriocins to prevent the growth of undesirable or pathogenic bacteria. In this study, Enterococcus faecium C1 isolated from fermented cow milk was able to produce bacteriocin BacC1 and inhibit the growth of selected food-spoilage bacteria. The bacteriocin was purified through 4 steps: ammonium sulfate precipitation, hydrophobic interaction column, a series of centrifugal steps, and finally reversed-phase HPLC. A membrane permeability test using SYTOX green dye (Invitrogen, Grand Island, NY) showed that the bacteriocin caused significant disruptions to the test bacterial membrane, as shown by transmission electron microscopy. The molecular weight of the BacC1 obtained from SDS-PAGE was around 10kDa, and N-terminal sequencing revealed a partial amino acid sequence of BacC1: GPXGPXGP. The bacterial strain was nonhemolytic and not antibiotic resistant. Therefore, it has high potential for application in the food industry as an antimicrobial agent to extend the shelf life of food products. PMID:26004828

  20. Perioperatively acquired disorders of coagulation

    PubMed Central

    Grottke, Oliver; Fries, Dietmar; Nascimento, Bartolomeu

    2015-01-01

    Purpose of review To provide an overview of acquired coagulopathies that can occur in various perioperative clinical settings. Also described are coagulation disturbances linked to antithrombotic medications and currently available strategies to reverse their antithrombotic effects in situations of severe hemorrhage. Recent findings Recent studies highlight the link between low fibrinogen and decreased fibrin polymerization in the development of acquired coagulopathy. Particularly, fibrin(ogen) deficits are observable after cardiopulmonary bypass in cardiac surgery, on arrival at the emergency room in trauma patients, and with ongoing bleeding after child birth. Regarding antithrombotic therapy, although new oral anticoagulants offer the possibility of efficacy and relative safety compared with vitamin K antagonists, reversal of their anticoagulant effect with nonspecific agents, including prothrombin complex concentrate, has provided conflicting results. Specific antidotes, currently being developed, are not yet licensed for clinical use, but initial results are promising. Summary Targeted hemostatic therapy aims to correct coagulopathies in specific clinical settings, and reduce the need for allogeneic transfusions, thus preventing massive transfusion and its deleterious outcomes. Although there are specific guidelines for reversing anticoagulation in patients treated with antiplatelet agents or warfarin, there is currently little evidence to advocate comprehensive recommendations to treat drug-induced coagulopathy associated with new oral anticoagulants. PMID:25734869

  1. Foodborne listeriosis acquired in hospitals.

    PubMed

    Silk, Benjamin J; McCoy, Morgan H; Iwamoto, Martha; Griffin, Patricia M

    2014-08-15

    Listeriosis is characterized by bacteremia or meningitis. We searched for listeriosis case series and outbreak investigations published in English by 2013, and assessed the strength of evidence for foodborne acquisition among patients who ate hospital food. We identified 30 reports from 13 countries. Among the case series, the median proportion of cases considered to be hospital-acquired was 25% (range, 9%-67%). The median number of outbreak-related illnesses considered to be hospital-acquired was 4.0 (range, 2-16). All patients were immunosuppressed in 18 of 24 (75%) reports with available data. Eight outbreak reports with strong evidence for foodborne acquisition in a hospital implicated sandwiches (3 reports), butter, precut celery, Camembert cheese, sausage, and tuna salad (1 report each). Foodborne acquisition of listeriosis among hospitalized patients is well documented internationally. The number of listeriosis cases could be reduced substantially by establishing hospital policies for safe food preparation for immunocompromised patients and by not serving them higher-risk foods. PMID:24846635

  2. Acquired hemophilia complicated by cardiorenal syndrome type 3

    PubMed Central

    Sharma, Rakesh; Dash, Sananta Kumar; Chawla, Rajesh; Kansal, Sudha; Agrawal, Devender Kumar; Dua, Harsh

    2013-01-01

    Development of autoantibodies against coagulation factor VIII (FVIII) leads to a rare condition defined as acquired hemophilia (AH). If not diagnosed and treated early, AH may be associated with high mortality and morbidity. A 65-year-old woman presented with history of macrohematuria, acute renal failure, cardiogenic shock, and acute respiratory failure. Blood investigation revealed azotemia, prolonged activated partial thromboplastin time (aPTT), coagulation FVIII level of <1%, and presence of FVIII inhibitor. Echocardiography showed global hypokinesia and ultrasonography and computed tomography (CT) revealed bilateral hydroureteronephrosis. The final diagnosis was acquired hemophilia A, complicated by acute obstructive renal failure and cardiorenal syndrome (CRS) type 3. Patient was managed with mechanical ventilation, heparin-free hemodialysis, negative fluid balance, recombinant activated factor VII, and prednisolone. Hematuria was relieved, renal function improved, and cardiac function showed improvement on repeat echocardiography. Patient was discharged on prednisolone with subsequent follow ups. PMID:24501492

  3. C1 Hermite shape preserving polynomial splines in R3

    NASA Astrophysics Data System (ADS)

    Gabrielides, Nikolaos C.

    2012-06-01

    The C 2 variable degree splines1-3 have been proven to be an efficient tool for solving the curve shape-preserving interpolation problem in two and three dimensions. Based on this representation, the current paper proposes a Hermite interpolation scheme, to construct C 1 shape-preserving splines of variable degree. After this, a slight modification of the method leads to a C 1 shape-preserving Hermite cubic spline. Both methods can easily be developed within a CAD system, since they compute directly (without iterations) the B-spline control polygon. They have been implemented and tested within the DNV Software CAD/CAE system GeniE. [Figure not available: see fulltext.

  4. Ceramide 1-phosphate enhances calcium entry through voltage-operated calcium channels by a protein kinase C-dependent mechanism in GH4C1 rat pituitary cells.

    PubMed Central

    Törnquist, Kid; Blom, Tomas; Shariatmadari, Ramin; Pasternack, Michael

    2004-01-01

    Sphingomyelin derivatives modulate a multitude of cellular processes, including the regulation of [Ca2+]i (the intracellular free calcium concentration). Previous studies have shown that these metabolites often inhibit calcium entry through VOCCs (voltage-operated calcium channels). In the present study, we show that, in pituitary GH4C1 cells, C1P (C2-ceramide 1-phosphate) enhances calcium entry in a dose-dependent manner. The phospholipase C inhibitor U73122 attenuated the response. C1P invoked a small, but significant, increase in the formation of inositol phosphates. Pre-treatment of the cells with pertussis toxin was without an effect on the C1P-evoked increase in [Ca2+]i. The effect of C1P was critically dependent on extracellular calcium, since no increase in [Ca2+]i was observed when cells in a calcium-free buffer were stimulated with C1P. Furthermore, if the cells were retreated with 300 nM of the VOCC inhibitor nimodipine, the effect of C1P was almost totally abolished. In addition, ceramide C8-1-phosphate evoked an increase in [Ca2+]i, but the onset of the response was slow compared with that of C1P. In cells treated with 1 mM thapsigargin for 15 min, C1P still evoked an increase in [Ca2+]i. In patch-clamp experiments in the whole-cell mode, C1P enhanced calcium entry through the VOCCs compared with vehicle-treated cells. Dialysis of the cells with C1P did not enhance the calcium current. On-cell patch-clamp experiments showed an enhanced probability of the VOCCs being open (P(open)) in the presence of C1P. Inhibition of PKC (protein kinase C) with GF109203X and down-regulation of PKC with PMA attenuated the C1P-evoked increase in [Ca2+]i. Furthermore, down-regulation of PKC abolished the effect of C1P on P(open). This is the first report showing that a sphingomyelin derivative enhances calcium entry through VOCCs. PMID:15018614

  5. The C1s core line in irradiated graphite

    SciTech Connect

    Speranza, Giorgio; Minati, Luca; Anderle, Mariano

    2007-08-15

    Recently, plasma deposited amorphous carbon films have been the subject of extensive experimental and theoretical investigations aimed at correlating their electronic, structural, and mechanical properties to growth parameters. To investigate these properties, different spectral parameters reflecting the electronic structure of carbon-based materials are proposed in literature. The effects of various electronic configurations on the carbon photoelectron spectra are analyzed here with particular attention to C1s core line with the aim to better interpret its structure. The latter is commonly fitted under the assumption that it can be described by using just two spectral components related to sp{sup 2} and sp{sup 3} hybrids. Their relative intensities are then used to estimate the sp{sup 2} and sp{sup 3} phases. We show that, in the presence of an amorphous network, the C1s line shape is the result of a more complex mixture of electronic states. Ar{sup +} irradiated graphite and successive oxidation was used to identify spectral features to better describe the C1s line shape.

  6. Acquired immunodeficiency syndrome: neuroradiologic findings.

    PubMed

    Kelly, W M; Brant-Zawadzki, M

    1983-11-01

    Central nervous system complications depicted by CT in ten patients with acquired immunodeficiency syndrome are described. Three patients had multifocal intra-axial enhancing lesions representing atypical brain abscesses (two with toxoplasmosis, one with candidiasis). A fourth patient with multifocal "ring" lesions whose biopsy was interpreted as suggestive of toxoplasmosis responded poorly to treatment. Following his death three months later of Pneumocystis carinii pneumonia, autopsy revealed primary intracerebral immunoblastic lymphoma. One patient had Kaposi sarcoma involving the right frontal lobe (seen as an enhancing mass on the CT scan). CT findings in the remaining five patients revealed mild to moderate enlargement of cerebrospinal fluid spaces (including ventricles and basal cisternae) as a result of cryptococcal meningitis in three patients and "aseptic" meningitis in two. The two patients in whom early biopsy confirmed toxoplasmosis responded well to anti-infective therapy, resulting in dramatic clinical recoveries. PMID:6622693

  7. Bejel: acquirable only in childhood?

    PubMed

    Rothschild, Bruce M; Rothschild, Christine; Naples, Virginia; Billard, Michel; Panero, Barbara

    2006-10-01

    Bejel clearly has a long history in the Middle East and the Sudan, but was it transmitted to Europe? As the major manifestation of bejel is presence of periosteal reaction in 20-40% of afflicted populations, absence of significant population frequency of periosteal reaction in Europe would exclude that diagnosis. Examination of skeletal populations from continental Europe revealed no significant periosteal reaction at the time of and immediately subsequent to the Crusades. Thus, there is no evidence for bejel in Europe, in spite of clear contact (the mechanism of bejel transmission in children) between warring groups, at least during the Crusades. This supports the hypothesis that bejel is a childhood-acquired disease and apparently cannot be contracted in adulthood. PMID:17049474

  8. Lymphoma in acquired generalized lipodystrophy.

    PubMed

    Brown, Rebecca J; Chan, Jean L; Jaffe, Elaine S; Cochran, Elaine; DePaoli, Alex M; Gautier, Jean-Francois; Goujard, Cecile; Vigouroux, Corinne; Gorden, Phillip

    2016-01-01

    Acquired generalized lipodystrophy (AGL) is a rare disease thought to result from autoimmune destruction of adipose tissue. Peripheral T-cell lymphoma (PTCL) has been reported in two AGL patients. We report five additional cases of lymphoma in AGL, and analyze the role of underlying autoimmunity and recombinant human leptin (metreleptin) replacement in lymphoma development. Three patients developed lymphoma during metreleptin treatment (two PTCL and one ALK-positive anaplastic large cell lymphoma), and two developed lymphomas (mycosis fungoides and Burkitt lymphoma) without metreleptin. AGL is associated with high risk for lymphoma, especially PTCL. Autoimmunity likely contributes to this risk. Lymphoma developed with or without metreleptin, suggesting metreleptin does not directly cause lymphoma development; a theoretical role of metreleptin in lymphoma progression remains possible. For most patients with AGL and severe metabolic complications, the proven benefits of metreleptin on metabolic disease will likely outweigh theoretical risks of metreleptin in lymphoma development or progression. PMID:25864863

  9. C1GALT1 overexpression promotes the invasive behavior of colon cancer cells through modifying O-glycosylation of FGFR2.

    PubMed

    Hung, Ji-Shiang; Huang, John; Lin, Yo-Chuen; Huang, Miao-Juei; Lee, Po-Huang; Lai, Hong-Shiee; Liang, Jin-Tung; Huang, Min-Chuan

    2014-04-30

    Core 1 β1,3-galactosyltransferase (C1GALT1) transfers galactose (Gal) to N-acetylgalactosamine (GalNAc) to form Galβ1,3GalNAc (T antigen). Aberrant O-glycans, such as T antigen, are commonly found in colorectal cancer. However, the role of C1GALT1 in colorectal cancer remains unclear. Here we showed that C1GALT1 was frequently overexpressed in colorectal tumors and is associated with poor survival. C1GALT1 overexpression promoted cell survival, migration, invasion, and sphere formation as well as tumor growth and metastasis of colon cancer cells. Conversely, knockdown of C1GALT1 with small interference (si) RNA was sufficient to suppress these malignant phenotypes in vitro and in vivo. Moreover, we are the first to show that fibroblast growth factor receptor (FGFR) 2 carried O-glycans in colon cancer cells. Mechanistic investigations showed that C1GALT1 modified the O-glycans on FGFR2 and enhanced bFGF-triggered activation of FGFR2 as well as increased bFGF-mediated malignant phenotypes. In addition, BGJ398, a selective inhibitor of FGFR, blocked the effects of C1GALT1. These findings suggest that C1GALT1 overexpression modifies O-glycans on FGFR2 and enhances its phosphorylation to promote the invasive behavior and cancer stem-like property in colon cancer cells, indicating a critical role of O-glycosylation in the pathogenesis of colorectal cancer. PMID:24758762

  10. Solid-phase C1q-directed bacterial capture followed by PCR for detection of Chlamydia trachomatis in clinical specimens.

    PubMed Central

    Herbrink, P; van den Munckhof, H A; Niesters, H G; Goessens, W H; Stolz, E; Quint, W G

    1995-01-01

    An antigen capture system based on the binding of bacteria to solid-phase immobilized complement C1q followed by PCR for detection of Chlamydia trachomatis in clinical samples was developed and clinically evaluated. Comparison of C1q-directed antigen capture PCR with cell culture and direct PCR on 71 consecutive clinical specimens revealed an identical sensitivity. In this group, all 11 cell culture-positive samples were positive by direct PCR and C1q-directed antigen capture PCR. In addition, two samples found negative by cell culture were found positive by both direct PCR and C1q-directed antigen capture PCR. To further assess the sensitivity of C1q-directed antigen capture PCR, 20 clinical samples with one to five inclusions in cell culture and 20 clinical samples with 6 to 20 inclusions in cell culture were tested. Results obtained showed sensitivities of 95 and 90% for clinical samples with 6 to 20 and 1 to 5 inclusions in cell culture, respectively. Using C1q-coated solid phases, C1q-binding Chlamydia particles can be concentrated from large volumes with concomitant removal of inhibitors of PCR, allowing the use of large volumes of clinical samples for clinical testing. Since C1q has been shown to bind to a range of gram-negative bacteria, the newly developed technique has utility for a broad range of bacteria. PMID:7714179

  11. C1GALT1 overexpression promotes the invasive behavior of colon cancer cells through modifying O-glycosylation of FGFR2

    PubMed Central

    Hung, Ji-Shiang; Huang, John; Lin, Yo-Chuen; Huang, Miao-Juei; Lee, Po-Huang; Lai, Hong-Shiee; Liang, Jin-Tung; Huang, Min-Chuan

    2014-01-01

    Core 1 β1,3-galactosyltransferase (C1GALT1) transfers galactose (Gal) to N-acetylgalactosamine (GalNAc) to form Galβ1,3GalNAc (T antigen). Aberrant O-glycans, such as T antigen, are commonly found in colorectal cancer. However, the role of C1GALT1 in colorectal cancer remains unclear. Here we showed that C1GALT1 was frequently overexpressed in colorectal tumors and is associated with poor survival. C1GALT1 overexpression promoted cell survival, migration, invasion, and sphere formation as well as tumor growth and metastasis of colon cancer cells. Conversely, knockdown of C1GALT1 with small interference (si) RNA was sufficient to suppress these malignant phenotypes in vitro and in vivo. Moreover, we are the first to show that fibroblast growth factor receptor (FGFR) 2 carried O-glycans in colon cancer cells. Mechanistic investigations showed that C1GALT1 modified the O-glycans on FGFR2 and enhanced bFGF-triggered activation of FGFR2 as well as increased bFGF-mediated malignant phenotypes. In addition, BGJ398, a selective inhibitor of FGFR, blocked the effects of C1GALT1. These findings suggest that C1GALT1 overexpression modifies O-glycans on FGFR2 and enhances its phosphorylation to promote the invasive behavior and cancer stem-like property in colon cancer cells, indicating a critical role of O-glycosylation in the pathogenesis of colorectal cancer. PMID:24758762

  12. A new water soluble MAPK activator exerts antitumor activity in melanoma cells resistant to the BRAF inhibitor vemurafenib.

    PubMed

    Graziani, Grazia; Artuso, Simona; De Luca, Anastasia; Muzi, Alessia; Rotili, Dante; Scimeca, Manuel; Atzori, Maria Grazia; Ceci, Claudia; Mai, Antonello; Leonetti, Carlo; Levati, Lauretta; Bonanno, Elena; Tentori, Lucio; Caccuri, Anna Maria

    2015-05-01

    Recovery of mitogen activated protein kinase (MAPK) or activation of alternative pathways, such as the PI3K/AKT/mTOR, are involved in acquired resistance to BRAF inhibitors which represent the first-line treatment of BRAF-mutated metastatic melanoma. We recently demonstrated that 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX) and its water soluble analog 2-(2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)ethoxy)ethoxy)ethanol (MC3181) trigger apoptosis in BRAF V600E mutated melanoma cells through activation of the MAPK c-Jun N-terminal kinase (JNK). Herein, we investigated whether NBDHEX and MC3181 might exert antitumor activity against BRAF V600E mutated human melanoma cells rendered resistant to the BRAF inhibitor vemurafenib. To this aim we generated a subline of A375 melanoma resistant in vitro and in vivo to vemurafenib (A375-VR8) and characterized by NRAS G13R mutation, high basal levels of CRAF protein and phospho-activation of AKT. In these cells ERK phosphorylation was not significantly down-modulated by vemurafenib concentrations capable of abrogating ERK phosphorylation in sensitive A375 cells. Both NBDHEX and MC3181 induced marked antiproliferative and apoptotic effects in A375-VR8 cells and, at equitoxic concentrations, caused a strong phosphorylation of JNK, p38, and of the downstream mediators of apoptosis ATF2 and p53. Drug treatment further increased ERK phosphorylation, which was required for the cellular response to the NBD derivatives, as apoptosis was antagonized by the ERK inhibitor FR180204. Finally, in vivo administration of MC3181 provoked JNK activation at the tumor site and markedly reduced A375-VR8 growth. These evidences strongly suggest that the activation of multiple pro-apoptotic MAPK pathways by MC3181 might represent a new strategy for the treatment of melanoma resistant to BRAF inhibitors. PMID:25795251

  13. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  14. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  15. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  16. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... REQUIREMENTS APPLICABLE TO CRANBERRIES NOT SUBJECT TO THE CRANBERRY MARKETING ORDER § 926.10 Acquire. Acquire means to obtain cranberries by any means whatsoever for the purpose of handling cranberries....

  17. Autophagy inhibitors.

    PubMed

    Pasquier, Benoit

    2016-03-01

    Autophagy is a lysosome-dependent mechanism of intracellular degradation. The cellular and molecular mechanisms underlying this process are highly complex and involve multiple proteins, including the kinases ULK1 and Vps34. The main function of autophagy is the maintenance of cell survival when modifications occur in the cellular environment. During the past decade, extensive studies have greatly improved our knowledge and autophagy has exploded as a research field. This process is now widely implicated in pathophysiological processes such as cancer, metabolic, and neurodegenerative disorders, making it an attractive target for drug discovery. In this review, we will summarize the different types of inhibitors that affect the autophagy machinery and provide some potential therapeutic perspectives. PMID:26658914

  18. Linearization of class C1 for contractions on Banach spaces

    NASA Astrophysics Data System (ADS)

    Rodrigues, Hildebrando M.; Solà-Morales, J.

    In this work we prove a C1-linearization result for contraction diffeomorphisms, near a fixed point, valid in infinite-dimensional Banach spaces. As an intermediate step, we prove a specific result of existence of invariant manifolds, which can be interesting by itself and that was needed on the proof of our main theorem. Our results essentially generalize some classical results by P. Hartman in finite dimensions, and a result of Mora-Sola-Morales in the infinite-dimensional case. It is shown that the result can be applied to some abstract systems of semilinear damped wave equations.

  19. Reduction of CO2 to C1 products and fuel

    USGS Publications Warehouse

    Mill, T.; Ross, D.

    2002-01-01

    Photochemical semiconductor processes readily reduced CO2 to a broad range of C1 products. However the intrinsic and solar efficiencies for the processes were low. Improved quantum efficiencies could be realized utilizing quantum-sized particles, but at the expense of using less of the visible solar spectrum. Conversely, semiconductors with small bandgaps used more of the visible solar spectrum at the expense of quantum efficiency. Thermal reduction of CO2 with Fe(II) was thermodynamically favored for forming many kinds of organic compounds and occurred readily with olivine and other Fe(II) minerals above 200??C to form higher alkanes and alkenes. No added hydrogen was required.

  20. C1-Cx revisited: intramolecular synergism in a cellulase.

    PubMed Central

    Din, N; Damude, H G; Gilkes, N R; Miller, R C; Warren, R A; Kilburn, D G

    1994-01-01

    Endoglucanase A (CenA) from the bacterium Cellulomonas fimi is composed of a catalytic domain and a nonhydrolytic cellulose-binding domain that can function independently. The individual domains interact synergistically in the disruption and hydrolysis of cellulose fibers. This intramolecular synergism is distinct from the well-known intermolecular synergism between individual cellulases. The catalytic domain corresponds to the hydrolytic Cx system and the cellulose-binding domain corresponds to the nonhydrolytic C1 system postulated by Reese et al. [Reese, E. T., Sui, R. G. H. & Levinson, H. S. (1950) J. Bacteriol. 59, 485-497] to be required for the hydrolysis of cellulose. PMID:7972069

  1. Acquired antithrombin III deficiency: laboratory diagnosis, incidence, clinical implications, and treatment with antithrombin III concentrate.

    PubMed

    Büller, H R; ten Cate, J W

    1989-09-11

    Antithrombin III (ATIII) is the predominant naturally occurring inhibitor of serine proteases generated during blood coagulation [Rosenberg RD: Annu Rev Med 1978; 29: 367-378]. Since 1965, several assays have been developed that allow rapid and precise determination of ATIII in plasma. As a consequence, the existence of acquired ATIII deficiency in many pathologic conditions has been described. Acquired ATIII deficiency is based on decreased synthesis, increased loss or increased consumption, or induced by drugs. An inherited ATIII deficiency is associated with a lifelong tendency to venous thromboembolism. In contrast, the clinical significance of acquired ATIII deficiency has been less well defined. A precise estimate of the risk of thromboembolism in the acquired ATIII deficiency state cannot easily be provided, owing to the lack of studies in consecutive patients. In 1978, a purified human ATIII concentrate became available for clinical investigation. Despite numerous small studies, the value of ATIII replacement therapy in patients with acquired deficiency remains to be demonstrated. PMID:2679070

  2. Acquired immune deficiency syndrome (AIDS).

    PubMed

    1987-02-01

    The International Planned Parenthood Medical Advisory Panel has developed recommendations to assist family planning associations in playing a more active role in the prevention and control of acquired immunodeficiency syndrome (AIDS). Of primary importance is an effective program of information and education aimed at communicating the following facts: AIDS is a fatal disease for which there is no cure; AIDS is spread by sexual intercourse, contaminated blood, and contaminated needles; an infected woman can transmit AIDS to her fetus during pregnancy; a monogamous sexual relationship is the surest way to avoid AIDS infection; condom use is good protection; an infected person can look and feel well, yet still be able to transmit the AIDS virus; and AIDS is not spread by ordinary contact with an infected person. Family planning associations should include information on AIDS in all existing IEC projects, as well as develop new materials. Among the target audiences for IEC activities are family planning workers, family planning clients, and the general public including youth, teachers, parents, employers, and national leaders. Special attention should be given to high-risk groups such as homosexual and bisexual men, hemophiliacs, male and female prostitutes, clients of sexually transmitted disease clinics, people with many sexual partners, illegal users of intravenous drugs, and the sexual partners of those in any of these groups. Wide promotion of condom use is a priority activity for family planning organizations. PMID:12340977

  3. Infections Acquired in the Garden.

    PubMed

    Cunha, Cheston B; Cunha, Burke A

    2015-10-01

    Gardening is a wonderful pastime, and the garden is a very peaceful place to enjoy one's vacation. However, the garden may be a treacherous place for very young or compromised hosts when one takes into account the infectious potential residing in the soil, as well as the insect vectors on plants and animals. Even normal hosts may acquire a variety of infections from the soil, animals, or animal-related insect bites. The location of the garden, its natural animal and insect inhabitants, and the characteristics of the soil play a part in determining its infectious potential. The most important factor making the garden an infectious and dangerous place is the number and interaction of animals, whether they are pets or wild, that temporarily use the garden for part of their daily activities. The clinician should always ask about garden exposure, which will help in eliminating the diagnostic possibilities for the patient. The diagnostic approach is to use epidemiological principles in concert with clinical clues, which together should suggest a reasonable list of diagnostic possibilities. Organ involvement and specific laboratory tests help further narrow the differential diagnosis and determine the specific tests necessary to make a definitive diagnosis. PMID:26542044

  4. Associative Learning Through Acquired Salience

    PubMed Central

    Treviño, Mario

    2016-01-01

    Most associative learning studies describe the salience of stimuli as a fixed learning-rate parameter. Presumptive saliency signals, however, have also been linked to motivational and attentional processes. An interesting possibility, therefore, is that discriminative stimuli could also acquire salience as they become powerful predictors of outcomes. To explore this idea, we first characterized and extracted the learning curves from mice trained with discriminative images offering varying degrees of structural similarity. Next, we fitted a linear model of associative learning coupled to a series of mathematical representations for stimulus salience. We found that the best prediction, from the set of tested models, was one in which the visual salience depended on stimulus similarity and a non-linear function of the associative strength. Therefore, these analytic results support the idea that the net salience of a stimulus depends both on the items' effective salience and the motivational state of the subject that learns about it. Moreover, this dual salience model can explain why learning about a stimulus not only depends on the effective salience during acquisition but also on the specific learning trajectory that was used to reach this state. Our mathematical description could be instrumental for understanding aberrant salience acquisition under stressful situations and in neuropsychiatric disorders like schizophrenia, obsessive-compulsive disorder, and addiction. PMID:26793078

  5. Associative Learning Through Acquired Salience.

    PubMed

    Treviño, Mario

    2015-01-01

    Most associative learning studies describe the salience of stimuli as a fixed learning-rate parameter. Presumptive saliency signals, however, have also been linked to motivational and attentional processes. An interesting possibility, therefore, is that discriminative stimuli could also acquire salience as they become powerful predictors of outcomes. To explore this idea, we first characterized and extracted the learning curves from mice trained with discriminative images offering varying degrees of structural similarity. Next, we fitted a linear model of associative learning coupled to a series of mathematical representations for stimulus salience. We found that the best prediction, from the set of tested models, was one in which the visual salience depended on stimulus similarity and a non-linear function of the associative strength. Therefore, these analytic results support the idea that the net salience of a stimulus depends both on the items' effective salience and the motivational state of the subject that learns about it. Moreover, this dual salience model can explain why learning about a stimulus not only depends on the effective salience during acquisition but also on the specific learning trajectory that was used to reach this state. Our mathematical description could be instrumental for understanding aberrant salience acquisition under stressful situations and in neuropsychiatric disorders like schizophrenia, obsessive-compulsive disorder, and addiction. PMID:26793078

  6. Life-threatening hemorrhage from acquired hemophilia A as a presenting manifestation of prostate cancer.

    PubMed

    Sheth, Chirag; Gill, Amandeep; Sekhon, Sumeet

    2016-01-01

    Acquired factor VIII deficiency (acquired hemophilia A) is a rare condition characterized by the acquisition of autoantibodies that affect the clotting activity of factor VIII (fVIII). The most common manifestation in affected patients is a hemorrhagic diathesis. This disorder is associated with autoimmune diseases, pregnancy, postpartum period, drugs, and malignancy. Management of this condition begins with attempts to arrest an acute bleed based on the site and severity of bleeding and inhibitor titer. The next priority is eradication of the fVIII antibodies using immunosuppressive therapies. We report the case of a 66-year-old male who presented with spontaneous right thigh hematoma with prolonged activated partial prothrombin time and normal prothrombin time. Mixing studies confirmed the presence of an inhibitor. Further investigation for the underlying etiology of acquired hemophilia A leads to diagnosis of prostate cancer. Treatment consisted of bypassing agents including activated factor VII and activated prothrombin plasma concentrate to arrest the bleeding. Steroids and cyclophosphamide were added to suppress the fVIII inhibitors. Concomitant treatment of locally advanced prostate cancer with chemotherapy confirmed the eradication of the inhibitors. To our knowledge, this is the first reported case of prostate cancer diagnosed and treated simultaneously with acquired hemophilia A resulting in favorable patient outcome. PMID:27609734

  7. Land validation for GCOM-C1/SGLI using UAV

    NASA Astrophysics Data System (ADS)

    Honda, Yhosiaki; Kajiwara, Koji; Sharma, Ram; Ono, Akiko; Imaoka, Keiji; Murakami, Hiroshi; Hori, Masahiro; Ono, Yusaku; Rostand, Dim

    2012-09-01

    Japan Aerospace Exploration Agency (JAXA) is going to launch new Earth observation satellite GCOM-C1 in near future. The core sensor of GCOM-C1, Second Generation Global Imager (SGLI) has a set of along track slant viewing Visible and Near Infrared Radiometer (VNR). These multi-angular views aim to detect the structural information from vegetation canopy, especially forest canopy, for estimating productivity of the vegetation. SGLI Land science team has been developing the algorithm for above ground biomass, canopy roughness index, shadow index, etc. In this paper, we introduce the ground observation method developed by using Unmanned Aerial Vehicle (UAV) in order to contribute the algorithm development and its validation. Mainly, multi-angular spectral observation method and simple BRF model have been developed for estimating slant view response of forest canopy. The BRF model developed by using multi-angular measurement has been able to obtain structural information from vegetation canopy. In addition, we have conducted some observation campaigns on typical forest in Japan in collaboration with other science team experienced with vegetation phenology and carbon flux measurement. Primary results of these observations are also be demonstrated.

  8. Paracoccus denitrificans cytochrome c1 gene replacement mutants.

    PubMed Central

    Gerhus, E; Steinrücke, P; Ludwig, B

    1990-01-01

    We describe the construction and characterization of gene replacement mutants for the respiratory chain component cytochrome c1 in the bacterium Paracoccus denitrificans. Its structural gene (fbcC) was inactivated by insertion of the kanamycin resistance gene, introduced into a suicide vector, and conjugated into Paracoccus; chromosomal mutants obtained by homologous recombination were selected by antibiotic resistance screening and further characterized biochemically. They showed the complete spectral, enzymatic, and immunological loss of the fbcC gene product together with a serious defect in the assembly of the two other gene products of the fbc operon, cytochrome b and the FeS protein. A possible role of the cytochrome c1 in the assembly process for the enzyme complex is discussed. A functional restoration to wild-type phenotype was achieved by complementing in trans with a newly constructed broad-host-range vector carrying the fbcC gene cassette. When the complete fbc operon was present on this vector, overexpression of complex III subunits was observed. Apart from their physiological significance, such mutants are a prerequisite for probing structure-function relationships by site-directed mutagenesis in order to understand molecular details of electron transport and energy transduction processes of this respiratory enzyme in bacteria and in mitochondria. Images PMID:2158969

  9. Interaction of HmC1q with leech microglial cells: involvement of C1qBP-related molecule in the induction of cell chemotaxis

    PubMed Central

    2012-01-01

    Background In invertebrates, the medicinal leech is considered to be an interesting and appropriate model to study neuroimmune mechanisms. Indeed, this non-vertebrate animal can restore normal function of its central nervous system (CNS) after injury. Microglia accumulation at the damage site has been shown to be required for axon sprouting and for efficient regeneration. We characterized HmC1q as a novel chemotactic factor for leech microglial cell recruitment. In mammals, a C1q-binding protein (C1qBP alias gC1qR), which interacts with the globular head of C1q, has been reported to participate in C1q-mediated chemotaxis of blood immune cells. In this study, we evaluated the chemotactic activities of a recombinant form of HmC1q and its interaction with a newly characterized leech C1qBP that acts as its potential ligand. Methods Recombinant HmC1q (rHmC1q) was produced in the yeast Pichia pastoris. Chemotaxis assays were performed to investigate rHmC1q-dependent microglia migration. The involvement of a C1qBP-related molecule in this chemotaxis mechanism was assessed by flow cytometry and with affinity purification experiments. The cellular localization of C1qBP mRNA and protein in leech was investigated using immunohistochemistry and in situ hybridization techniques. Results rHmC1q-stimulated microglia migrate in a dose-dependent manner. This rHmC1q-induced chemotaxis was reduced when cells were preincubated with either anti-HmC1q or anti-human C1qBP antibodies. A C1qBP-related molecule was characterized in leech microglia. Conclusions A previous study showed that recruitment of microglia is observed after HmC1q release at the cut end of axons. Here, we demonstrate that rHmC1q-dependent chemotaxis might be driven via a HmC1q-binding protein located on the microglial cell surface. Taken together, these results highlight the importance of the interaction between C1q and C1qBP in microglial activation leading to nerve repair in the medicinal leech. PMID:22356764

  10. Clinicopathological associations of acquired erythroblastopenia

    PubMed Central

    Gunes, Gursel; Malkan, Umit Yavuz; Yasar, Hatime Arzu; Eliacik, Eylem; Haznedaroglu, Ibrahim Celalettin; Demiroglu, Haluk; Sayinalp, Nilgun; Aksu, Salih; Etgul, Sezgin; Aslan, Tuncay; Goker, Hakan; Ozcebe, Osman Ilhami; Buyukasik, Yahya

    2015-01-01

    Introduction: Acquired erythroblastopenia (AE) is a rare clinical situation. It is characterized by the reduction of erythroid precursors in the bone marrow together with the low reticulocyte counts in the peripheral blood. Background: Main secondary causes of AE are drugs, Parvovirus B19 and other infectious reasons, lymphoid and myeloid neoplasia, autoimmune diseases, thymoma and pregnancy. The aim of this study is to assess the frequencies and clinical associations of AE via analyzing 12340 bone marrow samples in a retrospective manner. Material and method: Bone marrow aspirations which were obtained from patients who applied to Hacettepe University Hematology Clinic between 2002 and 2013, were analyzed retrospectively. Results: Thirty four erythroblastopenia cases were found. Patients ranged in age from 16 to 80 years with a median of 38 years. Fifteen patients were men (44%) and nineteen were women (56%). In these patients, detected causes of erythroblastopenia were MDS, idiopathic pure red cell aplasia (PRCA), parvovirus infection, post chemotherapy aplasia, plasma proliferative diseases, copper deficiency due to secondary amyloidosis, fever of unknown origin, hemophagocytic syndrome, enteric fever and legionella pneumonia. We found that between those reasons the most common causes of erythroblastopenia are MDS (17.7%) and idiopathic PRCA (17.7%). Discussion: As a result, erythroblastopenia in the bone marrow may be an early sign of MDS. In those AE cases possibility of being MDS must be kept in mind as it can be mistaken for PRCA. Conclusion: To conclude, in adults MDS without excess blast is one of the most common causes of erythroblastopenia in clinical practice and in case of erythroblastopenia the presence of MDS should be investigated. PMID:26885236

  11. Surface Sampler Arm Acquiring Sample

    NASA Technical Reports Server (NTRS)

    1976-01-01

    Operation of the surface sampler in obtaining Martian soil for Viking 2's molecular analysis experiment last Saturday (September 25) was closely monitored by one of the Lander cameras because of the precision required in trenching the small area--8 by 9 inches-surrounded by rocks. Dubbed 'Bonneville Salt Flats,' the exposure of thin crust appeared unique in contrast with surrounding materials and became a prime target for organic analysis in spite of potential hazards. Large rock in foreground is 8 inches high. At left, the sampler scoop has touched the surface, missing the rock at upper left by a comfortable 6 inches, and the backhoe has penetrated the surface about one-half inch. The scoop was then pulled back to sample the desired point and (second photo) the backhoe furrowed the surface pulling a piece of thin crust toward the spacecraft. The initial touchdown and retraction sequence was used to avoid a collision between a rock in the shadow of the arm and a plate joining the arm and scoop. The rock was cleared by 2 to 3 inches. The third picture was taken 8 minutes after the scoop touched the surface and shows that the collector head has acquired a quantity of soil. With surface sampler withdrawn (right), the foot-long trench is seen between the rocks. The trench is three inches wide and about 1 1/2 to 2 inches deep. The scoop reached to within 3 inches of the rock at far end of trench. Penetration appears to have left a cavernous opening roofed by the crust and only about one inch of undisturbed crust separates the deformed surface and the rock.

  12. A case series of acquired haemophilia in a Malaysian hospital: unpredictably rare medical emergency.

    PubMed

    Lee, Chiou Perng; Khalid, Bahariah Bt

    2015-10-01

    Acquired haemophilia (AH) is a rare bleeding disorder characterized by the presence of acquired inhibitors against Factor VIII causing disruption of coagulation cascade. It has no known genetic inheritance, and diagnosis remains a challenge. The peculiar presentations are later age of onset as acute pain in weight-bearing joints and spontaneous muscle haematoma with isolated prolonged activated partial thrombin time (APTT). Prevalence is 1 per million per year affecting both genders equally where blood product transfusion is seen in almost 87% of cases. The direct cause of AH is still unknown, and autoimmune dysregulation has been postulated, which predisposes to the development of the factor inhibitors. Being extremely rare, we are reporting two consecutive patients diagnosed by unusual bleeding episodes with isolated prolonged APTT due to Factor VIII inhibitors. AH deserves a special mention as high index of suspicion is required. More studies are required to provide better guidance in diagnosis and management of this condition. PMID:26568837

  13. Targeting Atp6v1c1 Prevents Inflammation and Bone Erosion Caused by Periodontitis and Reveals Its Critical Function in Osteoimmunology

    PubMed Central

    Wang, Lin; Lu, Yun; Li, Qian; Zhu, Zheng; Shao, Jian-Zhong; Chen, Wei

    2015-01-01

    Periodontal disease (Periodontitis) is a serious disease that affects a majority of adult Americans and is associated with other systemic diseases, including diabetes, rheumatoid arthritis, and other inflammatory diseases. While great efforts have been devoted toward understanding the pathogenesis of periodontitis, there remains a pressing need for developing potent therapeutic strategies for targeting this pervasive and destructive disease. In this study, we utilized novel adeno-associated virus (AAV)-mediated Atp6v1c1 knockdown gene therapy to treat bone erosion and inflammatory caused by periodontitis in mouse model. Atp6v1c1 is a subunit of the V-ATPase complex and regulator of the assembly of the V0 and V1 domains of the V-ATPase complex. We demonstrated previously that Atp6v1c1 has an essential function in osteoclast mediated bone resorption. We hypothesized that Atp6v1c1 may be an ideal target to prevent the bone erosion and inflammation caused by periodontitis. To test the hypothesis, we employed AAV RNAi knockdown of Atp6v1c1 gene expression to prevent bone erosion and gingival inflammation simultaneously. We found that lesion-specific injection of AAV-shRNA-Atp6v1c1 into the periodontal disease lesions protected against bone erosion (>85%) and gingival inflammation caused by P. gingivalis W50 infection. AAV-mediated Atp6v1c1 knockdown dramatically reduced osteoclast numbers and inhibited the infiltration of dendritic cells and macrophages in the bacteria-induced inflammatory lesions in periodontitis. Silencing of Atp6v1c1 expression also prevented the expressions of osteoclast-related genes and pro-inflammatory cytokine genes. Our data suggests that AAV-shRNA-Atp6v1c1 treatment can significantly attenuate the bone erosion and inflammation caused by periodontitis, indicating the dual function of AAV-shRNA-Atp6v1c1 as an inhibitor of bone erosion mediated by osteoclasts, and as an inhibitor of inflammation through down-regulation of pro

  14. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition.

    PubMed

    Rathert, Philipp; Roth, Mareike; Neumann, Tobias; Muerdter, Felix; Roe, Jae-Seok; Muhar, Matthias; Deswal, Sumit; Cerny-Reiterer, Sabine; Peter, Barbara; Jude, Julian; Hoffmann, Thomas; Boryń, Łukasz M; Axelsson, Elin; Schweifer, Norbert; Tontsch-Grunt, Ulrike; Dow, Lukas E; Gianni, Davide; Pearson, Mark; Valent, Peter; Stark, Alexander; Kraut, Norbert; Vakoc, Christopher R; Zuber, Johannes

    2015-09-24

    Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML), bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced haematological malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL-AF9;Nras(G12D)-driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistant mouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting

  15. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition

    PubMed Central

    Neumann, Tobias; Muerdter, Felix; Roe, Jae-Seok; Muhar, Matthias; Deswal, Sumit; Cerny-Reiterer, Sabine; Peter, Barbara; Jude, Julian; Hoffmann, Thomas; Boryń, Łukasz M.; Axelsson, Elin; Schweifer, Norbert; Tontsch-Grunt, Ulrike; Dow, Lukas E.; Gianni, Davide; Pearson, Mark; Valent, Peter; Stark, Alexander; Kraut, Norbert; Vakoc, Christopher R.; Zuber, Johannes

    2016-01-01

    Summary Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukemia (AML)1,2, BET inhibitors are being explored as promising therapeutic avenue in numerous cancers3–5. While clinical trials have reported single-agent activity in advanced hematologic malignancies6, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukemia, we performed a chromatin-focused RNAi screen in a sensitive MLL/AF9; NrasG12D -driven AML model, and investigated dynamic transcriptional profiles in sensitive and resistant murine and human leukemias. Our screen reveals that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodeling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukemias regardless of their sensitivity, resistant leukemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signaling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic ChIP- and STARR-seq enhancer profiles reveal that BET-resistant states are characterized by remodeled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signaling as a driver and candidate biomarker of primary and acquired BET resistance in leukemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies. PMID:26367798

  16. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 2 2011-04-01 2011-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES AND... Statements of Smaller Reporting Companies § 210.8-06 Real estate operations acquired or to be acquired....

  17. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 2 2013-04-01 2013-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES AND...-06 Real estate operations acquired or to be acquired. If, during the period for which...

  18. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 3 2014-04-01 2014-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES AND...-06 Real estate operations acquired or to be acquired. If, during the period for which...

  19. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 2 2012-04-01 2012-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES AND...-06 Real estate operations acquired or to be acquired. If, during the period for which...

  20. 17 CFR 210.8-06 - Real estate operations acquired or to be acquired.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false Real estate operations acquired or to be acquired. 210.8-06 Section 210.8-06 Commodity and Securities Exchanges SECURITIES AND... Statements of Smaller Reporting Companies § 210.8-06 Real estate operations acquired or to be acquired....

  1. C1,1 regularity for degenerate elliptic obstacle problems

    NASA Astrophysics Data System (ADS)

    Daskalopoulos, Panagiota; Feehan, Paul M. N.

    2016-03-01

    The Heston stochastic volatility process is a degenerate diffusion process where the degeneracy in the diffusion coefficient is proportional to the square root of the distance to the boundary of the half-plane. The generator of this process with killing, called the elliptic Heston operator, is a second-order, degenerate-elliptic partial differential operator, where the degeneracy in the operator symbol is proportional to the distance to the boundary of the half-plane. In mathematical finance, solutions to the obstacle problem for the elliptic Heston operator correspond to value functions for perpetual American-style options on the underlying asset. With the aid of weighted Sobolev spaces and weighted Hölder spaces, we establish the optimal C 1 , 1 regularity (up to the boundary of the half-plane) for solutions to obstacle problems for the elliptic Heston operator when the obstacle functions are sufficiently smooth.

  2. [C1Q NEPHROPATHY: CASE REPORTS AND LITERATURE REVIEW].

    PubMed

    Galešić, Krešimir; Horvatić, Ivica; Batinić, Danica; Milošević, Danko; Saraga, Marijan; Durdov, Merica Glavina; Ljubanović, Danica Galešić

    2015-01-01

    C1q nephropathy is considered a form of glomerulonephritis, defined by histological findings of dominant Clq immune deposits in renal biopsy. It is a rare disease, most often manifested in children and young adults. The most common clinical manifestation of the disease is nephrotic syndrome, but other renal syndromes could also be found. The cause of the disease is not known, but the immune pathogenesis could be assumed. Often, resistance to glucocorticoid or other immunosuppressive therapy is present, potentially leading to chronic renal insufficiency. We present ten patients with renal biopsy and clinical findings of Clq nephropathy. None of the patients had clinical or serological manifestations of systemic lupus. All patients had normal findings of C3 and C4 components of complement, as well as normal ANF, anti-dsD-NA and ANCA antibodies. PMID:26749950

  3. A Selection of Recent Advances in C1 Chemistry.

    PubMed

    Mesters, Carl

    2016-06-01

    This review presents a selection of recent publications related to the chemistry and catalysis of C1 molecules, including methane, methanol, carbon monoxide, and carbon dioxide. These molecules play an important role in the current supply of energy and chemicals and will likely become even more relevant because of the need to decarbonize fuels (shift from coal to natural gas) in line with CO2 capture and use to mitigate global warming, as well as a gradual shift on the supply side from crude oil to natural gas. This review includes both recent industrial developments, such as the huge increase in methanol-to-olefins-capacity build in China and the demonstration of oxidative coupling of methane, and scientific developments in these chemistries facilitated by improved capabilities in, for example, analytical tools and computational modeling. PMID:27276549

  4. Plasma enhanced C1 chemistry for green technology

    NASA Astrophysics Data System (ADS)

    Nozaki, Tomohiro

    2013-09-01

    Plasma catalysis is one of the innovative next generation green technologies that meet the needs for energy and materials conservation as well as environmental protection. Non-thermal plasma uniquely generates reactive species independently of reaction temperature, and these species are used to initiate chemical reactions at unexpectedly lower temperatures than normal thermochemical reactions. Non-thermal plasma thus broadens the operation window of existing chemical conversion processes, and ultimately allows modification of the process parameters to minimize energy and material consumption. We have been specifically focusing on dielectric barrier discharge (DBD) as one of the viable non-thermal plasma sources for practical fuel reforming. In the presentation, room temperature one-step conversion of methane to methanol and hydrogen using a miniaturized DBD reactor (microplasma reactor) is highlighted. The practical impact of plasma technology on existing C1-chemistry is introduced, and then unique characteristics of plasma fuel reforming such as non-equilibrium product distribution is discussed.

  5. C(1) metabolism and CVD outcomes in older adults.

    PubMed

    McNulty, Helene; Strain, J J; Pentieva, Kristina; Ward, Mary

    2012-05-01

    CVD is the most common cause of death in people over 65 years. This review considers the latest evidence for a potential protective effect of C(1) donors (folate and the metabolically related B-vitamins) in CVD. Such an effect may or may not be mediated via the role of these nutrients in maintaining plasma homocysteine concentrations within a desirable range. Despite predictions from epidemiological studies that lowering plasma homocysteine would reduce cardiovascular risk, several secondary prevention trials in at-risk patients published since 2004 have failed to demonstrate a benefit of homocysteine-lowering therapy with B-vitamins on CVD events generally. All these trials were performed in CVD patients with advanced disease; thus current evidence suggests that intervention with high-dose folic acid is of no benefit in preventing another event, at least in the case of heart disease. The evidence at this time, however, is stronger for stroke, with meta-analyses of randomised trials showing that folic acid reduces the risk of stroke, particularly in people with no history of stroke. Genetic studies provide convincing evidence to support a causal relationship between sub-optimal B-vitamin status and CVD. People homozygous for the common C677T variant in the gene encoding the folate-metabolising enzyme, methylenetetrahydrofolate reductase (MTHFR), typically have a 14-21% higher risk of CVD. Apart from folate, riboflavin is required as a co-factor for MTHFR. New evidence shows that riboflavin intervention results in marked lowering of blood pressure, specifically in patients with the MTHFR 677TT genotype. This novel gene-nutrient interaction may provide insights as to the mechanism that links C(1) metabolism with CVD outcomes. PMID:22152927

  6. Prophylaxe beim hereditären Angioödem (HAE) mit C1-Inhibitormangel.

    PubMed

    Greve, Jens; Strassen, Ulrich; Gorczyza, Marina; Dominas, Nina; Frahm, Uta-Marie; Mühlberg, Heike; Wiednig, Michaela; Zampeli, Vasiliki; Magerl, Markus

    2016-03-01

    Das hereditäre Angioödem (engl.: hereditary angioedema, HAE) ist eine seltene angeborene Erkrankung, die durch wiederkehrende Episoden subkutaner oder submuköser Ödeme charakterisiert ist. Kehlkopf-Manifestationen können lebensbedrohlich sein. In den meisten Fällen kann die Erkrankung mit einem On-Demand-Ansatz angemessen behandelt werden - in einigen Fällen ist jedoch eine Kurz- oder Langzeitprophylaxe angebracht. Attenuierte Androgene waren einmal das Standardmedikament; sie werden jedoch mit erheblichen Nebenwirkungen in Verbindung gebracht und sind in den deutschsprachigen Ländern der EU nicht mehr kommerziell erhältlich. Zurzeit werden sie von wirksameren und besser verträglichen Therapien wie C1-Esterase-Inhibitoren, dem Kallikrein-Inhibitor Ecallantid und dem B2-Rezeptorantagonisten Icatibant verdrängt, welche kürzlich auf dem Markt zugelassen wurden. Diese neuen Medikamente hatten einen erheblichen Einfluss, insbesondere auf die Indikationsstellung und das Vorgehen bei einer Langzeitprophylaxe. Nach den neuesten internationalen Konsenspapieren und unserer eigenen Erfahrung sind selbstverabreichte C1-Inhibitoren nun die erste Option bei der Langzeitprophylaxe. Die Entscheidung für eine Prophylaxe sollte nicht länger auf der Grundlage einzelner Parameter wie der Häufigkeit der Anfälle getroffen werden, sondern auf einer adäquaten allgemeinen Krankheitskontrolle, einschließlich der Lebensqualität. Zurzeit werden weitere Medikamente entwickelt, welche zu weiteren Veränderungen bei den Behandlungsalgorithmen des HAE führen könnten. PMID:26972190

  7. Acquired tracheoesophageal fistula in infancy and childhood.

    PubMed

    Szold, A; Udassin, R; Seror, D; Mogle, P; Godfrey, S

    1991-06-01

    Acquired tracheoesophageal fistula (TEF) is a rare entity in the pediatric age group. We report two pediatric patients with acquired TEF caused by shells of pistachio nuts. In both patients the primary operation did not resolve the problem and a second intervention for recurrent fistula was needed. The special nature of acquired TEF, particularly the one described herein, requires delayed surgical intervention and meticulous separation of the respiratory and alimentary tracts by an intercostal muscle flap. PMID:1941455

  8. Acquired stuttering due to recurrent anaplastic astrocytoma

    PubMed Central

    Peters, Katherine B; Turner, Scott

    2013-01-01

    Acquired (neurogenic) stuttering is a rare phenomenon seen after cerebral infarction or brain injury. Aetiology of this symptom is unclear, but recent evidence supports that it is a disturbance in the left hemispheric neural network involving the interplay between the cortex and basal ganglia. We present the case of a patient who develops acquired stuttering after a recurrence of a right temporoparietal anaplastic astrocytoma (WHO grade III). We also review other cases of acquired stuttering and known anatomical correlates. PMID:24252834

  9. Inhibition of Ebola Virus Infection: Identification of Niemann-Pick C1 as the Target by Optimization of a Chemical Probe

    PubMed Central

    2012-01-01

    A high-throughput screen identified adamantane dipeptide 1 as an inhibitor of Ebola virus (EboV) infection. Hit-to-lead optimization to determine the structure–activity relationship (SAR) identified the more potent EboV inhibitor 2 and a photoaffinity labeling agent 3. These antiviral compounds were employed to identify the target as Niemann-Pick C1 (NPC1), a host protein that binds the EboV glycoprotein and is essential for infection. These studies establish NPC1 as a promising target for antiviral therapy. PMID:23526644

  10. Immunoadsorption for pregnancy-associated severe acquired hemophilia.

    PubMed

    Zeitler, Heike; Ulrich-Merzenich, Gudrun; Marquardt, Natascha; Oldenburg, Johannes; Goldmann, Georg

    2014-02-01

    Postpartum hemorrhage is a common cause of maternal mortality. Acquired hemophilia (AH) is a rare, life-threatening bleeding disorder induced by autoantibodies against coagulation factors (inhibitors). We report about eight patients with postpartum AH (out of 82). Seven AH patients with severe bleeding complications were treated by the "Modified Bonn-Malmö Protocol (MBMP)" which consists of inhibitor elimination via immunoadsorption (IA) in combination with immunosuppression and high-dose Factor VIII substitution. One patient was treated only by immunosuppression. Seven out of eight patients with severe AH and mean inhibitor titers (IT) of 118 BU/mL were referred to our center. They were severe cases with a median delay of diagnosis of 30.5 days (range 7-278 days). After a median of 3 IA sessions (range 3-5 days), no inhibitor was detectable. The factor substitution was discontinued after a median of 13 IA sessions (range 8-24 days) and IA was terminated after a median of 15 sessions (range 9-27 days). One less severe affected patient (IT: 2.1 BU/mL) received prednisolone (1.5 mg/kg BW) for 120 days. Complete remission was achieved in all patients with a median follow-up of 100 months (range 56-126 m). The delayed diagnosis of pregnancy-associated AH leads to a high bleeding risk with bleeding associated complications. Immunoadsorption offers an important treatment option in severe AH, enabling a fast reconstitution of the blood coagulation with a reduced time for the Factor VIII substitution and for immunosuppressive treatment. In cases of postpartum bleeding the diagnosis of AH should be routinely considered. PMID:24499091

  11. Angiotensin Converting Enzyme Inhibitor-related Angioedema: A Case of an Unexpected Death.

    PubMed

    Atalay, Eray; Özdemir, Mehmet Tamer; Çiğsar, Gülşen; Omurca, Ferhat; Aslan, Nurullah; Yildiz, Mehmet; Gey, Zehra Bahar

    2015-11-01

    Angioedema is an asymmetric non-pitting oedema on face, lips, tongue and mucous membranes; any delay in diagnosis and treatment can be fatal. Treatment with lisinopril as an angiotensin converting enzyme (ACE) inhibitor, can be a reason of angioedema. Here we report a case who developed oral-facial edema four years after using lisinopril/hydrochlorothiazide. Laryngeal oedema is a main cause of death in angioedema. The treatment of choice in angioedema including fresh frozen plasma, C1 inhibitor concentrations and BRK-2 antagonists (bradykinin B2 receptor antagonists) were used. In this case; a 77 years old female patient suffering from hypertension was considered. This patient was suffering two days from swelling on her face and neck. Non- allergic angioedema was distinguished in five major forms; acquired (AAO), hereditary (HAE), renin-angiotensin-aldosterone system (RAAS) blocker-dependent, pseudoallergic angioedema (PAS) and an idiopathic angioedema (IAO). She was admitted to our clinic with the diagnosis of hereditary angioedema. Patient had skin edema and life threatening laryngeal edema. In emergency department treatment was started using intravenous methylprednisolone, diphenydramine as well as inhaled and subcutaneous epinephrine simultaneously. Despite the initial treatment, the patient died due to the insufficient respiration and cardiac arrest. The patient has no history of kidney disease. PMID:26725563

  12. L-C1qDC-1, a novel C1q domain-containing protein from Lethenteron camtschaticum that is involved in the immune response.

    PubMed

    Pei, Guangying; Liu, Ge; Pan, Xiong; Pang, Yue; Li, Qingwei

    2016-01-01

    The C1q domain-containing (C1qDC) proteins are a family of proteins characterized by a globular C1q (gC1q) domain at their C-terminus. These proteins are involved in various processes in vertebrates and are assumed to serve as important pattern recognition receptors in innate immunity in invertebrates. Here, a novel C1qDC protein from Lethenteron camtschaticum was identified and characterized (designated as L-C1qDC-1). After a partial cDNA sequence of L-C1qDC-1 was identified in a L. camtschaticum liver cDNA library, the full-length cDNA was obtained using 3'- and 5'-rapid amplification of cDNA ends (RACE). L-C1qDC-1 encodes 236 amino acids and contains a signal peptide, a collagen-like sequence with Gly-Xaa-Yaa repeats, and a C-terminal gC1q domain. The L-C1qDC-1 protein was primarily distributed in the gut, liver and supraneural body of L. camtschaticum and was also marginally detectable in leukocytes via real-time PCR and immunofluorescence assays. Furthermore, both immunoprecipitation and immunofluorescence results showed that in L. camtschaticum serum, L-C1qDC-1 could interact with variable lymphocyte receptor (VLR) B and displayed strong colocalization with cancer cell immune responses. These results indicated that the L-C1qDC-1 gene encodes a novel C1qDC protein that may play an important role in the immune responses of L. camtschaticum, providing clues for understanding the universal functions of C1qDC proteins in other species and suggesting that these proteins could serve as pattern recognition molecules in immunotherapy. PMID:26342581

  13. Inhibitors of Kallikrein in Human Plasma

    PubMed Central

    McConnell, David J.

    1972-01-01

    Human plasma was fractionated by ammonium sulfate precipitation, DEAE-cellulose chromatography, and Sephadex G-200 gel filtration to determine which method would give the greatest number of clearly separable kallikrein inhibitory peaks. With G-200 gel filtration three peaks could be separated which were demonstrated to contain α2-macroglobulin, C1̄ inactivator, and α1-antitrypsin. No other kallikrein inhibitors could be identified. The fractions containing C1̄ inactivator and α2-macroglobulin appeared to be more effective against kallikrein than that containing α1-antitrypsin. A patient with hereditary angioneurotic edema was shown to have an abnormal C1̄ inactivator protein capable of interfering with kallikrein's biologic, but not its esterolytic activity. Heat-treated human plasma, a commonly used source of kininogen for experiments with kallikrein, was shown to have kallikrein inhibitory activity. PMID:4113391

  14. Anatomic Consideration of the C1 Laminar Arch for Lateral Mass Screw Fixation via C1 Lateral Lamina : A Landmark between the Lateral and Posterior Lamina of the C1

    PubMed Central

    Kim, Jung-Hwan; Kwak, Dai-Soon; Han, Seung-Ho; Cho, Sung-Min; You, Seung-Hoon

    2013-01-01

    Objective To clarify the landmark for deciding the entry point for C1 lateral mass screws via the posterior arch by using 3-dimensional (3D) computed images. Methods Resnick insisted that the C1 posterior arch could be divided into pure posterior and lateral lamina (C1 pedicle). Authors studied where this transition point (TP) is located between the posterior lamina and the C1 pedicle and how it can be recognized. The 3D computed images of 86 cadaver C1s (M : F=45 : 41) were used in this study. Results The superior ridge of the C1 posterior arch had 2 types of orientation. One was in the vertical direction in the C1 posterior lamina and the other was in the horizontal direction in the C1 pedicle. The TP was located at the border between the 2 areas, the same site as the posterior end of the groove of the vertebral artery. On posterior-anterior projection, the posterior arch was sharpened abruptly at TP. We were unable to identify the TP in 6.4% of specimens due to complete or partial osseous bridges. A total of 93.8% of the TP were located between the most enlarged point of the spinal canal and the medial wall of the vertebral artery. Conclusion The anatomic entry zone of C1 lateral laminar screws was clarified and identified based on the TP by using preoperative 3D computed images. PMID:24044076

  15. Radiation damage of the HEAO C-1 germanium detectors

    NASA Technical Reports Server (NTRS)

    Mahoney, W. A.; Ling, J. C.; Jacobson, A. S.

    1981-01-01

    The effects of radiation damage from proton bombardment of the four HEAO C-1 high purity germanium detectors have been measured and compared to predictions. Because of the presence of numerous gamma-ray lines in the detector background spectra and because of the relatively long exposure time of the HEAO 3 satellite to cosmic-ray and trapped protons, it has been possible to measure both the energy and time dependence of radiation damage. After 100 d in orbit, each of the four detectors has been exposed to approximately 3 x 10 to the 7th protons/sq cm, and the average energy resolution at 1460 keV had degraded from 3.2 keV fwhm to 8.6 keV fwhm. The lines were all broadened to the low energy side although the line profile was different for each of the four detectors. The damage-related contribution to the degradation in energy resolution was found to be linear in energy and proton influence.

  16. Near-ultraviolet spectroscopy of Comet Austin (1989c1)

    NASA Technical Reports Server (NTRS)

    Valk, Jacobus H.; O'Dell, C. R.; Cochran, Anita L.; Cochran, William D.; Opal, Chet B. S.; Barker, Edwin S.

    1992-01-01

    Comet Austin (1989c1) was observed post-perihelion at a heliocentric distance near 1.25 AU. The wavelength range was from the atmospheric cutoff at 3000 to 4000 A. The coma spectra were calibrated into flux units and the contaminating sky spectrum and solar scattered light continuum were subtracted, leaving an ultraviolet spectrum of about 1.5-A resolution and excellent signal-to-noise ratio. The spectrum is dominated by emissions from OH, NH, CH, C3, and CN, some of the weaker emissions of which are seen here for the first time. More bands of CO(2+) were found than in any previous investigation and several intensity anomalies were noted; H2CO, OH(+), NCN, N(2+), and CN(+) may be present. Several emission features well above the noise level remain unidentified. The relative intensities of the OH and CN bands agree with the predictions of resonance fluorescence when one considers the potential effects of contamination by other molecules. The effects of the ozone absorption spectrum are not fully removed by the data-reduction process, although this does not affect these results.

  17. Structure of human Niemann-Pick C1 protein.

    PubMed

    Li, Xiaochun; Wang, Jiawei; Coutavas, Elias; Shi, Hang; Hao, Qi; Blobel, Günter

    2016-07-19

    Niemann-Pick C1 protein (NPC1) is a late-endosomal membrane protein involved in trafficking of LDL-derived cholesterol, Niemann-Pick disease type C, and Ebola virus infection. NPC1 contains 13 transmembrane segments (TMs), five of which are thought to represent a "sterol-sensing domain" (SSD). Although present also in other key regulatory proteins of cholesterol biosynthesis, uptake, and signaling, the structure and mechanism of action of the SSD are unknown. Here we report a crystal structure of a large fragment of human NPC1 at 3.6 Å resolution, which reveals internal twofold pseudosymmetry along TM 2-13 and two structurally homologous domains that protrude 60 Å into the endosomal lumen. Strikingly, NPC1's SSD forms a cavity that is accessible from both the luminal bilayer leaflet and the endosomal lumen; computational modeling suggests that this cavity is large enough to accommodate one cholesterol molecule. We propose a model for NPC1 function in cholesterol sensing and transport. PMID:27307437

  18. Structure of human Niemann–Pick C1 protein

    PubMed Central

    Li, Xiaochun; Wang, Jiawei; Coutavas, Elias; Shi, Hang; Hao, Qi; Blobel, Günter

    2016-01-01

    Niemann–Pick C1 protein (NPC1) is a late-endosomal membrane protein involved in trafficking of LDL-derived cholesterol, Niemann–Pick disease type C, and Ebola virus infection. NPC1 contains 13 transmembrane segments (TMs), five of which are thought to represent a “sterol-sensing domain” (SSD). Although present also in other key regulatory proteins of cholesterol biosynthesis, uptake, and signaling, the structure and mechanism of action of the SSD are unknown. Here we report a crystal structure of a large fragment of human NPC1 at 3.6 Å resolution, which reveals internal twofold pseudosymmetry along TM 2–13 and two structurally homologous domains that protrude 60 Å into the endosomal lumen. Strikingly, NPC1's SSD forms a cavity that is accessible from both the luminal bilayer leaflet and the endosomal lumen; computational modeling suggests that this cavity is large enough to accommodate one cholesterol molecule. We propose a model for NPC1 function in cholesterol sensing and transport. PMID:27307437

  19. Acquired Surface Dyslexia: The Evidence from Hebrew.

    ERIC Educational Resources Information Center

    Birnboim, Smadar

    1995-01-01

    Investigates the symptoms of acquired surface dyslexia in Hebrew. Four acquired surface dyslexic adults were compared with eight normal second graders in terms of reading strategy. Homophones and homographs were a major source of difficulty for native Hebrew surface dyslexic readers; the normal second graders used a non-lexical strategy. (45…

  20. Acquiring and Managing Electronic Journals. ERIC Digest.

    ERIC Educational Resources Information Center

    Curtis, Donnelyn; Yue, Paoshan

    Electronic journals are both a blessing and a curse for libraries. To be meaningful in the current information environment--to meet users' ever-increasing demands--libraries must acquire as many appropriate full text resources as possible, as quickly as possible, and make them easy to use. This Digest provides tips for acquiring and providing…

  1. Acquired Zinc Deficiency in an Adult Female

    PubMed Central

    Saritha, Mohanan; Gupta, Divya; Chandrashekar, Laxmisha; Thappa, Devinder M; Rajesh, Nachiappa G

    2012-01-01

    Acrodermatitis enteropathica is an autosomal recessive inherited disorder of zinc absorption. Acquired cases are reported occasionally in patients with eating disorders or Crohn's disease. We report a 24-year-old housewife with acquired isolated severe zinc deficiency with no other comorbidities to highlight the rare occurrence of isolated nutritional zinc deficiency in an otherwise normal patient. PMID:23248371

  2. Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target.

    PubMed

    Cougnoux, A; Cluzeau, C; Mitra, S; Li, R; Williams, I; Burkert, K; Xu, X; Wassif, C A; Zheng, W; Porter, F D

    2016-01-01

    Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder due to mutation of the NPC1 gene. The NPC1 phenotype is characterized by progressive neuronal dysfunction, including cerebellar ataxia and dementia. There is histological evidence of neuroinflammation and progressive neuronal loss, with cerebellar Purkinje cells particularly vulnerable to loss of NPC1 function. Necroptosis was evaluated as a mechanism of neuronal loss. Receptor-interacting protein kinase 1 (RIP1) and RIP3 are key components of the necrosomal complex that regulates necroptotic cell death. We report increased expression of RIP1 and RIP3 in NPC1 fibroblasts, NPC1 iPS cell-derived neuronal precursors, and in cerebellar tissue from both NPC1 mice and patients. Our data suggest a positive correlation between NPC1 neurological disease severity and assembly of the necrosome complex. Furthermore, we demonstrate that pharmacological inhibition of RIP1 decreases cell death both in vitro and in vivo. Treatment of Npc1-mutant mice with necrostatin-1, an allosteric inhibitor of RIP1, significantly delayed cerebellar Purkinje cell loss, progression of neurological symptoms, and death. Collectively, our data identified necroptosis as a key component of the molecular network that contributes to neuronal loss in NPC1 and establish that inhibition of necroptosis is a potential therapeutic intervention. PMID:26986514

  3. Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1.

    PubMed

    Wang, Han; Shi, Yi; Song, Jian; Qi, Jianxun; Lu, Guangwen; Yan, Jinghua; Gao, George F

    2016-01-14

    Filoviruses, including Ebola and Marburg, cause fatal hemorrhagic fever in humans and primates. Understanding how these viruses enter host cells could help to develop effective therapeutics. An endosomal protein, Niemann-Pick C1 (NPC1), has been identified as a necessary entry receptor for this process, and priming of the viral glycoprotein (GP) to a fusion-competent state is a prerequisite for NPC1 binding. Here, we have determined the crystal structure of the primed GP (GPcl) of Ebola virus bound to domain C of NPC1 (NPC1-C) at a resolution of 2.3 Å. NPC1-C utilizes two protruding loops to engage a hydrophobic cavity on head of GPcl. Upon enzymatic cleavage and NPC1-C binding, conformational change in the GPcl further affects the state of the internal fusion loop, triggering membrane fusion. Our data therefore provide structural insights into filovirus entry in the late endosome and the molecular basis for design of therapeutic inhibitors of viral entry. PMID:26771495

  4. Necroptosis in Niemann–Pick disease, type C1: a potential therapeutic target

    PubMed Central

    Cougnoux, A; Cluzeau, C; Mitra, S; Li, R; Williams, I; Burkert, K; Xu, X; Wassif, C A; Zheng, W; Porter, F D

    2016-01-01

    Niemann–Pick disease, type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder due to mutation of the NPC1 gene. The NPC1 phenotype is characterized by progressive neuronal dysfunction, including cerebellar ataxia and dementia. There is histological evidence of neuroinflammation and progressive neuronal loss, with cerebellar Purkinje cells particularly vulnerable to loss of NPC1 function. Necroptosis was evaluated as a mechanism of neuronal loss. Receptor-interacting protein kinase 1 (RIP1) and RIP3 are key components of the necrosomal complex that regulates necroptotic cell death. We report increased expression of RIP1 and RIP3 in NPC1 fibroblasts, NPC1 iPS cell-derived neuronal precursors, and in cerebellar tissue from both NPC1 mice and patients. Our data suggest a positive correlation between NPC1 neurological disease severity and assembly of the necrosome complex. Furthermore, we demonstrate that pharmacological inhibition of RIP1 decreases cell death both in vitro and in vivo. Treatment of Npc1-mutant mice with necrostatin-1, an allosteric inhibitor of RIP1, significantly delayed cerebellar Purkinje cell loss, progression of neurological symptoms, and death. Collectively, our data identified necroptosis as a key component of the molecular network that contributes to neuronal loss in NPC1 and establish that inhibition of necroptosis is a potential therapeutic intervention. PMID:26986514

  5. Niemann-Pick C1-Like 1 (NPC1L1) Inhibition and Cardiovascular Diseases.

    PubMed

    Pirillo, A; Catapano, A L; Norata, G D

    2016-01-01

    Circulating levels of cholesterol are derived from either endogenous production or intestinal absorption of dietary and biliary cholesterol. Niemann-Pick C1-Like 1 (NPC1L1) is a transmembrane protein that plays a key role in the intestinal absorption of cholesterol by facilitating its uptake through vesicular endocytosis. NPC1L1 is the molecular target of ezetimibe which binds its extracellular loop and inhibits sterol absorption without affecting the absorption of other molecules. Ezetimibe significantly reduces plasma levels of total and low density lipoprotein cholesterol (LDL-C) as monotherapy or when added to statins, the association with a low dose of statin is of particular interest for patients experiencing statin-related side effects. The recent results of the IMPROVE-IT study, which evaluated the cardiovascular effect of ezetimibe added to simvastatin therapy in subjects who had had an acute coronary syndrome and with LDL-C levels within the recommended range, showed that a further LDL-C lowering reduced the incidence of cardiovascular events. To date, ezetimibe represents the only inhibitor of NPC1L1 available for clinical use, however, novel aminoß- lactam ezetimibe derivatives have been synthesized and their efficacy to inhibit NPC1L1 protein and decrease plasma cholesterol levels is under evaluation. PMID:26923679

  6. Studies on contact activation: effects of surface and inhibitors.

    PubMed

    Cameron, C L; Fisslthaler, B; Sherman, A; Reddigari, S; Silverberg, M

    1989-01-01

    Contact activation is initiated when the plasma proteins, Hageman factor (factor XII), prekallikrein and high molecular weight kininogen interact with negatively charged materials. The activation of the intrinsic pathway of blood coagulation and the production of bradykinin are among the sequelae of contact activation. The kinetics of the activation of the contact system are modified by plasma inhibitors, C1 inhibitor being quantitatively the most important. We propose that the activation of the system requires that the stimulus provided by the surface must be greater than a threshold value to overcome the effects of the inhibitors. We show in this paper that the amount of surface required for activation is much reduced in the absence of C1 inhibitor (Hereditary Angioedema) or in the cold where the inhibitor loses much of its effectiveness. Antithrombin III inhibition of activated Hageman factor is augmented by heparin which is also an activator of Hageman factor. The rate constants for inhibition remain much lower than for C1 inhibitor, however. PMID:2530427

  7. Acquired hemophilia masked by warfarin therapy: report on two cases.

    PubMed

    Uggla, Bertil; Linder, Olle; Schulman, Sam

    2003-12-01

    Spontaneous appearance of acquired anticoagulants is a rare phenomenon. We present two cases, where such antibodies against factor VIII were masked by warfarin therapy. The two patients were anticoagulated with warfarin due to mechanical heart valve and recurrent thromboembolic events, respectively. Different therapies against the inhibitor of factor VIII were used in the two cases. One patient received corticosteroids and high-dose gammaglobulin with temporary effect and was then effectively treated with cyclophosphamide. The other patient was successfully treated with cyclosporine. The special problems of keeping the balance between thrombosis and bleeding in this group of patients with need of anticoagulation due to mechanical heart valves or other thrombogenic factors are discussed. PMID:14614359

  8. Potential disadvantages of using socially acquired information.

    PubMed Central

    Giraldeau, Luc-Alain; Valone, Thomas J; Templeton, Jennifer J

    2002-01-01

    The acquisition and use of socially acquired information is commonly assumed to be profitable. We challenge this assumption by exploring hypothetical scenarios where the use of such information either provides no benefit or can actually be costly. First, we show that the level of incompatibility between the acquisition of personal and socially acquired information will directly affect the extent to which the use of socially acquired information can be profitable. When these two sources of information cannot be acquired simultaneously, there may be no benefit to socially acquired information. Second, we assume that a solitary individual's behavioural decisions will be based on cues revealed by its own interactions with the environment. However, in many cases, for social animals the only socially acquired information available to individuals is the behavioural actions of others that expose their decisions, rather than the cues on which these decisions were based. We argue that in such a situation the use of socially acquired information can lead to informational cascades that sometimes result in sub-optimal behaviour. From this theory of informational cascades, we predict that when erroneous cascades are costly, individuals should pay attention only to socially generated cues and not behavioural decisions. We suggest three scenarios that might be examples of informational cascades in nature. PMID:12495513

  9. Managing acquired resistance in EGFR-mutated non-small cell lung cancer.

    PubMed

    Forde, Patrick M; Ettinger, David S

    2015-08-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) deliver high response rates with relatively modest toxicity in patients with advanced EGFR-mutated non-small cell lung cancer. Despite this, nearly all tumors eventually develop resistance to first-line therapy. At present, the only standard treatment option for patients with acquired resistance is cytotoxic chemotherapy. In this article, we review the latest research into methods of targeting acquired resistance to EGFR TKI therapy, including third-generation EGFR TKIs that target the T790M resistance mutation and other novel agents in development. PMID:26351816

  10. Prospects for novel inhibitors of peptidoglycan transglycosylases

    PubMed Central

    Galley, Nicola F.; O’Reilly, Amy M.; Roper, David I.

    2014-01-01

    The lack of novel antimicrobial drugs under development coupled with the increasing occurrence of resistance to existing antibiotics by community and hospital acquired infections is of grave concern. The targeting of biosynthesis of the peptidoglycan component of the bacterial cell wall has proven to be clinically valuable but relatively little therapeutic development has been directed towards the transglycosylase step of this process. Advances towards the isolation of new antimicrobials that target transglycosylase activity will rely on the development of the enzymological tools required to identify and characterise novel inhibitors of these enzymes. Therefore, in this article, we review the assay methods developed for transglycosylases and review recent novel chemical inhibitors discovered in relation to both the lipidic substrates and natural product inhibitors of the transglycosylase step. PMID:24924926

  11. Proton pump inhibitors

    MedlinePlus

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by glands in ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This is a ...

  12. Human diploid fibroblasts have receptors for the globular domain of C1Q

    SciTech Connect

    Bordin, S.; Page, R.C.

    1986-03-01

    The authors showed that mass cultures of fibroblasts grown from gingival explants in DB medium with 10% human serum are enriched in a phenotype that binds C1q with an affinity much higher than the rest of the population. Because of potential biologic importance of C1q receptors, the authors studied whether the interaction between C1q and this phenotype was mediated by the globular or collagenous domains of the molecule. Globular fragments were prepared by digesting C1q with collagenase, and collagenous fragments obtained after pepsin treatment. C1q binding on cells in suspension was determined by reaction with /sup 125/I-C1q as reported. Competition experiments were performed under conditions in which intact /sup 125/I-C1q binding saturated all available receptors. The results showed that collagenous fragments inhibited 20% of the /sup 125/I-C1q binding to high affinity receptors, whereas inhibition by globular fragments was 70%. Unlabeled intact C1q and collagen type 1 were used as controls, and inhibited 92% and 17% of C1q binding, respectively. These studies show that C1q interacts with the fibroblast phenotype expressing high affinity receptors through its globular domain. The authors suggest that at sites of trauma, native C1 may bind to the surface of these cells via the globular domain of C1q, and that this unique phenotype may play an important role in tissue repair.

  13. Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer.

    PubMed

    Herrera-Abreu, Maria Teresa; Palafox, Marta; Asghar, Uzma; Rivas, Martín A; Cutts, Rosalind J; Garcia-Murillas, Isaac; Pearson, Alex; Guzman, Marta; Rodriguez, Olga; Grueso, Judit; Bellet, Meritxell; Cortés, Javier; Elliott, Richard; Pancholi, Sunil; Baselga, José; Dowsett, Mitch; Martin, Lesley-Ann; Turner, Nicholas C; Serra, Violeta

    2016-04-15

    Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, although their cytostatic effects are limited by primary and acquired resistance. Here we report that ER-positive breast cancer cells can adapt quickly to CDK4/6 inhibition and evade cytostasis, in part, via noncanonical cyclin D1-CDK2-mediated S-phase entry. This adaptation was prevented by cotreatment with hormone therapies or PI3K inhibitors, which reduced the levels of cyclin D1 (CCND1) and other G1-S cyclins, abolished pRb phosphorylation, and inhibited activation of S-phase transcriptional programs. Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient-derived tumor xenograft (PDX) models, resulting in tumor regression and improved disease control. Furthermore, a triple combination of endocrine therapy, CDK4/6, and PI3K inhibition was more effective than paired combinations, provoking rapid tumor regressions in a PDX model. Mechanistic investigations showed that acquired resistance to CDK4/6 inhibition resulted from bypass of cyclin D1-CDK4/6 dependency through selection of CCNE1 amplification or RB1 loss. Notably, although PI3K inhibitors could prevent resistance to CDK4/6 inhibitors, they failed to resensitize cells once resistance had been acquired. However, we found that cells acquiring resistance to CDK4/6 inhibitors due to CCNE1 amplification could be resensitized by targeting CDK2. Overall, our results illustrate convergent mechanisms of early adaptation and acquired resistance to CDK4/6 inhibitors that enable alternate means of S-phase entry, highlighting strategies to prevent the acquisition of therapeutic resistance to these agents. Cancer Res; 76(8); 2301-13. ©2016 AACR. PMID:27020857

  14. 26 CFR 31.3302(c)-1 - Limit on total credits.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Limit on total credits. 31.3302(c)-1 Section 31.3302(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT... Federal Unemployment Tax Act (Chapter 23, Internal Revenue Code of 1954) § 31.3302(c)-1 Limit on...

  15. 26 CFR 1.666(c)-1A - Pro rata portion of taxes deemed distributed.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Pro rata portion of taxes deemed distributed. 1.666(c)-1A Section 1.666(c)-1A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Taxable Years Beginning Before January 1, 1969 § 1.666(c)-1A Pro rata portion of taxes deemed...

  16. 26 CFR 1.666(c)-1 - Pro rata portion of taxes deemed distributed.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Pro rata portion of taxes deemed distributed. 1.666(c)-1 Section 1.666(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Taxable Years Beginning Before January 1, 1969 § 1.666(c)-1 Pro rata portion of taxes deemed...

  17. 17 CFR 270.18c-1 - Exemption of privately held indebtedness.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Exemption of privately held indebtedness. 270.18c-1 Section 270.18c-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.18c-1 Exemption of privately held indebtedness. The issuance or...

  18. 26 CFR 1.503(c)-1 - Future status of organizations denied exemption.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 7 2014-04-01 2013-04-01 true Future status of organizations denied exemption. 1.503(c)-1 Section 1.503(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Exempt Organizations § 1.503(c)-1 Future status of organizations denied exemption. (a)...

  19. 26 CFR 1.666(c)-1 - Pro rata portion of taxes deemed distributed.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ....666(c)-1 Section 1.666(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.666(c)-1 Pro rata portion of taxes deemed distributed. (a) If an accumulation distribution is deemed under § 1.666(a)-1 to be distributed on the...

  20. 26 CFR 1.666(c)-1A - Pro rata portion of taxes deemed distributed.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ....666(c)-1A Section 1.666(c)-1A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.666(c)-1A Pro rata portion of taxes deemed distributed. (a) If an accumulation distribution is deemed under § 1.666(a)-1A to be distributed on the...

  1. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Substantial Owners § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter...

  2. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Substantial Owners § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter...

  3. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Substantial Owners § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter...

  4. 26 CFR 1.509(c)-1 - Status of organization after termination of private foundation status.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... private foundation status. 1.509(c)-1 Section 1.509(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Private Foundations § 1.509(c)-1 Status of organization after termination of private foundation status. (a) In...

  5. 26 CFR 1.509(c)-1 - Status of organization after termination of private foundation status.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... private foundation status. 1.509(c)-1 Section 1.509(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Private Foundations § 1.509(c)-1 Status of organization after termination of private foundation status. (a) In...

  6. 26 CFR 1.509(c)-1 - Status of organization after termination of private foundation status.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... private foundation status. 1.509(c)-1 Section 1.509(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Private Foundations § 1.509(c)-1 Status of organization after termination of private foundation status. (a) In...

  7. 26 CFR 1.509(c)-1 - Status of organization after termination of private foundation status.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... private foundation status. 1.509(c)-1 Section 1.509(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Private Foundations § 1.509(c)-1 Status of organization after termination of private foundation status. (a) In...

  8. 26 CFR 1.1244(c)-1 - Section 1244 stock defined.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 11 2014-04-01 2014-04-01 false Section 1244 stock defined. 1.1244(c)-1 Section 1.1244(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Special Rules for Determining Capital Gains and Losses § 1.1244(c)-1 Section 1244 stock defined. (a)...

  9. 26 CFR 1.503(c)-1 - Future status of organizations denied exemption.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Future status of organizations denied exemption. 1.503(c)-1 Section 1.503(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Exempt Organizations § 1.503(c)-1 Future...

  10. 26 CFR 1.503(c)-1 - Future status of organizations denied exemption.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 7 2012-04-01 2012-04-01 false Future status of organizations denied exemption. 1.503(c)-1 Section 1.503(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Exempt Organizations § 1.503(c)-1 Future...

  11. 26 CFR 1.503(c)-1 - Future status of organizations denied exemption.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 7 2013-04-01 2013-04-01 false Future status of organizations denied exemption. 1.503(c)-1 Section 1.503(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Exempt Organizations § 1.503(c)-1 Future...

  12. 26 CFR 1.860C-1 - Taxation of holders of residual interests.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 9 2010-04-01 2010-04-01 false Taxation of holders of residual interests. 1.860C-1 Section 1.860C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Real Estate Investment Trusts § 1.860C-1 Taxation of...

  13. 26 CFR 1.666(c)-1A - Pro rata portion of taxes deemed distributed.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ....666(c)-1A Section 1.666(c)-1A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.666(c)-1A Pro rata portion of taxes deemed distributed. (a) If an accumulation distribution is deemed under § 1.666(a)-1A to be distributed on the...

  14. 26 CFR 1.666(c)-1 - Pro rata portion of taxes deemed distributed.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ....666(c)-1 Section 1.666(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.666(c)-1 Pro rata portion of taxes deemed distributed. (a) If an accumulation distribution is deemed under § 1.666(a)-1 to be distributed on the...

  15. 26 CFR 1.666(c)-1A - Pro rata portion of taxes deemed distributed.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ....666(c)-1A Section 1.666(c)-1A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.666(c)-1A Pro rata portion of taxes deemed distributed. (a) If an accumulation distribution is deemed under § 1.666(a)-1A to be distributed on the...

  16. 26 CFR 1.666(c)-1A - Pro rata portion of taxes deemed distributed.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ....666(c)-1A Section 1.666(c)-1A Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.666(c)-1A Pro rata portion of taxes deemed distributed. (a) If an accumulation distribution is deemed under § 1.666(a)-1A to be distributed on the...

  17. 26 CFR 1.666(c)-1 - Pro rata portion of taxes deemed distributed.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ....666(c)-1 Section 1.666(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.666(c)-1 Pro rata portion of taxes deemed distributed. (a) If an accumulation distribution is deemed under § 1.666(a)-1 to be distributed on the...

  18. 26 CFR 1.666(c)-1 - Pro rata portion of taxes deemed distributed.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ....666(c)-1 Section 1.666(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... Applicable to Taxable Years Beginning Before January 1, 1969 § 1.666(c)-1 Pro rata portion of taxes deemed distributed. (a) If an accumulation distribution is deemed under § 1.666(a)-1 to be distributed on the...

  19. Serum IgG antibodies to C1q in hypocomplementemic urticarial vasculitis syndrome.

    PubMed

    Wisnieski, J J; Naff, G B

    1989-09-01

    Urticaria, angioedema, and arthritis are cardinal features of hypocomplementemic urticarial vasculitis syndrome (HUVS). Considered to be an immune complex-mediated disorder, HUVS has been differentiated from systemic lupus erythematosus (SLE), based on its clinical manifestations and the C1q precipitin (C1q-p) reaction, which is manifested as gel precipitation of C1q by a small percentage of HUVS IgG molecules. This phenomenon has been attributed to an Fc region abnormality, and the responsible IgG molecules are said to possess C1q-p activity. We purified IgG from 4 HUVS patients and confirmed that HUVS IgG contains C1q binding activity. F(ab')2 fragments from these patients also bound to C1q, as measured by 2 different C1q binding methods at physiologic ionic strength; HUVS IgG Fc fragments did not bind to C1q. Preincubation of HUVS F(ab')2 fragments with antibody to human F(ab')2 prevented subsequent binding to C1q. We conclude that IgG antibodies to C1q are present in HUVS serum, and it is likely that these antibodies are C1q-p. Because the clinical manifestations of HUVS and the presence of anti-C1q antibodies have been described in patients with SLE, our findings support the concept that HUVS is an autoimmune syndrome related to SLE. PMID:2528353

  20. 26 CFR 1.674(c)-1 - Excepted powers exercisable only by independent trustees.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Excepted powers exercisable only by independent trustees. 1.674(c)-1 Section 1.674(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... § 1.674(c)-1 Excepted powers exercisable only by independent trustees. Section 674(c) provides...

  1. Potent inhibition of the classical pathway of complement by a novel C1q-binding peptide derived from the human astrovirus coat protein.

    PubMed

    Gronemus, Jenny Q; Hair, Pamela S; Crawford, Katrina B; Nyalwidhe, Julius O; Cunnion, Kenji M; Krishna, Neel K

    2010-01-01

    Previous work from our laboratories has demonstrated that purified, recombinant human astrovirus coat protein (HAstV CP) binds C1q and mannose-binding lectin (MBL) inhibiting activation of the classical and lectin pathways of complement, respectively. Analysis of the 787 amino acid CP molecule revealed that residues 79-139 share limited sequence homology with human neutrophil defensin-1 (HNP-1), a molecule previously demonstrated to bind C1q and MBL, inhibiting activation of the classical and lectin pathways of complement, respectively. A 30 amino acid peptide derived from this region of the CP molecule competitively inhibited the binding of wild-type CP to C1q. The parent peptide and various derivatives were subsequently assayed for C1q binding, inhibition of C1 and C4 activation as well as suppression of complement activation in hemolytic assays. The parent peptide and several derivatives inhibited complement activation in these functional assays to varying degrees. One peptide derivative in particular (E23A) displayed superior inhibition of complement activation in multiple assays of classical complement pathway activation. Further analysis revealed homology to a plant defensin allowing development of a proposed structural model for E23A. Based upon these findings, we hypothesize that further rationale optimization of E23A may result in a promising therapeutic inhibitor for the treatment of inflammatory and autoimmune diseases in which dysregulated activation of the classical and lectin pathways of complement contribute to pathogenesis. PMID:20728940

  2. Chemical characterization and location of ionic interactions involved in the assembly of the C1 complex of human complement.

    PubMed

    Illy, C; Thielens, N M; Arlaud, G J

    1993-12-01

    The C1 complex of human complement comprises two loosely interacting subunits, C1q and the Ca(2+)-dependent C1s-C1r-C1r-C1s tetramer. With a view to gain information on the nature of the ionic interactions involved in C1 assembly, we have studied the effects of the chemical modifications of charged residues of C1q or the tetramer on their ability to reconstitute the C1 complex. Treatment of C1q with pyridoxal-5'-phosphate, acetic anhydride, and citraconic anhydride, as well as with cyclohexanedione and diethylpyrocarbonate, inhibited its ability to associate with C1s-C1r-C1r-C1s. Treatment of the collagen-like fragments of C1q with the same reagents yielded the same effects. Treatment of C1s-C1r-C1r-C1s with 1-ethyl-3-[-3-(dimethylamino) propyl] carbodiimide also prevented C1 assembly, through modification of acidic amino acids which were shown to be located in C1r. Further studies on the location of the interaction sites within C1q, using ligand-blotting and competition experiments with synthetic peptides, were unsuccessful, suggesting that these sites are contributed to by two or three of the C1q chains. It is concluded that C1 assembly involves interactions between acidic amino acids of C1r and lysine (hydroxylysine) and arginine residues located within the collagen-like region of C1q. Sequence comparison with mannan binding protein, another collagen-like molecule which binds the C1s-C1r-C1r-C1s tetramer, suggests Arg A38, and HyL B32, B65, and C29 of C1q as possible interaction sites. PMID:8136028

  3. Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells

    PubMed Central

    Gaspar, Nathalie; Sharp, Swee Y; Pacey, Simon; Jones, Chris; Walton, Michael; Vassal, Gilles; Eccles, Suzanne; Pearson, Andrew; Workman, Paul

    2009-01-01

    HSP90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) which is currently in phase II/III clinical trials, are promising new anticancer agents. Here, we explored acquired resistance to HSP90 inhibitors in glioblastoma, a primary brain tumor with poor prognosis. Glioblastoma cells were exposed continuously to increased 17-AAG concentrations. Four 17-AAG-resistant glioblastoma cell lines were generated. High resistance levels with resistance indices (RI=resistant line IC50/parental line IC50) of 20-137 were obtained rapidly (2-8 weeks). After cessation of 17-AAG exposure, RI decreased and then stabilised. Cross-resistance was found with other ansamycin benzoquinones but not with the structurally unrelated HSP90 inhibitors, radicicol, the purine BIIB021 and the resorcinylic pyrazole/isoxazole amide compounds VER-49009, VER-50589, and NVP-AUY922. An inverse correlation between NQO1 expression/activity and 17-AAG IC50 was observed in the resistant lines. The NQO1 inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines. NQO1 mRNA levels and NQO1 DNA polymorphism analysis indicated different underlying mechanisms: reduced expression and selection of the inactive NQO1*2 polymorphism. Decreased NQO1 expression was also observed in a melanoma line with acquired resistance to 17-AAG. No resistance was generated with VER-50589 and NVP-AUY922. In conclusion, low NQO1 activity is a likely mechanism of acquired resistance to 17-AAG in glioblastoma, melanoma and possibly other tumor types. Such resistance can be overcome with novel HSP90 inhibitors. PMID:19244114

  4. Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer

    PubMed Central

    Xie, Caifeng; Jin, Jiangbo; Bao, Xujie; Zhan, Wei-Hua; Han, Tian-Yu; Gan, Mingxi; Zhang, Chengfu; Wang, Jianbin

    2016-01-01

    The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has been approved based on the clinical benefit in non-small cell lung cancer (NSCLC) patients over the past decade. Unfortunately, cancer cells become resistant to this agent via various mechanisms, and this limits the improvement in patient outcomes. Thus, it is urgent to develop novel agents to overcome erlotinib resistance. Here, we propose a novel strategy to overcome acquired erlotinib resistance in NSCLC by inhibiting glutaminase activity. Compound 968, an inhibitor of the glutaminase C (GAC), when combined with erlotinib potently inhibited the cell proliferation of erlotinib-resistant NSCLC cells HCC827ER and NCI-H1975. The combination of compound 968 and erlotinib not only decreased GAC and EGFR protein expression but also inhibited GAC activity in HCC827ER cells. The growth of erlotinib-resistant cells was glutamine-dependent as proved by GAC gene knocked down and rescue experiment. More importantly, compound 968 combined with erlotinib down-regulated the glutamine and glycolysis metabolism in erlotinib-resistant cells. Taken together, our study provides a valuable approach to overcome acquired erlotinib resistance by blocking glutamine metabolism and suggests that combination of EGFR-TKI and GAC inhibitor maybe a potential treatment strategy for acquired erlotinib-resistant NSCLC. PMID:26575584

  5. Niemann-Pick C1-Like 1 (NPC1L1) Protein in Intestinal and Hepatic Cholesterol Transport

    PubMed Central

    Jia, Lin; Betters, Jenna L.; Yu, Liqing

    2014-01-01

    Increased blood cholesterol is an independent risk factor for atherosclerotic cardiovascular disease. Cholesterol homeostasis in the body is controlled mainly by endogenous synthesis, intestinal absorption, and hepatic excretion. Niemann-Pick C1-Like 1 (NPC1L1) is a polytopic transmembrane protein localized at the apical membrane of enterocytes and the canalicular membrane of hepatocytes. It functions as a sterol transporter to mediate intestinal cholesterol absorption and counterbalances hepatobiliary cholesterol excretion. NPC1L1 is the molecular target of ezetimibe, a potent cholesterol absorption inhibitor that is widely used in treating hypercholesterolemia. Recent findings suggest that NPC1L1 deficiency or ezetimibe treatment also prevents diet-induced hepatic steatosis and obesity in addition to reducing blood cholesterol. Future studies should focus on molecular mechanisms underlying NPC1L1-dependent cholesterol transport and elucidation of how a cholesterol transporter modulates the pathogenesis of metabolic diseases. PMID:20809793

  6. Optical Spectral Observations of a Flickering White-light Kernel in a C1 Solar Flare

    NASA Astrophysics Data System (ADS)

    Kowalski, Adam F.; Cauzzi, Gianna; Fletcher, Lyndsay

    2015-01-01

    We analyze optical spectra of a two-ribbon, long-duration C1.1 flare that occurred on 2011 August 18 within AR 11271 (SOL2011-08-18T15:15). The impulsive phase of the flare was observed with a comprehensive set of space-borne and ground-based instruments, which provide a range of unique diagnostics of the lower flaring atmosphere. Here we report the detection of enhanced continuum emission, observed in low-resolution spectra from 3600 Å to 4550 Å acquired with the Horizontal Spectrograph at the Dunn Solar Telescope. A small, <=0.''5 (1015 cm2) penumbral/umbral kernel brightens repeatedly in the optical continuum and chromospheric emission lines, similar to the temporal characteristics of the hard X-ray variation as detected by the Gamma-ray Burst Monitor on the Fermi spacecraft. Radiative-hydrodynamic flare models that employ a nonthermal electron beam energy flux high enough to produce the optical contrast in our flare spectra would predict a large Balmer jump in emission, indicative of hydrogen recombination radiation from the upper flare chromosphere. However, we find no evidence of such a Balmer jump in the bluemost spectral region of the continuum excess. Just redward of the expected Balmer jump, we find evidence of a "blue continuum bump" in the excess emission which may be indicative of the merging of the higher order Balmer lines. The large number of observational constraints provides a springboard for modeling the blue/optical emission for this particular flare with radiative-hydrodynamic codes, which are necessary to understand the opacity effects for the continuum and emission line radiation at these wavelengths.

  7. OPTICAL SPECTRAL OBSERVATIONS OF A FLICKERING WHITE-LIGHT KERNEL IN A C1 SOLAR FLARE

    SciTech Connect

    Kowalski, Adam F.; Cauzzi, Gianna; Fletcher, Lyndsay

    2015-01-10

    We analyze optical spectra of a two-ribbon, long-duration C1.1 flare that occurred on 2011 August 18 within AR 11271 (SOL2011-08-18T15:15). The impulsive phase of the flare was observed with a comprehensive set of space-borne and ground-based instruments, which provide a range of unique diagnostics of the lower flaring atmosphere. Here we report the detection of enhanced continuum emission, observed in low-resolution spectra from 3600 Å to 4550 Å acquired with the Horizontal Spectrograph at the Dunn Solar Telescope. A small, ≤0.''5 (10{sup 15} cm{sup 2}) penumbral/umbral kernel brightens repeatedly in the optical continuum and chromospheric emission lines, similar to the temporal characteristics of the hard X-ray variation as detected by the Gamma-ray Burst Monitor on the Fermi spacecraft. Radiative-hydrodynamic flare models that employ a nonthermal electron beam energy flux high enough to produce the optical contrast in our flare spectra would predict a large Balmer jump in emission, indicative of hydrogen recombination radiation from the upper flare chromosphere. However, we find no evidence of such a Balmer jump in the bluemost spectral region of the continuum excess. Just redward of the expected Balmer jump, we find evidence of a ''blue continuum bump'' in the excess emission which may be indicative of the merging of the higher order Balmer lines. The large number of observational constraints provides a springboard for modeling the blue/optical emission for this particular flare with radiative-hydrodynamic codes, which are necessary to understand the opacity effects for the continuum and emission line radiation at these wavelengths.

  8. Suppression of methylation-mediated transcriptional gene silencing by βC1-SAHH protein interaction during geminivirus-betasatellite infection.

    PubMed

    Yang, Xiuling; Xie, Yan; Raja, Priya; Li, Sizhun; Wolf, Jamie N; Shen, Qingtang; Bisaro, David M; Zhou, Xueping

    2011-10-01

    DNA methylation is a fundamental epigenetic modification that regulates gene expression and represses endogenous transposons and invading DNA viruses. As a counter-defense, the geminiviruses encode proteins that inhibit methylation and transcriptional gene silencing (TGS). Some geminiviruses have acquired a betasatellite called DNA β. This study presents evidence that suppression of methylation-mediated TGS by the sole betasatellite-encoded protein, βC1, is crucial to the association of Tomato yellow leaf curl China virus (TYLCCNV) with its betasatellite (TYLCCNB). We show that TYLCCNB complements Beet curly top virus (BCTV) L2⁻ mutants deficient for methylation inhibition and TGS suppression, and that cytosine methylation levels in BCTV and TYLCCNV genomes, as well as the host genome, are substantially reduced by TYLCCNB or βC1 expression. We also demonstrate that while TYLCCNB or βC1 expression can reverse TGS, TYLCCNV by itself is ineffective. Thus its AC2/AL2 protein, known to have suppression activity in other geminiviruses, is likely a natural mutant in this respect. A yeast two-hybrid screen of candidate proteins, followed by bimolecular fluorescence complementation analysis, revealed that βC1 interacts with S-adenosyl homocysteine hydrolase (SAHH), a methyl cycle enzyme required for TGS. We further demonstrate that βC1 protein inhibits SAHH activity in vitro. That βC1 and other geminivirus proteins target the methyl cycle suggests that limiting its product, S-adenosyl methionine, may be a common viral strategy for methylation interference. We propose that inhibition of methylation and TGS by βC1 stabilizes geminivirus/betasatellite complexes. PMID:22028660

  9. Suppression of Methylation-Mediated Transcriptional Gene Silencing by βC1-SAHH Protein Interaction during Geminivirus-Betasatellite Infection

    PubMed Central

    Raja, Priya; Li, Sizhun; Wolf, Jamie N.; Shen, Qingtang; Bisaro, David M.; Zhou, Xueping

    2011-01-01

    DNA methylation is a fundamental epigenetic modification that regulates gene expression and represses endogenous transposons and invading DNA viruses. As a counter-defense, the geminiviruses encode proteins that inhibit methylation and transcriptional gene silencing (TGS). Some geminiviruses have acquired a betasatellite called DNA β. This study presents evidence that suppression of methylation-mediated TGS by the sole betasatellite-encoded protein, βC1, is crucial to the association of Tomato yellow leaf curl China virus (TYLCCNV) with its betasatellite (TYLCCNB). We show that TYLCCNB complements Beet curly top virus (BCTV) L2- mutants deficient for methylation inhibition and TGS suppression, and that cytosine methylation levels in BCTV and TYLCCNV genomes, as well as the host genome, are substantially reduced by TYLCCNB or βC1 expression. We also demonstrate that while TYLCCNB or βC1 expression can reverse TGS, TYLCCNV by itself is ineffective. Thus its AC2/AL2 protein, known to have suppression activity in other geminiviruses, is likely a natural mutant in this respect. A yeast two-hybrid screen of candidate proteins, followed by bimolecular fluorescence complementation analysis, revealed that βC1 interacts with S-adenosyl homocysteine hydrolase (SAHH), a methyl cycle enzyme required for TGS. We further demonstrate that βC1 protein inhibits SAHH activity in vitro. That βC1 and other geminivirus proteins target the methyl cycle suggests that limiting its product, S-adenosyl methionine, may be a common viral strategy for methylation interference. We propose that inhibition of methylation and TGS by βC1 stabilizes geminivirus/betasatellite complexes. PMID:22028660

  10. Acquired cutis laxa associated with cutaneous mastocytosis.

    PubMed

    Hoang, Minh Van; Dang, Phuoc Van; Bui, Duc Van; Mejbel, Haider; Mani, Divya Thomas; Smoller, Bruce Robert; Phung, Thuy Linh

    2015-07-01

    Cutis laxa is characterized by dramatic wrinkling of skin that is lacking in elasticity due to inherent defects in dermal elastic fibers. Cutis laxa can be caused by genetic and metabolic disorders. It can also be acquired, possibly resulting from inflammatory processes with destruction of elastic fibers. This report describes a 26-year old woman who developed acquired cutis laxa and cutaneous mastocytosis leading to premature aging. She represents a unique co-occurrence of these two separate disease entities. To our knowledge, there has been only one published case report of acquired cutis laxa occurring in association with urticaria pigmentosa in a 4-year old girl. Our case would be a second case that exhibits the coexistence of these two disorders in an adult female. PMID:26436968

  11. Magnetic resonance imaging of acquired cardiac disease.

    PubMed Central

    Carrol, C L; Higgins, C B; Caputo, G R

    1996-01-01

    Over the last 15 years, advances in magnetic resonance imaging techniques have increased the accuracy and applicability of cardiovascular magnetic resonance imaging. These advances have improved the utility of magnetic resonance imaging in evaluating cardiac morphology, blood flow, and myocardial contractility, all significant diagnostic features in the evaluation of the patient with acquired heart disease. Utilization of cardiovascular magnetic resonance imaging has been limited, primarily due to clinical reliance upon nuclear scintigraphy and echocardiography. Recent developments in fast and ultrafast imaging should continue to enhance the significance of magnetic resonance imaging in this field. Widespread use of magnetic resonance imaging in the evaluation of the cardiovascular system will ultimately depend upon its maturation into a comprehensive, noninvasive imaging technique for the varying manifestations of acquired heart disease, including cardiomyopathy, ischemic heart disease, and acquired valvular disease. Images PMID:8792545

  12. The Next Wave of EGFR Tyrosine Kinase Inhibitors Enter the Clinic.

    PubMed

    Politi, Katerina; Ayeni, Deborah; Lynch, Thomas

    2015-06-01

    The T790M mutation in EGFR accounts for approximately half of all lung cancer cases with acquired resistance to the current clinical EGFR tyrosine kinase inhibitors. In tyrosine kinase inhibitor-resistant lung tumors, rociletinib and AZD9291 are highly active when T790M is present and modestly active when T790M is absent. PMID:26058074

  13. Cytokine-mediated induction of metallothionein in Hepa-1c1c7 cells by oleanolic acid.

    PubMed

    Kim, Ji Young; Lee, Kyung Jin; Kim, Dong Hee; Jeong, Tae Cheon; Lee, Eung Seok; Choi, Young Muk; Jeong, Hye Gwang

    2004-12-17

    Oleanolic acid (OA), a pentacyclic triterpene acid, has been reported to possess inducing activity of hepatic metallothionein (MT). However, the mechanism underlying its effects is unknown. This study investigated the effects of OA on the regulation of MT expression in an in vitro model. OA that was added directly to Hepa-1c1c7 cells had no effect on MT induction. However, MT and its mRNA levels increased markedly when the Hepa-1c1c7 cells were cultured with the OA-treated conditioned media from the RAW 264.7 cells. Co-treating the RAW 264.7 cells with OA and pentoxifylline, a TNF-alpha synthesis inhibitor, resulted in a decrease in the effects of OA on the MT induction. In the OA-exposed RAW 264.7 cell cultures, production and mRNA levels of TNF-alpha and IL-6 were increased. However, the MT induction activity was inhibited when antibodies to TNF-alpha and/or IL-6 were added to the OA-treated conditioned media from the RAW 264.7 cells. These results suggest that the up-regulation of MT expression by OA was mediated by the TNF-alpha and IL-6 released from UA-activated macrophages. PMID:15541359

  14. Systemic reduction of rice blast by inhibitors of antioxidant enzymes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Systemic acquired disease resistance (SAR) of plants may result from an oxidative burst in their tissues caused by both increased production of ROS and decreased antioxidant activity, in particular, enzymatic. Here we tested whether the exogenous inhibitors of superoxide dismutase (SOD) and catalase...

  15. CT-based morphometric analysis of C1 laminar dimensions: C1 translaminar screw fixation is a feasible technique for salvage of atlantoaxial fusions

    PubMed Central

    Yew, Andrew; Lu, Derek; Lu, Daniel C.

    2015-01-01

    Background: Translaminar screw fixation has become an alternative in the fixation of the axial and subaxial cervical spine. We report utilization of this approach in the atlas as a salvage technique for atlantoaxial stabilization when C1 lateral mass screws are precluded. To assess the feasibility of translaminar fixation at the atlas, we have characterized the dimensions of the C1 lamina in the general adult population using computed tomography (CT)-based morphometry. Methods: A 46-year-old male with symptomatic atlantoaxial instability secondary to os odontoideum underwent bilateral C1 and C2 translaminar screw/rod fixation as C1 lateral mass fixation was precluded by an anomalous vertebral artery. The follow-up evaluation 2½ years postoperatively revealed an asymptomatic patient without recurrent neck/shoulder pain or clinical signs of instability. To better assess the feasibility of utilizing this approach in the general population, we retrospectively analyzed 502 consecutive cervical CT scans performed over a 3-month period in patients aged over 18 years at a single institution. Measurements of C1 bicortical diameter, bilateral laminar length, height, and angulation were performed. Laminar and screw dimensions were compared to assess instrumentation feasibility. Results: Review of CT imaging found that 75.9% of C1 lamina had a sufficient bicortical diameter, and 63.7% of C1 lamina had sufficient height to accept bilateral translaminar screw placement. Conclusions: CT-based measurement of atlas morphology in the general population revealed that a majority of C1 lamina had sufficient dimensions to accept translaminar screw placement. Although these screws appear to be a feasible alternative when lateral mass screws are precluded, further research is required to determine if they provide comparable fixation strength versus traditional instrumentation methods. PMID:26005585

  16. Structure-activity relationships of C1 and C6 side chains of zaragozic acid A derivatives.

    PubMed

    Ponpipom, M M; Girotra, N N; Bugianesi, R L; Roberts, C D; Berger, G D; Burk, R M; Marquis, R W; Parsons, W H; Bartizal, K F; Bergstom, J D

    1994-11-11

    Systematic modification of the C6 acyl side chain of zaragozic acid A, a potent squalene synthase inhibitor, was undertaken to improve its biological activity. Simplification of the C6 side chain to the octanoyl ester has deleterious effects; increasing the linear chain length improves the in vitro activity up to the tetradecanoyl ester. An omega-phenoxy group is a better activity enhancer than an omega-phenyl group. A number of C6 carbamates, ethers, and carbonates were prepared and found to have similar activity profiles as the C6 esters. In the preparation of C6 ethers, C4 and C4,6 bisethers were also isolated; their relative activity is: C6 > C4 > C4,6. These C6 long-chain derivatives are subnanomolar squalene synthase inhibitors; they are, however, only weakly active in inhibiting hepatic cholesterol synthesis in mice. The C6 short-chain derivatives are much less active in vitro, but they all have improved oral activity in mice. Modification of the C1 alkyl side chain of the n-butanoyl analogue (ED50 4.5 mg/kg) did not improve the po activity further. A number of these C6 long-chain derivatives are also potent antifungal agents in vitro. PMID:7966163

  17. C1q component of complement binds to fibrinogen and fibrin

    SciTech Connect

    Entwistle, R.A.; Furcht, L.T.

    1988-01-12

    The interaction of complement component C1q with fibrinogen and fibrin was studied by using a solid-phase direct binding assay. Scatchard analysis of radioiodinated fibrinogen binding to C1q indicated at least two high-affinity binding constants (Kd) calculated as 8.5 and 120 nM. In contrast, binding of radioiodinated fibrin to C1q showed only a single class of binding sites with a calculated Kd of 600 nM. Fibrinogen-C1q binding was shown to decrease as a function of increasing salt concentrations, indicating either the presence of charged amino acids in the binding sites or an ionic strength induced conformational dependency of the binding. In direct binding studies using isolated fragments of C1q, both the collagen-like domain of C1q and the globular domains of C1q were shown to bind fibrinogen, indicating at least one binding site for fibrinogen is located in each of the major domains of C1q. Addition of the thrombin-generated peptides of fibrinogen, fibrinopeptides A and B, enhanced C1q-fibrinogen binding, again indicating a complex binding interaction. These results indicate that C1q and fibrinogen are capable of high-affinity interactions that may serve to sequester these complexes in areas of tumors, immune complex deposition, or wounds.

  18. Colonizing populations of Candida albicans are clonal in origin but undergo microevolution through C1 fragment reorganization as demonstrated by DNA fingerprinting and C1 sequencing.

    PubMed Central

    Lockhart, S R; Fritch, J J; Meier, A S; Schröppel, K; Srikantha, T; Galask, R; Soll, D R

    1995-01-01

    The genetic homogeneity of nine commensal and infecting populations of Candida albicans has been assessed by fingerprinting multiple isolates from each population by Southern blot hybridization first with the Ca3 probe and then with the 0.98-kb C1 fragment of the Ca3 probe. The isolates from each population were highly related, demonstrating the clonal origin of each population, but each population contained minor variants, demonstrating microevolution. Variation in each case was limited to bands of the Ca3 fingerprint pattern which hybridized with the 0.98-kb C1 fragment. The C1 fragment was therefore sequenced and demonstrated to contain an RPS repetitive element. The C1 fragment also contained part or all of a true end of the RPS element. These results, therefore, demonstrate that most colonizing C. albicans populations in nonimmuno-suppressed patients are clonal, that microevolution can be detected in every colonizing population by C1 hybridization, and that C1 contains the repeat RPS element. PMID:7650175

  19. Increased Complement C1q Level Marks Active Disease in Human Tuberculosis

    PubMed Central

    Zhang, Mingxia; Liu, Haiying; Zhang, Guoliang; Deng, Qunyi; Huang, Jian; Gao, Zhiliang; Zhou, Boping; Feng, Carl G.; Chen, Xinchun

    2014-01-01

    Background Complement functions as an important host defense system and complement C5 and C7 have been implicated in immunopathology of tuberculosis. However, little is known about the role of other complement components in tuberculosis. Methods Complement gene expression in peripheral blood mononuclear cells of tuberculosis patients and controls were determined using whole genome transcriptional microarray assays. The mRNA and protein levels of three C1q components, C1qA, C1qB, and C1qC, were further validated by qRT-PCR and enzyme-linked immunosorbent assay, respectively. The percentages of C1q expression in CD14 positive cells were determined by flow cytometry. Finally, C1qC protein level was quantified in the pleural fluid of tuberculosis and non-tuberculosis pleurisy. Results C1q expression increases significantly in the peripheral blood of patients with active tuberculosis compared to healthy controls and individuals with latent TB infection. The percentage of C1q-expressing CD14 positive cells is significantly increased in active TB patients. C1q expression in the peripheral blood correlates with sputum smear positivity in tuberculosis patients and is reduced after anti-tuberculosis chemotherapy. Notably, receiver operating characteristic analysis showed that C1qC mRNA levels in peripheral blood efficiently discriminate active from latent tuberculosis infection and healthy controls. Additionally, C1qC protein level in pleural effusion shows improved power in discriminating tuberculosis from non-tuberculosis pleurisy when compared to other inflammatory markers, such as IL-6 and TNF-α. Conclusions C1q expression correlates with active disease in human tuberculosis. C1q could be a potential diagnostic marker to discriminate active tuberculosis from latent tuberculosis infection as well as tuberculosis pleurisy from non-tuberculosis pleurisy. PMID:24647646

  20. Ultrasound of Inherited vs. Acquired Demyelinating Polyneuropathies

    PubMed Central

    Zaidman, Craig M.; Harms, Matthew B.; Pestronk, Alan

    2013-01-01

    Introduction We compared features of nerve enlargement in inherited and acquired demyelinating neuropathies using ultrasound. Methods We measured median and ulnar nerve cross-sectional areas in proximal and distal regions in 128 children and adults with inherited (Charcot-Marie Tooth-1 (CMT-1) (n=35)) and acquired (Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (n=55), Guillaine-Barre Syndrome (GBS) (n=21) and Multifocal Motor Neuropathy (MMN) (n=17)) demyelinating neuropathies. We classified nerve enlargement by degree and number of regions affected. We defined patterns of nerve enlargement as: none- no enlargement; mild-nerves enlarged but never more than twice normal; regional- nerves normal at at least one region and enlarged more than twice normal at atleast one region; diffuse- nerves enlarged at all four regions with atleast one region more than twice normal size. Results Nerve enlargement was commonly diffuse (89%) and generally more than twice normal size in CMT-1, but not (p<0.001) in acquired disorders which mostly had either no, mild or regional nerve enlargement (CIDP (64%), GBS (95%), and MMN (100%)). In CIDP, subjects treated within three months of disease onset had less nerve enlargement than those treated later. Discussion Ultrasound identified patterns of diffuse nerve enlargement can be used to screen patients suspected of having CMT-1. Normal, mildly, or regionally enlarged nerves in demyelinating polyneuropathy suggests an acquired etiology. Early treatment in CIDP may impede nerve enlargement. PMID:24101129

  1. Acquiring a Second Language for School.

    ERIC Educational Resources Information Center

    Collier, Virginia P.

    1995-01-01

    This report offers a conceptual model for use with language minority children who are entering a new school when they must acquire the language of the majority student population. The model has four development components or processes: sociocultural, linguistic, academic, and cognitive. These four components are described in detail. Research is…

  2. 7 CFR 989.17 - Acquire.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 8 2013-01-01 2013-01-01 false Acquire. 989.17 Section 989.17 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN...

  3. 7 CFR 989.17 - Acquire.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 8 2014-01-01 2014-01-01 false Acquire. 989.17 Section 989.17 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN...

  4. 7 CFR 989.17 - Acquire.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Acquire. 989.17 Section 989.17 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN...

  5. 7 CFR 989.17 - Acquire.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 8 2011-01-01 2011-01-01 false Acquire. 989.17 Section 989.17 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN...

  6. Eye Movement Correlates of Acquired Central Dyslexia

    ERIC Educational Resources Information Center

    Schattka, Kerstin I.; Radach, Ralph; Huber, Walter

    2010-01-01

    Based on recent progress in theory and measurement techniques, the analysis of eye movements has become one of the major methodological tools in experimental reading research. Our work uses this approach to advance the understanding of impaired information processing in acquired central dyslexia of stroke patients with aphasia. Up to now there has…

  7. How Did Light Acquire a Velocity?

    ERIC Educational Resources Information Center

    Lauginie, Pierre

    2013-01-01

    We discuss how light acquired a velocity through history, from the ancient Greeks to the early modern era. Combining abstract debates, models of light, practical needs, planned research and chance, this history illustrates several key points that should be brought out in science education.

  8. Group Treatment in Acquired Brain Injury Rehabilitation

    ERIC Educational Resources Information Center

    Bertisch, Hilary; Rath, Joseph F.; Langenbahn, Donna M.; Sherr, Rose Lynn; Diller, Leonard

    2011-01-01

    The current article describes critical issues in adapting traditional group-treatment methods for working with individuals with reduced cognitive capacity secondary to acquired brain injury. Using the classification system based on functional ability developed at the NYU Rusk Institute of Rehabilitation Medicine (RIRM), we delineate the cognitive…

  9. 7 CFR 989.17 - Acquire.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE RAISINS PRODUCED FROM GRAPES GROWN IN... possession of raisins by a handler at his packing or processing plant or at any other established receiving station operated by him: Provided, That a handler shall not be deemed to acquire any raisins...

  10. 7 CFR 926.10 - Acquire.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Acquire. 926.10 Section 926.10 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE DATA COLLECTION, REPORTING AND...

  11. Acquiring Financial Management Software: A Prototyping Approach.

    ERIC Educational Resources Information Center

    Wilson, John H.

    1990-01-01

    When the Smithsonian Institution recently acquired a new financial management system, the concept of prototyping was used throughout the process, but in a broader sense than in software development. It was used to refine requirements, establish software management techniques, test a logistical system, and implement and apply the package. (MSE)

  12. A Case Of Bilateral Acquired Localized Lipoatrophy

    PubMed Central

    Tanrıkulu, Osman; Yesilova, Yavuz; Aksoy, Mustafa

    2016-01-01

    Lipoatrophy is characterized by inflammation and tissue loss in fatty tissue. This disease may be congenital or acquired, primary or secondary. Secondary lipoatrophy develops with infections, collagen tissue diseases, tumors and drug injections. In this report, we present the case of a 14-year-old female patient who developed lipoatrophy following intramuscular steroid injection to both buttocks. PMID:27504088

  13. Neural Correlates of Acquired Color Category Effects

    ERIC Educational Resources Information Center

    Clifford, Alexandra; Franklin, Anna; Holmes, Amanda; Drivonikou, Vicky G.; Ozgen, Emre; Davies, Ian R. L.

    2012-01-01

    Category training can induce category effects, whereby color discrimination of stimuli spanning a newly learned category boundary is enhanced relative to equivalently spaced stimuli from within the newly learned category (e.g., categorical perception). However, the underlying mechanisms of these acquired category effects are not fully understood.…

  14. Acquired structural defects of the hair.

    PubMed

    Chetty, G N; Kamalam, A; Thambiah, A S

    1981-03-01

    Acquired hair shaft abnormalities resembling genetic trichorrhexis nodosa were seen in two patients. Selenium shampoo and bacterial infection with trichomycosis axillaris may have been the contributing factors. There is a possibility that strongyloides larvae caused trichonodosis in one patient. PMID:7216593

  15. Community-acquired Acinetobacter meningitis in adults.

    PubMed

    Chang, W N; Lu, C H; Huang, C R; Chuang, Y C

    2000-01-01

    Community-acquired Acinetobacter meningitis in adults is an extremely rare infection of the central nervous system (CNS). Here we report one adult case of this rare CNS infection and review the clinical data of another seven cases reported in the English language literature. In total, eight patients (six men and two women) aged between 19 and 63 years were studied. The causative pathogen in our patient was Acinetobacter baumannii; in the other reported cases they were most likely Acinetobacter Iwoffii, Acinetobacter johnsonii, Acinetobacter junii, a genomic species 3 or 6. No underlying disease was found in seven of the eight cases and six of the eight patients acquired the infections before the age of 30 years. Fever and consciousness disturbance were the most common clinical manifestations. Waterhouse-Friderichsen syndrome (WFS) was found in two cases. Unlike the Acinetobacter strains found in nosocomial infections, the strain of Acinetobacter meningitis in the community-acquired case did not show multiple antibiotic resistance. Most adult patients with community-acquired Acinetobacter meningitis can be saved by timely therapy with appropriate antibiotics before deterioration of the systemic condition and impairment of consciousness. PMID:11139162

  16. Interviewing Children with Acquired Brain Injury (ABI)

    ERIC Educational Resources Information Center

    Boylan, Anne-Marie; Linden, Mark; Alderdice, Fiona

    2009-01-01

    Research into the lives of children with acquired brain injury (ABI) often neglects to incorporate children as participants, preferring to obtain the opinions of the adult carer (e.g. McKinlay et al., 2002). There has been a concerted attempt to move away from this position by those working in children's research with current etiquette…

  17. Support Network Responses to Acquired Brain Injury

    ERIC Educational Resources Information Center

    Chleboun, Steffany; Hux, Karen

    2011-01-01

    Acquired brain injury (ABI) affects social relationships; however, the ways social and support networks change and evolve as a result of brain injury is not well understood. This study explored ways in which survivors of ABI and members of their support networks perceive relationship changes as recovery extends into the long-term stage. Two…

  18. The importance of polarizability: comparison of models of carbon disulphide in the ionic liquids [C1C1im][NTf2] and [C4C1im][NTf2].

    PubMed

    Lynden-Bell, Ruth M; Quitevis, Edward L

    2016-06-28

    The local environment of CS2 and in solution in two ionic liquids ([C1C1im][NTf2] and [C4C1im][NTf2]) are investigated by atomistic simulation and compared with that in neat CS2. The intermolecular vibrational densities of states of CS2 are calculated and compared with experimental OHD-RIKES spectra. The fair agreement of the results from solutions but poor agreement of the results from neat CS2 suggest that while collective effects are unimportant in solutions, they have a major effect on the OHD-RIKES spectrum of neat CS2. Comparing polarizable and unpolarizable models for CS2 emphasizes the importance of polarizability in determining local structure. PMID:27273458

  19. [Inhibitors of xanthine oxidoreductase].

    PubMed

    Okamoto, Ken

    2008-04-01

    Inhibitors of xanthine oxidoreductase decrease production of uric acid, thus they act as hypouricemic drugs. Allopurinol, a prototypical xanthine oxidoreductase inhibitor, has been widely prescribed for treatment of gout and hyperuricemia. However, severe side effects of allopurinol may occur in patients with renal insufficiency. Recently, novel nonpurine selective inhibitors of xanthine oxidoreductase have been developed as potential alternatives to allopurinol. They have different inhibition mechanisms, utilizing the enzyme structure and the reaction mechanism. Such variation of the inhibition mechanism affects/in vivo/hypouricemic effects of the inhibitors. PMID:18409526

  20. Nuclear EGFR Contributes to Acquired Resistance to Cetuximab

    PubMed Central

    Li, Chunrong; Iida, Mari; Dunn, Emily F.; Ghia, Amol J.; Wheeler, Deric L.

    2010-01-01

    Epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase involved in the etiology of several human cancers. Cetuximab is an EGFR blocking-antibody that has been approved for the treatment of patients with cancers of the head and neck (HNSCC) and metastatic colorectal cancer (mCRC). Previous reports have shown that EGFR translocation to the nucleus is associated with cell proliferation. Here we investigated mechanisms of acquired resistance to cetuximab using a model derived from the non-small cell lung cancer line H226. We demonstrated that cetuximab-resistant cells overexpress HER family ligands including epidermal growth factor (EGF), amphiregulin (AR), heparin-binding EGF (HB-EGF) and β-cellulin. Overexpression of these ligands is associated with the nuclear translocation of the EGFR and this process was mediated by the Src family kinases (SFK). Treatment of cetuximab-resistant cells with the SFK inhibitor, dasatinib, resulted in loss of nuclear EGFR, increased membrane expression of the EGFR and re-sensitization to cetuximab. In addition, expression of a nuclear localization sequence tagged EGFR in cetuximab-sensitive cells increased resistance to cetuximab both in vitro and in mouse xenografts. Collectively, these data suggest that nuclear expression of EGFR may be an important molecular determinant of resistance to cetuximab therapy and provides a rationale for investigating nuclear EGFR as a biomarker for cetuximab response. Further, these data suggest a rationale for the design of clinical trials that examine the value of treating patients with cetuximab-resistant tumors with inhibitors of SFKs in combination with cetuximab. PMID:19684613

  1. Nuclear EGFR contributes to acquired resistance to cetuximab.

    PubMed

    Li, C; Iida, M; Dunn, E F; Ghia, A J; Wheeler, D L

    2009-10-29

    Epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase involved in the etiology of several human cancers. Cetuximab is an EGFR-blocking antibody that has been approved for the treatment of patients with head and neck squamous cell carcinoma and metastatic colorectal cancer. Previous reports have shown that EGFR translocation to the nucleus is associated with cell proliferation. Here we investigated mechanisms of acquired resistance to cetuximab using a model derived from the non-small cell lung cancer line H226. We demonstrated that cetuximab-resistant cells overexpress HER family ligands including epidermal growth factor (EGF), amphiregulin, heparin-binding EGF and beta-cellulin. Overexpression of these ligands is associated with the nuclear translocation of the EGFR and this process was mediated by the Src family kinases (SFK). Treatment of cetuximab-resistant cells with the SFK inhibitor, dasatinib, resulted in loss of nuclear EGFR, increased membrane expression of the EGFR and resensitization to cetuximab. In addition, expression of a nuclear localization sequence-tagged EGFR in cetuximab-sensitive cells increased resistance to cetuximab both in vitro and in mouse xenografts. Collectively, these data suggest that nuclear expression of EGFR may be an important molecular determinant of resistance to cetuximab therapy and provides a rationale for investigating nuclear EGFR as a biomarker for cetuximab response. Further, these data suggest a rationale for the design of clinical trials that examine the value of treating patients with cetuximab-resistant tumors with inhibitors of SFKs in combination with cetuximab. PMID:19684613

  2. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.

    PubMed

    Tan, Li; Wang, Jun; Tanizaki, Junko; Huang, Zhifeng; Aref, Amir R; Rusan, Maria; Zhu, Su-Jie; Zhang, Yiyun; Ercan, Dalia; Liao, Rachel G; Capelletti, Marzia; Zhou, Wenjun; Hur, Wooyoung; Kim, NamDoo; Sim, Taebo; Gaudet, Suzanne; Barbie, David A; Yeh, Jing-Ruey Joanna; Yun, Cai-Hong; Hammerman, Peter S; Mohammadi, Moosa; Jänne, Pasi A; Gray, Nathanael S

    2014-11-11

    The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket. PMID:25349422

  3. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

    PubMed Central

    Tan, Li; Wang, Jun; Tanizaki, Junko; Huang, Zhifeng; Aref, Amir R.; Rusan, Maria; Zhu, Su-Jie; Zhang, Yiyun; Ercan, Dalia; Liao, Rachel G.; Capelletti, Marzia; Zhou, Wenjun; Hur, Wooyoung; Kim, NamDoo; Sim, Taebo; Gaudet, Suzanne; Barbie, David A.; Yeh, Jing-Ruey Joanna; Yun, Cai-Hong; Hammerman, Peter S.; Mohammadi, Moosa; Jänne, Pasi A.; Gray, Nathanael S.

    2014-01-01

    The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a “DFG-out” covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket. PMID:25349422

  4. Placement of C1 Pedicle Screws Using Minimal Exposure: Radiographic, Clinical, and Literature Validation

    PubMed Central

    Storey, Christopher M.; Nixon, Menarvia K.C.; Haydel, Justin; Nanda, Anil; Sin, Anthony

    2015-01-01

    Background Traditional C1-2 fixation involves placement of C1 lateral mass screws. Evolving techniques have led to the placement of C1 pedicle screws to avoid exposure of the C1-C2 joint capsule. Our minimal dissection technique utilizes anatomical landmarks with isolated exposure of C2 and the inferior posterior arch of C1. We evaluate this procedure clinically and radiographically through a technical report. Methods Consecutive cases of cranial-vertebral junction surgery were reviewed for one fellowship trained spinal surgeon from 2008-2014. Information regarding sex, age, indication for surgery, private or public hospital, intra-operative complications, post-operative neurological deterioration, death, and failure of fusion was extracted. Measurement of pre-operative axial and sagittal CT scans were performed for C1 pedicle width and C1 posterior arch height respectively. Results 64 patients underwent posterior cranio-vertebral junction fixation surgery. 40 of these patients underwent occipital-cervical fusion procedures. 7/9 (77.8%) C1 instrumentation cases were from trauma with the remaining two (22.2%) from oncologic lesions. The average blood loss among isolated C1-C2 fixation was 160cc. 1/9 patients (11.1%) suffered pedicle breech requiring sub-laminar wiring at the C1 level. On radiographic measurement, the average height of the C1 posterior arch was noted at 4.3mm (range 3.8mm to 5.7mm). The average width of the C1 pedicle measured at 5.3mm (range 2.8 to 8.7mm). The patient with C1 pedicle screw failure had a pedicle width of 2.78mm on pre-operative axial CT imaging. Conclusion Our study directly adds to the literature with level four evidence supporting a minimal dissection of C1 arch in the placement of C1 pedicle screws with both radiographic and clinical validation. Clinical Relevance Justification of this technique avoids C2 nerve root manipulation or sacrifice, reduces bleeding associated with the venous plexus, and leaves the third segment of the

  5. Mutations in the membrane anchor of yeast cytochrome c1 compensate for the absence of Oxa1p and generate carbonate-extractable forms of cytochrome c1.

    PubMed Central

    Hamel, P; Lemaire, C; Bonnefoy, N; Brivet-Chevillotte, P; Dujardin, G

    1998-01-01

    Oxa1p is a mitochondrial inner membrane protein that is mainly required for the insertion/assembly of complex IV and ATP synthase and is functionally conserved in yeasts, humans, and plants. We have isolated several independent suppressors that compensate for the absence of Oxa1p. Molecular cloning and sequencing reveal that the suppressor mutations (CYT1-1 to -6) correspond to amino acid substitutions that are all located in the membrane anchor of cytochrome c1 and decrease the hydrophobicity of this anchor. Cytochrome c1 is a catalytic subunit of complex III, but the CYT1-1 mutation does not seem to affect the electron transfer activity. The double-mutant cyt1-1,164, which has a drastically reduced electron transfer activity, still retains the suppressor activity. Altogether, these results suggest that the suppressor function of cytochrome c1 is independent of its electron transfer activity. In addition to the membrane-bound cytochrome c1, carbonate-extractable forms accumulate in all the suppressor strains. We propose that these carbonate-extractable forms of cytochrome c1 are responsible for the suppressor function by preventing the degradation of the respiratory complex subunits that occur in the absence of Oxa1p. PMID:9755193

  6. Current treatment options of acquired flatfoot.

    PubMed

    Lesić, Aleksandar R; Atkinson, Henry Dushan E; Zagorac, Slavisa G; Bumbasirević, Marko

    2013-01-01

    Symptomatic acquired flatfoot is an important orthopaedic problem, due to progressive loss of whole foot function and the increasing problem of patient disability. It is a complex entity, involving the tibialis posterior tendon, ankle joint, hindfoot and midfoot. In most cases the posterior tibial tendon (PTT) is the root cause of acquired flat foot, but there are other contributors and many different factors have an influence. The clinical picture varies depending on the stage of the deformity, as well as the treatment approach. Initially soft tissue procedures, synoviectomy and augmentation of the PTT are advised. In stage 2, lateral column lengthening and calcaneal osteotomy, with soft tissue - tendon transfers (TA, FHL, FDL) are recommended. In stage 3 subtalar, double or triplearthodesis is preferable, while in stage 4 pantalar fusion is indicated. This article elaborates on the etiology, the clinical picture, diagnosis and treatment modalities. PMID:24669559

  7. Acquired Cystic Fibrosis Transmembrane Conductance Regulator Deficiency.

    PubMed

    Cho, Do-Yeon; Woodworth, Bradford A

    2016-01-01

    In the genetic airway disease cystic fibrosis (CF), deficiency or dysfunction of the cystic fibrosis membrane conductance regulator (CFTR) alters anion transport in respiratory epithelium and consequently disrupts mucociliary clearance. An enriched understanding of the role of CFTR in the maintenance of normal epithelial function has revealed that mild and variable CFTR mutations play a causative role in a number of diseases not classically associated with CF. Furthermore, recent evidence indicates that acquired defects in wild-type CFTR protein processing, endocytic recycling and function can contribute to the pathogenesis of airway diseases, such as chronic obstructive pulmonary disease. In this chapter, we discuss emerging findings implicating acquired CFTR dysfunction in the pathogenesis of chronic rhinosinusitis and propose a new and leading edge approach to future CRS therapy using CFTR potentiators. PMID:27466849

  8. Novel corrosion inhibitor technology

    SciTech Connect

    Van de Ven, P.; Fritz, P.; Pellet, R.

    1999-11-01

    A novel, patented corrosion inhibitor technology has been identified for use in heat transfer applications such as automotive and heavy-duty coolant. The new technology is based on a low-toxic, virtually depletion-free carboxylic acid corrosion inhibitor package that performs equally well in mono ethylene glycol and in less toxic propylene glycol coolants. An aqueous inhibitor concentrate is available to provide corrosion protection where freezing protection is not an issue. In the present paper, this inhibitor package is evaluated in the different base fluids: mono ethylene glycol, mono propylene glycol and water. Results are obtained in both standardized and specific corrosion tests as well as in selected field trials. These results indicate that the inhibitor package remains effective and retains the benefits previously identified in automotive engine coolant applications: excellent corrosion protection under localized conditions, general corrosion conditions as well as at high temperature.

  9. Earth Knowledge Acquired by Middle School Students

    NASA Technical Reports Server (NTRS)

    Ride, Sally

    2008-01-01

    Earth Knowledge Acquired by Middle School Students (EarthKAM), an education activity, allows middle school students to program a digital camera on board the International Space Station to photograph a variety of geographical targets for study in the classroom. Photos are made available on the web for viewing and study by participating schools around the world. Educators use the images for projects involving Earth Science, geography, physics, and social science.

  10. Intrinsic and acquired resistance mechanisms in enterococcus

    PubMed Central

    Hollenbeck, Brian L.; Rice, Louis B.

    2012-01-01

    Enterococci have the potential for resistance to virtually all clinically useful antibiotics. Their emergence as important nosocomial pathogens has coincided with increased expression of antimicrobial resistance by members of the genus. The mechanisms underlying antibiotic resistance in enterococci may be intrinsic to the species or acquired through mutation of intrinsic genes or horizontal exchange of genetic material encoding resistance determinants. This paper reviews the antibiotic resistance mechanisms in Enterococcus faecium and Enterococcus faecalis and discusses treatment options. PMID:23076243

  11. [Pharmacogenetics of community-acquired pneumonia].

    PubMed

    Suleĭmanov, S Sh; Molchanova, O V; Kirpichnikova, N V; Sukhotina, N V; Gorbach, A A

    2010-01-01

    The rate of acetylation of xenobiotics affects the course and prognosis of infectious diseases. The efficacy of antibiotic therapy of community-acquired pneumonia in RA-patients is lower than that in LA-ones. In order to ensure the best antimicrobial effect on the onset of the disease it is required to use regimens with the maximum permissible dose of antibacterial drugs in the regions where the rapid type prevails. PMID:21400754

  12. Domestically acquired fascioliasis in northern California.

    PubMed

    Weisenberg, Scott A; Perlada, David E

    2013-09-01

    Two cases of domestically acquired fascioliasis are reported. Patient One was a 63-year-old male who developed a febrile illness 2 months after eating watercress in Marin County. Patient Two was a 38-year-old male who had eaten watercress with Patient One, and also developed a febrile illness. Both patients had eosinophilia and liver lesions on imaging. Diagnosis was made by serology and treatment was with triclabendazole. PMID:23836562

  13. Domestically Acquired Fascioliasis in Northern California

    PubMed Central

    Weisenberg, Scott A.; Perlada, David E.

    2013-01-01

    Two cases of domestically acquired fascioliasis are reported. Patient One was a 63-year-old male who developed a febrile illness 2 months after eating watercress in Marin County. Patient Two was a 38-year-old male who had eaten watercress with Patient One, and also developed a febrile illness. Both patients had eosinophilia and liver lesions on imaging. Diagnosis was made by serology and treatment was with triclabendazole. PMID:23836562

  14. Acquired protein energy malnutrition in glutaric acidemia.

    PubMed

    Ma, Liqiao; Savory, Stephanie; Agim, Nnenna G

    2013-01-01

    We report a case of acquired protein energy malnutrition with associated zinc deficiency in an 18-month-old boy with type 1 glutaric acidemia. Physical examination findings included generalized nonpitting edema, widespread desquamative plaques, and sparse hair with a reddish tinge. Laboratory abnormalities included low levels of zinc, albumin, alkaline phosphatase, and iron. A review of skin manifestations of nutritional deficiencies, specifically kwashiorkor, is presented, as well as the relatively new entity called acrodermatitis dysmetabolica. PMID:23330977

  15. Acquired Antibiotic Resistance Genes: An Overview

    PubMed Central

    van Hoek, Angela H. A. M.; Mevius, Dik; Guerra, Beatriz; Mullany, Peter; Roberts, Adam Paul; Aarts, Henk J. M.

    2011-01-01

    In this review an overview is given on antibiotic resistance (AR) mechanisms with special attentions to the AR genes described so far preceded by a short introduction on the discovery and mode of action of the different classes of antibiotics. As this review is only dealing with acquired resistance, attention is also paid to mobile genetic elements such as plasmids, transposons, and integrons, which are associated with AR genes, and involved in the dispersal of antimicrobial determinants between different bacteria. PMID:22046172

  16. System Acquires Data On Reactivities Of Foams

    NASA Technical Reports Server (NTRS)

    Walls, Joe T.

    1994-01-01

    Data-acquisition and -plotting system, called DAPS(TM), developed enabling accurate and objective determination of physical properties related to reactivities of polyurethane and polyisocyanurate foams. Automated, computer-controlled test apparatus that acquires data on rates of rise, rise profiles, exothermic temperatures, and internal pressures of foams prepared from both manual and machine-mixed batches. Data used to determine minute differences between reaction kinetics and exothermic profiles of foam formulations, properties of end products which are statistically undifferentiated.

  17. Acquired resistance to immunotherapy and future challenges.

    PubMed

    Restifo, Nicholas P; Smyth, Mark J; Snyder, Alexandra

    2016-02-01

    Advances in immunotherapy have resulted in remarkable clinical responses in some patients. However, one of the biggest challenges in cancer therapeutics is the development of resistant disease and disease progression on or after therapy. Given that many patients have now received various types of immunotherapy, we asked three scientists to give their views on the current evidence for whether acquired resistance to immunotherapy exists in patients and the future challenges posed by immunotherapy. PMID:26822578

  18. Functional C1q is present in the skin mucus of Siberian sturgeon (Acipenser baerii).

    PubMed

    Fan, Chunxin; Wang, Jian; Zhang, Xuguang; Song, Jiakun

    2015-01-01

    The skin mucus of fish acts as the first line of self-protection against pathogens in the aquatic environment and comprises a number of innate immune components. However, the presence of the critical classical complement component C1q, which links the innate and adaptive immune systems of mammalians, has not been explored in a primitive actinopterygian fish. In this study, we report that C1q is present in the skin mucus of the Siberian sturgeon (Acipenser baerii). The skin mucus was able to inhibit the growth of Escherichia coli. The bacteriostatic activity of the skin mucus was reduced by heating and by pre-incubation with EDTA or mouse anti-human C1q antibody. We also detected C1q protein in skin mucus using the western blot procedure and isolated a cDNA that encodes the Siberian sturgeon C1qC, which had 44.7-51.4% identity with C1qCs in teleosts and tetrapods. A phylogenetic analysis revealed that Siberian sturgeon C1qC lies at the root of the actinopterygian branch and is separate from the tetrapod branch. The C1qC transcript was expressed in many tissues as well as in skin. Our data indicate that C1q is present in the skin mucus of the Siberian sturgeon to protect against water-borne bacteria, and the C1qC found in the sturgeon may represent the primitive form of teleost and tetrapod C1qCs. PMID:24920077

  19. Receptor-mediated binding of C1 q on pulmonary endothelial cells

    SciTech Connect

    Zhang, S.C.; Schultz, D.; Ryan, U.

    1986-03-01

    Normal undamaged pulmonary endothelial cells (EC) do not express receptors for C3b or the Fc portion of IgG, but both receptors become unmasked after viral infection or exposure to white cell lysates. Here, highly purified human C1q was labeled with /sup 125/I, and the globular subunits were separated from the collagenous portion by collagenase digestion and chromatography. Bovine pulmonary artery EC were cultured without exposure to proteolytic enzymes. Binding assays were carried out at 0/sup 0/C, pH 7.4, ..mu.. = 0.15. Results showed that /sup 125/I-C1q binds to EC, the binding is dose-dependent, and the receptor is saturable. Saturation was approached at a C1q concentration of ca 0.1 ug. By Scatchard analysis, maximum binding was 0.219 pmoles in a volume of 250 ..mu..l for 7 x 10/sup 5/ cells, and the average number of binding sites per cell was 1.88 x 10/sup 5/. Isolated /sup 125/I-C1q heads do not bind, and when native /sup 125/I-C1q was bound to EC radioactivity was eliminated after collagenase treatment for 4 h at 37/sup 0/C. Thus, C1q binds to EC via the collagenous portion. That Fc receptors (globular heads) are exposed was shown by rosette formation with EA and EC bound C1q. Using similar conditions, native C1(C1w x 2C1r x 2C1s) did not bind to EC. These results suggest a mechanism for localizing immune complexes on undamaged pulmonary vessels which may be important for initiation of the inflammatory response.

  20. Spinolaminar Line Test as a Screening Tool for C1 Stenosis.

    PubMed

    Oshima, Yasushi; Kelly, Michael P; Song, Kwang-Sup; Park, Moon Soo; Chuntarapas, Tapanut; Vo, Katie D; Yeom, Jin S; Takeshita, Katsushi; Riew, K Daniel

    2016-06-01

    Study Design Retrospective cohort. Objective To clarify the sensitivity of C3-C2 spinolaminar line test as a screening tool for the stenosis of C1 space available for the cord (SAC). Methods Spine clinic records from April 2005 to August 2011 were reviewed. The C1 SAC was measured on lateral radiographs, and the relative positions between a C1 posterior arch and the C3-C2 spinolaminar line were examined and considered "positive" when the C1 ring lay ventral to the line. Computed tomography (CT) scans and magnetic resonance imaging (MRI) were utilized to measure precise diameters of C1 and C2 SAC and to check the existence of spinal cord compression. Results Four hundred eighty-seven patients were included in this study. There were 246 men and 241 women, with an average age of 53 years (range: 18 to 86). The mean SAC at C1 on radiographs was 21.2 mm (range: 13.5 to 28.2). Twenty-one patients (4.3%) were positive for the spinolaminar line test; all of these patients had C1 SAC of 19.4 mm or less. Eight patients (1.6%) had C1 SAC smaller than C2 on CT examination; all of these patients had a positive spinolaminar test, with high sensitivity (100%) and specificity (97%). MRI analysis revealed that two of the eight patients with a smaller C1 SAC had spinal cord compression at the C1 level. Conclusion Although spinal cord compression at the level of atlas without instability is a rare condition, the spinolaminar line can be used as a screening of C1 stenosis. PMID:27190740

  1. Spinolaminar Line Test as a Screening Tool for C1 Stenosis

    PubMed Central

    Oshima, Yasushi; Kelly, Michael P.; Song, Kwang-Sup; Park, Moon Soo; Chuntarapas, Tapanut; Vo, Katie D.; Yeom, Jin S.; Takeshita, Katsushi; Riew, K. Daniel

    2015-01-01

    Study Design Retrospective cohort. Objective To clarify the sensitivity of C3–C2 spinolaminar line test as a screening tool for the stenosis of C1 space available for the cord (SAC). Methods Spine clinic records from April 2005 to August 2011 were reviewed. The C1 SAC was measured on lateral radiographs, and the relative positions between a C1 posterior arch and the C3–C2 spinolaminar line were examined and considered “positive” when the C1 ring lay ventral to the line. Computed tomography (CT) scans and magnetic resonance imaging (MRI) were utilized to measure precise diameters of C1 and C2 SAC and to check the existence of spinal cord compression. Results Four hundred eighty-seven patients were included in this study. There were 246 men and 241 women, with an average age of 53 years (range: 18 to 86). The mean SAC at C1 on radiographs was 21.2 mm (range: 13.5 to 28.2). Twenty-one patients (4.3%) were positive for the spinolaminar line test; all of these patients had C1 SAC of 19.4 mm or less. Eight patients (1.6%) had C1 SAC smaller than C2 on CT examination; all of these patients had a positive spinolaminar test, with high sensitivity (100%) and specificity (97%). MRI analysis revealed that two of the eight patients with a smaller C1 SAC had spinal cord compression at the C1 level. Conclusion Although spinal cord compression at the level of atlas without instability is a rare condition, the spinolaminar line can be used as a screening of C1 stenosis. PMID:27190740

  2. The C1q Family of Proteins: Insights into the Emerging Non-Traditional Functions

    PubMed Central

    Ghebrehiwet, Berhane; Hosszu, Kinga K.; Valentino, Alisa; Peerschke, Ellinor I. B.

    2012-01-01

    Research conducted over the past 20 years have helped us unravel not only the hidden structural and functional subtleties of human C1q, but also has catapulted the molecule from a mere recognition unit of the classical pathway to a well-recognized molecular sensor of damage-modified self or non-self antigens. Thus, C1q is involved in a rapidly expanding list of pathological disorders – including autoimmunity, trophoblast migration, preeclampsia, and cancer. The results of two recent reports are provided to underscore the critical role C1q plays in health and disease. First is the observation by Singh et al. (2011) showing that pregnant C1q−/− mice recapitulate the key features of human preeclampsia that correlate with increased fetal death. Treatment of the C1q−/− mice with pravastatin restored trophoblast invasiveness, placental blood flow, and angiogenic balance and, thus, prevented the onset of preeclampsia. Second is the report by Hong et al. (2009) which showed that C1q can induce apoptosis of prostate cancer cells by activating the tumor suppressor molecule WW-domain containing oxydoreductase (WWOX or WOX1) and destabilizing cell adhesion. Downregulation of C1q on the other hand, enhanced prostate hyperplasia and cancer formation due to failure of WOX1 activation. C1q belongs to a family of structurally and functionally related TNF-α-like family of proteins that may have arisen from a common ancestral gene. Therefore C1q not only shares the diverse functions with the tumor necrosis factor family of proteins, but also explains why C1q has retained some of its ancestral “cytokine-like” activities. This review is intended to highlight some of the structural and functional aspects of C1q by underscoring the growing list of its non-traditional functions. PMID:22536204

  3. Resistant mechanisms to BRAF inhibitors in melanoma.

    PubMed

    Manzano, José Luís; Layos, Laura; Bugés, Cristina; de Los Llanos Gil, María; Vila, Laia; Martínez-Balibrea, Eva; Martínez-Cardús, Anna

    2016-06-01

    Patients with advanced melanoma have traditionally had very poor prognosis. However, since 2011 better understanding of the biology and epidemiology of this disease has revolutionized its treatment, with newer therapies becoming available. These newer therapies can be classified into immunotherapy and targeted therapy. The immunotherapy arsenal includes inhibitors of CTLA4, PD-1 and PDL-1, while targeted therapy focuses on BRAF and MEK. BRAF inhibitors (vemurafenib, dabrafenib) have shown benefit in terms of overall survival (OS) compared to chemotherapy, and their combination with MEK inhibitors has recently been shown to improve progression-free survival (PFS), compared with monotherapy with BRAF inhibitors. However, almost 20% of patients initially do not respond, due to intrinsic resistance to therapy and, of those who do, most eventually develop mechanisms of acquired resistance, including reactivation of the MAP kinase pathway, persistent activation of receptor tyrosine kinase (RTKS) receptor, activation of phosphatidyinositol-3OH kinase, overexpression of epidermal growth factor receptor (EGFR), and interactions with the tumor microenvironment. Herein we comment in detail on mechanisms of resistance to targeted therapy and discuss the strategies to overcome them. PMID:27429963

  4. Resistant mechanisms to BRAF inhibitors in melanoma

    PubMed Central

    Layos, Laura; Bugés, Cristina; de los Llanos Gil, María; Vila, Laia; Martínez-Balibrea, Eva; Martínez-Cardús, Anna

    2016-01-01

    Patients with advanced melanoma have traditionally had very poor prognosis. However, since 2011 better understanding of the biology and epidemiology of this disease has revolutionized its treatment, with newer therapies becoming available. These newer therapies can be classified into immunotherapy and targeted therapy. The immunotherapy arsenal includes inhibitors of CTLA4, PD-1 and PDL-1, while targeted therapy focuses on BRAF and MEK. BRAF inhibitors (vemurafenib, dabrafenib) have shown benefit in terms of overall survival (OS) compared to chemotherapy, and their combination with MEK inhibitors has recently been shown to improve progression-free survival (PFS), compared with monotherapy with BRAF inhibitors. However, almost 20% of patients initially do not respond, due to intrinsic resistance to therapy and, of those who do, most eventually develop mechanisms of acquired resistance, including reactivation of the MAP kinase pathway, persistent activation of receptor tyrosine kinase (RTKS) receptor, activation of phosphatidyinositol-3OH kinase, overexpression of epidermal growth factor receptor (EGFR), and interactions with the tumor microenvironment. Herein we comment in detail on mechanisms of resistance to targeted therapy and discuss the strategies to overcome them. PMID:27429963

  5. [Diagnosis and treatment of hemophilia A acquired during postpartum ].

    PubMed

    Castillo-Cañadas, Ana María; Serrano-Diana, Carolina; López-Del Cerro, Esther; Gómez-García, María Teresa; González De Merlo, Gaspar

    2014-10-01

    Acquired hemophilia A is a truly exceptional hemorrhagic diathesis, that consists of the emergence of polyclonal autoantibodies (inhibitor) IgG-type (subclasses 1 and 4, in most cases) against the coagulant function of the circulating factor VIII, which acts in the domains C2, A2 and A3 of the molecule, thus interfering their interaction with the factor IXa, the phospholipids and the Von Willebrand factor. Its morbidity and mortality are high, but nevertheless its low incidence (1-1.5 cases per million population per year) is the most frequent autoimmune disorder. This paper reports the clinical case of two patients; the first one, 36 years old, who the tenth day of postpartum required re-entry due to a diagnosis of hematoma of the abdominal wall that was surgically drained twice. The patient of case 2 was 39 years old and at six days of postpartum went to the emergency room due to bleeding, she was underwent to curettage and therapeutic transfusion of 3 UCH. Because of the persistence of bleeding, which was not possible to control with medical treatment and conservative measures, therapeutic hysterectomy was performed, with blood transfusion later. Due to the hemorrhagic complications of this condition and the serious clinical consequences derived from them, it is important to establish an early diagnosis; it is therefore critical to know the existence of this very rare disease to be able to avoid its consequences. PMID:25510060

  6. Atypical pathogens and challenges in community-acquired pneumonia.

    PubMed

    Thibodeau, Kristopher P; Viera, Anthony J

    2004-04-01

    Atypical organisms such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila are implicated in up to 40 percent of cases of community-acquired pneumonia. Antibiotic treatment is empiric and includes coverage for both typical and atypical organisms. Doxycycline, a fluoroquinolone with enhanced activity against Streptococcus pneumoniae, or a macrolide is appropriate for outpatient treatment of immunocompetent adult patients. Hospitalized adults should be treated with cefotaxime or ceftriaxone plus a macrolide, or with a fluoroquinolone alone. The same agents can be used in adult patients in intensive care units, although fluoroquinolone monotherapy is not recommended; ampicillin-sulbactam or piperacillin-tazobactam can be used instead of cefotaxime or ceftriaxone. Outpatient treatment of children two months to five years of age consists of high-dose amoxicillin given for seven to 10 days. A single dose of ceftriaxone can be used in infants when the first dose of antibiotic is likely to be delayed or not absorbed. Older children can be treated with a macrolide. Hospitalized children should be treated with a macrolide plus a beta-lactam inhibitor. In a bioterrorist attack, pulmonary illness may result from the organisms that cause anthrax, plague, or tularemia. Sudden acute respiratory syndrome begins with a flu-like illness, followed two to seven days later by cough, dyspnea and, in some instances, acute respiratory distress. PMID:15086042

  7. Transsynaptic Modulation of Kainate Receptor Functions by C1q-like Proteins.

    PubMed

    Matsuda, Keiko; Budisantoso, Timotheus; Mitakidis, Nikolaos; Sugaya, Yuki; Miura, Eriko; Kakegawa, Wataru; Yamasaki, Miwako; Konno, Kohtarou; Uchigashima, Motokazu; Abe, Manabu; Watanabe, Izumi; Kano, Masanobu; Watanabe, Masahiko; Sakimura, Kenji; Aricescu, A Radu; Yuzaki, Michisuke

    2016-05-18

    Postsynaptic kainate-type glutamate receptors (KARs) regulate synaptic network activity through their slow channel kinetics, most prominently at mossy fiber (MF)-CA3 synapses in the hippocampus. Nevertheless, how KARs cluster and function at these synapses has been unclear. Here, we show that C1q-like proteins C1ql2 and C1ql3, produced by MFs, serve as extracellular organizers to recruit functional postsynaptic KAR complexes to the CA3 pyramidal neurons. C1ql2 and C1ql3 specifically bound the amino-terminal domains of postsynaptic GluK2 and GluK4 KAR subunits and the presynaptic neurexin 3 containing a specific sequence in vitro. In C1ql2/3 double-null mice, CA3 synaptic responses lost the slow, KAR-mediated components. Furthermore, despite induction of MF sprouting in a temporal lobe epilepsy model, KARs were not recruited to postsynaptic sites in C1ql2/3 double-null mice, leading to reduced recurrent circuit activities. C1q family proteins, broadly expressed, are likely to modulate KAR function throughout the brain and represent promising antiepileptic targets. PMID:27133466

  8. 29 CFR Appendix B to Subpart C of... - Figures C-1 through C-16

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false Figures C-1 through C-16 B Appendix B to Subpart C of Part 1928 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... Structures Pt. 1928, Subpt. C, App. B Appendix B to Subpart C of Part 1928—Figures C-1 through C-16...

  9. 26 CFR 1.503(c)-1 - Future status of organizations denied exemption.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Future status of organizations denied exemption. 1.503(c)-1 Section 1.503(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY... notified the Commissioner that it is applying for recognition of its exempt status under section 508(a)...

  10. 26 CFR 1.475(c)-1 - Definitions-dealer in securities.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 6 2010-04-01 2010-04-01 false Definitions-dealer in securities. 1.475(c)-1 Section 1.475(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... a manner that allows recognition of unrealized gains or losses or deductions for additions to...

  11. 26 CFR 1.509(c)-1 - Status of organization after termination of private foundation status.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Status of organization after termination of private foundation status. 1.509(c)-1 Section 1.509(c)-1 Internal Revenue INTERNAL REVENUE SERVICE... recognition of section 501(c)(3) status pursuant to the provisions of section 508(a). (b) Effect upon...

  12. 26 CFR 1.641(c)-1 - Electing small business trust.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Electing small business trust. 1.641(c)-1... small business trust. (a) In general. An electing small business trust (ESBT) within the meaning of... meaning of section 642(c)(1). The limitations of section 681, regarding unrelated business income,...

  13. 26 CFR 25.2523(c)-1 - Interest in unidentified assets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 14 2012-04-01 2012-04-01 false Interest in unidentified assets. 25.2523(c)-1 Section 25.2523(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... from the trust and at the termination of the trust the trustee is to turn over to H's wife, W,...

  14. 26 CFR 1.267(c)-1 - Constructive ownership of stock.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 3 2010-04-01 2010-04-01 false Constructive ownership of stock. 1.267(c)-1 Section 1.267(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... the outstanding stock of the M Corporation. The M Corporation in turn owned 80 percent of...

  15. 26 CFR 1.267(c)-1 - Constructive ownership of stock.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 3 2014-04-01 2014-04-01 false Constructive ownership of stock. 1.267(c)-1 Section 1.267(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... 25 percent, of the outstanding stock of the M Corporation. The M Corporation in turn owned 80...

  16. 26 CFR 1.267(c)-1 - Constructive ownership of stock.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 3 2012-04-01 2012-04-01 false Constructive ownership of stock. 1.267(c)-1 Section 1.267(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... 25 percent, of the outstanding stock of the M Corporation. The M Corporation in turn owned 80...

  17. 26 CFR 1.267(c)-1 - Constructive ownership of stock.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 3 2011-04-01 2011-04-01 false Constructive ownership of stock. 1.267(c)-1 Section 1.267(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... 25 percent, of the outstanding stock of the M Corporation. The M Corporation in turn owned 80...

  18. 26 CFR 25.2523(c)-1 - Interest in unidentified assets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 14 2013-04-01 2013-04-01 false Interest in unidentified assets. 25.2523(c)-1 Section 25.2523(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... from the trust and at the termination of the trust the trustee is to turn over to H's wife, W,...

  19. 26 CFR 1.267(c)-1 - Constructive ownership of stock.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 3 2013-04-01 2013-04-01 false Constructive ownership of stock. 1.267(c)-1 Section 1.267(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... 25 percent, of the outstanding stock of the M Corporation. The M Corporation in turn owned 80...

  20. 26 CFR 25.2523(c)-1 - Interest in unidentified assets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 14 2014-04-01 2013-04-01 true Interest in unidentified assets. 25.2523(c)-1 Section 25.2523(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... from the trust and at the termination of the trust the trustee is to turn over to H's wife, W,...

  1. 17 CFR 240.24c-1 - Access to nonpublic information.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Access to nonpublic information. (a) For purposes of this section, the term “nonpublic information” means... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Access to nonpublic information. 240.24c-1 Section 240.24c-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE...

  2. Generalized van der Waals Hamiltonian: periodic orbits and C1 nonintegrability.

    PubMed

    Guirao, Juan L G; Llibre, Jaume; Vera, Juan A

    2012-03-01

    The aim of this paper is to study the periodic orbits of the generalized van der Waals Hamiltonian system. The tool for studying such periodic orbits is the averaging theory. Moreover, for this Hamiltonian system we provide information on its C(1) nonintegrability, i.e., on the existence of a second first integral of class C(1). PMID:22587198

  3. 26 CFR 31.3406(c)-1 - Notified payee underreporting of reportable interest or dividend payments.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 15 2012-04-01 2012-04-01 false Notified payee underreporting of reportable interest or dividend payments. 31.3406(c)-1 Section 31.3406(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX...

  4. 26 CFR 48.4216(c)-1 - Computation of tax on leases and installment sales.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Computation of tax on leases and installment sales. 48.4216(c)-1 Section 48.4216(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Special Provisions Applicable to Manufacturers Taxes §...

  5. 26 CFR 40.6302(c)-1 - Use of Government depositaries.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Section 40.6302(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES EXCISE TAX PROCEDURAL REGULATIONS § 40.6302(c)-1 Use of Government depositaries. (a... deposit of tax for each semimonthly period (as defined in § 40.0-1(c)) in which tax liability is...

  6. 26 CFR 31.3121(c)-1 - Included and excluded services.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Included and excluded services. 31.3121(c)-1 Section 31.3121(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX...

  7. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  8. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  9. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  10. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  11. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  12. 26 CFR 1.512(c)-1 - Special rules applicable to partnerships; in general.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Special rules applicable to partnerships; in general. 1.512(c)-1 Section 1.512(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of...

  13. 26 CFR 1.412(c)(1)-2 - Shortfall method.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Shortfall method. 1.412(c)(1)-2 Section 1.412(c... (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.412(c)(1)-2 Shortfall method. (a) In general—(1) Shortfall method. The shortfall method is a funding method that adapts a...

  14. 26 CFR 31.3306(c)(1)-1 - Agricultural labor.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Agricultural labor. 31.3306(c)(1)-1 Section 31.3306(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Federal Unemployment Tax Act (Chapter...

  15. 26 CFR 31.3306(c)(1)-1 - Agricultural labor.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Agricultural labor. 31.3306(c)(1)-1 Section 31.3306(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED... SOURCE Federal Unemployment Tax Act (Chapter 23, Internal Revenue Code of 1954) §...

  16. 26 CFR 1.641(c)-1 - Electing small business trust.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Electing small business trust. 1.641(c)-1...) INCOME TAX (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.641(c)-1 Electing small business trust. (a) In general. An electing small business trust (ESBT) within the meaning of section...

  17. 26 CFR 1.641(c)-1 - Electing small business trust.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Electing small business trust. 1.641(c)-1... small business trust. (a) In general. An electing small business trust (ESBT) within the meaning of... meaning of section 642(c)(1). The limitations of section 681, regarding unrelated business income,...

  18. Characterization of a human colorectal carcinoma cell line with acquired resistance to flavopiridol.

    PubMed

    Smith, V; Raynaud, F; Workman, P; Kelland, L R

    2001-11-01

    Flavopiridol is a broad-spectrum inhibitor of cyclin-dependent kinases (cdks) and represents the first in this anticancer class to enter clinical trials. In anticipation of the likelihood that, as with other cancer drugs, acquired resistance may limit the drug's efficacy, an acquired resistance model has been established by in vitro drug exposure of the human colon carcinoma cell line HCT116. This stably resistant line, possessing 8-fold resistance to flavopiridol, showed a lack of cross-resistance to the anticancer agents etoposide, doxorubicin, paclitaxel, topotecan, and cisplatin, and notably to other chemical classes of cdk inhibitors: the aminopurines roscovitine and purvalanol A, 9-nitropaullone, and hymenialdisine. Resistance did not seem to be related to differences in the levels of multidrug resistance drug efflux proteins, P-glycoprotein, and MRP1. Moreover, there were no changes in overall drug accumulation between the resistant and sensitive cell lines. Flavopiridol induced cell cycle arrest, apoptosis, and inhibition of retinoblastoma gene product phosphorylation on serine 780 in both parental and resistant lines, but the latter required 8-fold higher concentrations to achieve these effects. Cyclin E protein levels and cyclin E-associated kinase activity were increased in the resistant line, suggesting that overexpression of cyclin E may be the mechanism of resistance to flavopiridol. However, transfection of cyclin E to increase expression of this protein did not result in an increase in resistance to flavopiridol. Thus, up-regulation of cyclin E alone does not seem to cause resistance to this cdk inhibitor. PMID:11641415

  19. Screening of telomerase inhibitors.

    PubMed

    Kleideiter, Elke; Piotrowska, Kamilla; Klotz, Ulrich

    2007-01-01

    Shortening of telomeres prevents cells from uncontrolled proliferation. Progressive telomere shortening occurs at each cell division until a critical telomeric length is reached. Telomerase expression is switched off after embryonic differentiation in most normal cells, but it is expressed in a very high percentage of tumors of different origin. Thus, telomerase is regarded as the best tumor marker and a promising novel molecular target for cancer treatment. Therefore, different strategies to inhibit telomerase have been developed. However, systematic screening of telomerase inhibitors has not been performed to compare their therapeutic potential. We propose a suitable strategy for estimation of the therapeutic potential of telomerase inhibitors, which is based on a systematic screening of different inhibitors in the same cell system. From the long list of compounds discussed in the literature, we have selected four telomerase inhibitors of different structure and mode of action: BRACO19 (G-quadruplex-interactive compound), BIBR1532 (non-nucleosidic reverse transcriptase inhibitor), 2'-O-methyl RNA, and peptide nucleic acids (PNAs; hTR antisense oligonucleotides). To determine minimal effective concentrations for telomerase inhibition, telomerase activity was measured using the cell-free telomerase repeat amplification protocol (TRAP) assay. We also tested inhibitors in long-term cell-culture experiments by exposing A-549 cells to non-cytotoxic concentrations of inhibitors for a period of 99 days. Subsequently, telomerase activity of A-549 cells was investigated using the TRAP assay, and telomere length of samples was assessed by telomere restriction fragment (TRF) Southern blot analysis. PMID:18369824

  20. Interaction between complement subcomponent C1q and the Klebsiella pneumoniae porin OmpK36.

    PubMed Central

    Albertí, S; Marqués, G; Hernández-Allés, S; Rubires, X; Tomás, J M; Vivanco, F; Benedí, V J

    1996-01-01

    The interaction between C1q, a subcomponent of the complement classical pathway component C1, and OmpK36, a porin protein from Klebsiella pneumoniae, was studied in a solid-phase direct-binding assay, inhibition assays with the purified globular and collagen-like regions of C1q, and cross-linking experiments. We have shown that the binding of C1q to the OmpK36 porin of the serum-sensitive strain K. pneumoniae KT707 occurs in an in vivo situation and that this binding leads to activation of the complement classical pathway and the subsequent deposition of complement components C3b and C5b-9 on the OmpK36 porin. Scatchard analysis of the binding of [125I]C1q to the OmpK36 porin showed two binding sites with dissociation constants of 1.5 and 75 nM. The decrease of [125I]C1q binding to the OmpK36 porin in buffer with increasing salt concentrations and the pIs of the C1q subcomponent (10.3) and OmpK36 porin (4.5) suggest that charged amino acids are involved in the binding phenomenon. In inhibition assays, only the globular regions of C1q inhibited the interaction between C1q and OmpK36 porin, demonstrating that C1q binds to porin through its globular region and not through the collagen-like stalks. PMID:8890231

  1. C1GALT1 enhances proliferation of hepatocellular carcinoma cells via modulating MET glycosylation and dimerization.

    PubMed

    Wu, Yao-Ming; Liu, Chiung-Hui; Huang, Miao-Juei; Lai, Hong-Shiee; Lee, Po-Huang; Hu, Rey-Heng; Huang, Min-Chuan

    2013-09-01

    Altered glycosylation is a hallmark of cancer. The core 1 β1,3-galactosyltransferase (C1GALT1) controls the formation of mucin-type O-glycans, far overlooked and underestimated in cancer. Here, we report that C1GALT1 mRNA and protein are frequently overexpressed in hepatocellular carcinoma tumors compared with nontumor liver tissues, where it correlates with advanced tumor stage, metastasis, and poor survival. Enforced expression of C1GALT1 was sufficient to enhance cell proliferation, whereas RNA interference-mediated silencing of C1GALT1 was sufficient to suppress cell proliferation in vitro and in vivo. Notably, C1GALT1 attenuation also suppressed hepatocyte growth factor (HGF)-mediated phosphorylation of the MET kinase in hepatocellular carcinoma cells, whereas enforced expression of C1GALT1 enhanced MET phosphorylation. MET blockade with PHA665752 inhibited C1GALT1-enhanced cell viability. In support of these results, we found that the expression level of phospho-MET and C1GALT1 were associated in primary hepatocellular carcinoma tissues. Mechanistic investigations showed that MET was decorated with O-glycans, as revealed by binding to Vicia villosa agglutinin and peanut agglutinin. Moreover, C1GALT1 modified the O-glycosylation of MET, enhancing its HGF-induced dimerization and activation. Together, our results indicate that C1GALT1 overexpression in hepatocellular carcinoma activates HGF signaling via modulation of MET O-glycosylation and dimerization, providing new insights into how O-glycosylation drives hepatocellular carcinoma pathogenesis. PMID:23832667

  2. Photoacoustic microscopy for quantitative evaluation of angiogenesis inhibitor

    NASA Astrophysics Data System (ADS)

    Chen, Sung-Liang; Burnett, Joseph; Sun, Duxin; Xie, Zhixing; Wang, Xueding

    2014-03-01

    We present the photoacoustic microscopy (PAM) for evaluation of angiogenesis inhibitors on a chick embryo model. Microvasculature in the chorioallantoic membrane (CAM) of the chick embryos was imaged by PAM, and the optical microscopy (OM) images of the same set of CAMs were also acquired for comparisons, serving for validation of the results from PAM. The angiogenesis inhibitors, Sunitinib, with different concentrations applied to the CAM result in the change in microvascular density, which was quantified by both PAM and OM imaging. Similar change in microvascular density from PAM and OM imaging in response to angiogenesis inhibitor at different doses was observed, demonstrating that PAM has potential to provide objective evaluation of anti-angiogenesis medication. Besides, PAM is advantageous in three-dimensional and functional imaging compared with OM so that the emerging PAM technique may offer unique information on the efficacy of angiogenesis inhibitors and could benefit applications related to antiangiogenesis treatments.

  3. Four C1q domain-containing proteins involved in the innate immune response in Hyriopsis cumingii.

    PubMed

    Zhao, Ling-Ling; Jin, Min; Li, Xin-Cang; Ren, Qian; Lan, Jiang-Feng

    2016-08-01

    C1q is a key subcomponent of the complement C1 complex. This subcomponent contains a globular C1q (gC1q) domain with remarkable ligand binding properties. C1q domain-containing (C1qDC) proteins are composed of all proteins with a gC1q domain. C1qDC proteins exist in many invertebrates and recognize non-self-ligands. In our study, four C1qDC genes, namely, HcC1qDC1-HcC1qDC4, were identified from Hyriopsis cumingii. HcC1qDC1-HcC1qDC4 encode a protein of 224, 204, 305, and 332 amino acids, respectively. All C1qDC proteins consist of a gC1q domain at the C terminal. In addition to the gC1q domain, a coiled-coil region is found in HcC1qDC4. Multiple alignments and phylogenetic tree analysis revealed that the C1qDC proteins highly differ from one another. Tissue distribution analysis demonstrated that HcC1qDC1-HcC1qDC4 are widely distributed in hemocytes, hepatopancreas, gills, mantle, and foot. These C1qDC genes are regulated by bacteria to varying degrees. These recombinant HcC1qDC proteins exhibit a binding activity against different bacterial species. Our results may suggest the roles of HcC1qDC genes in anti-bacterial immune defense. PMID:27288256

  4. Separation and conductimetric detection of C1-C7 aliphatic monocarboxylic acids and C1-C7 aliphatic monoamines on unfunctionized polymethacrylate resin columns.

    PubMed

    Ohta, Kazutoku; Towata, Atsuya; Ohashi, Masayoshi; Takeuchi, Toyohide

    2004-06-11

    The application of unfunctionized polymethacrylate resin (TSKgel G3000PWXL) as a stationary phase in liquid chromatography with conductimetric detection for C1-C7 aliphatic monocarboxylic acids (formic acid, acetic acid, propionic acid, butyric acid, isovaleric acid, valeric acid, 3,3-dimethylbutyric acid, 4-methylvaleric acid, hexanoic acid, 2-methylhexanoic acid, 5-methylhexanoic acid and heptanoic acid) and C1-C7 aliphatic monoamines (methylamine, ethylamine, propylamine, isobutylamine, butylamine, isoamylamine, amylamine, 1,3-dimethylbutylamine, hexylamine, 2-heptylamine and heptylamine) was attempted with C8 aliphatic monocarboxylic acids (2-propylvaleric acid, 2-ethylhexanoic acid, 2-methylheptanoic acid and octanoic acid) and C8 aliphatic monoamines (1,5-dimethylhexylamine, 2-ethylhexylamine, 1-methylheptylamine and octylamine) as eluents, respectively. Using 1 mM 2-methylheptanoic acid at pH 4.0 as the eluent, excellent separation and relatively high sensitive detection for these C1-C7 carboxylic acids were achieved on a TSKgel G3000PWXL column (150 mm x 6 mm i.d.) in 60 min. Using 2 mM octylamine at pH 11.0 as the eluent, excellent separation and relatively high sensitive detection for these C1-C7 amines were also achieved on the TSKgel G3000PWXL column in 60 min. PMID:15250420

  5. Acquired prosopagnosia without word recognition deficits.

    PubMed

    Susilo, Tirta; Wright, Victoria; Tree, Jeremy J; Duchaine, Bradley

    2015-01-01

    It has long been suggested that face recognition relies on specialized mechanisms that are not involved in visual recognition of other object categories, including those that require expert, fine-grained discrimination at the exemplar level such as written words. But according to the recently proposed many-to-many theory of object recognition (MTMT), visual recognition of faces and words are carried out by common mechanisms [Behrmann, M., & Plaut, D. C. ( 2013 ). Distributed circuits, not circumscribed centers, mediate visual recognition. Trends in Cognitive Sciences, 17, 210-219]. MTMT acknowledges that face and word recognition are lateralized, but posits that the mechanisms that predominantly carry out face recognition still contribute to word recognition and vice versa. MTMT makes a key prediction, namely that acquired prosopagnosics should exhibit some measure of word recognition deficits. We tested this prediction by assessing written word recognition in five acquired prosopagnosic patients. Four patients had lesions limited to the right hemisphere while one had bilateral lesions with more pronounced lesions in the right hemisphere. The patients completed a total of seven word recognition tasks: two lexical decision tasks and five reading aloud tasks totalling more than 1200 trials. The performances of the four older patients (3 female, age range 50-64 years) were compared to those of 12 older controls (8 female, age range 56-66 years), while the performances of the younger prosopagnosic (male, 31 years) were compared to those of 14 younger controls (9 female, age range 20-33 years). We analysed all results at the single-patient level using Crawford's t-test. Across seven tasks, four prosopagnosics performed as quickly and accurately as controls. Our results demonstrate that acquired prosopagnosia can exist without word recognition deficits. These findings are inconsistent with a key prediction of MTMT. They instead support the hypothesis that face

  6. Clinicopathological correlation of acquired hypopigmentary disorders.

    PubMed

    Patel, Anisha B; Kubba, Raj; Kubba, Asha

    2013-01-01

    Acquired hypopigmentary disorders comprise a significant group of disorders that affect Indians and Asians. The pigment disturbance in darker skin individuals can be very distressing to the patient and the family. These disorders cover a wide array of pathologies including infections, autoimmune processes, lymphoproliferative disorders, and sclerosing diseases. Histological diagnosis is particularly important because treatments for these diseases are varied and specific. This review will focus on histopathological diagnosis based on clinicopathological correlation for commonly encountered disorders such as leprosy, vitiligo, lichen sclerosus, pityriasis alba (PA), and pityriasis versicolor (PV). Atypical or uncommon clinical presentation of classic diseases such as hypopigmented mycosis fungoides (HMF) and hypopigmented sarcoidosis are also included. PMID:23619442

  7. [Acquired immunodeficiency syndrome in pediatric patients].

    PubMed

    Molina Moguel, J L; Ruiz Illezcas, R; Forsbach Sánchez, S; Carreño Alvarez, S; Picco Díaz, I

    1990-12-01

    The object of this study was to determine how many of the patients treated at the Pediatric Odontology Clinic, a branch of the Maxillo-Facial Surgery Service at the Veinte de Noviembre Regional Hospital, ISSSTE, are VIH-positive of show serious manifestations of Acquired Immuno-Deficiency Syndrome (AIDS). For such purpose, 100 pediatric patients suffering from different systemic or local diseases were evaluated, the most common being hematological alterations. Results evidenced the presence of VIH in the blood of five of the pediatric subjects, all suffering from Hemophilia. PMID:2132469

  8. Acquired scalp alopecia. Part II: A review.

    PubMed

    Sullivan, J R; Kossard, S

    1999-05-01

    The neutrophil-associated and infiltrative scarring alopecias are reviewed including folliculitis decalvans, tufted folliculitis, dissecting cellulitis of the scalp, acne keloidalis and follicular degeneration syndrome. The management of acquired scalp alopecia is also reviewed including newer, promising therapies. More specific agents targeting components of the androgen system will make the treatment of androgenetic alopecia more rewarding. Similarly new immunomodulatory therapies show great promise for the lymphocyte-associated alopecias and include a new generation of macrolide immunosuppressives (tacrolimus, SDZ ASM 981, and SDZ 281-240), some of which appear to have good transcutaneous absorption. PMID:10333615

  9. Origins of species: acquired genomes and individuality

    NASA Technical Reports Server (NTRS)

    Margulis, L.

    1993-01-01

    Entire genomes with their accompanying protein synthetic systems are transferred throughout the biosphere primarily as bacteria and protists which become symbionts as they irreversibly integrate into pre-existing organisms to form more complex individuals. Individualization is stabilized by simultaneous transmission of once-separate heterologous genetic systems. The origin of new species is hypothesized to correlate with the acquisition, integration and subsequent inheritance of such acquired microbial genomes. These processes were recognized by Mereschkovsky ("Symbiogenesis" in Russian, 1909) and by Wallin ("Symbionticism", see p. 181, this issue).

  10. Acquired haemophilia masked by warfarin therapy.

    PubMed

    Vadikolia, C M; Riddell, A; Brooks, S; Yee, T T; Brown, S; Lee, C

    2007-02-01

    Acquired haemophilia is a rare phenomenon and prompt diagnosis is essential for successful treatment. Early laboratory detection could minimize its potentially devastating consequences and reduce mortality but when a masking element such as anticoagulant therapy is present, delay in diagnosis is not uncommon. A prolonged activated partial thromboplastin time (APTT) may be falsely attributed to warfarin alone, particularly when it is associated with oral anticoagulant overdose. We describe two patients on treatment with warfarin who presented with a bleeding diathesis and disproportionately prolonged APTT, which led to the diagnosis of antibodies directed against factor VIII. PMID:17224010

  11. Acquired Congenital Malalignment of the Great Toenails

    PubMed Central

    Decker, Ashley; Scher, Richard K.; Avarbock, Andrew

    2016-01-01

    Congenital malalignment is the lateral deviation of the nail plate along the longitudinal axis due to the lateral rotation of the nail matrix. The nail plate grows out in ridges caused by repeated microtrauma to the nail. Common complications include onychomycosis, Pseudomonas infection and acute or chronic paronychia. Treatment options range from conservative management to surgical options including realignment and nail matrixectomy. Congenital malalignment usually presents in infancy or childhood, but we present two cases of acquired malalignment occurring in the teenage years. PMID:27171597

  12. Acquired von Willebrand syndrome: an update.

    PubMed

    Franchini, Massimo; Lippi, Giuseppe

    2007-05-01

    Acquired von Willebrand syndrome (aVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease (VWD). However, unlike congenital VWD, it arises in individuals with no personal or family history of bleeding. aVWS occurs in association with a variety of underlying disorders, most frequently in lymphoproliferative disorders, myeloproliferative disorders, and cardiovascular diseases. Through an analysis of the more recent literature data, the pathophysiology and the clinical, laboratory, and therapeutic aspects of this syndrome are concisely reported in this review. PMID:17133419

  13. Acquired Congenital Malalignment of the Great Toenails.

    PubMed

    Decker, Ashley; Scher, Richard K; Avarbock, Andrew

    2016-02-01

    Congenital malalignment is the lateral deviation of the nail plate along the longitudinal axis due to the lateral rotation of the nail matrix. The nail plate grows out in ridges caused by repeated microtrauma to the nail. Common complications include onychomycosis, Pseudomonas infection and acute or chronic paronychia. Treatment options range from conservative management to surgical options including realignment and nail matrixectomy. Congenital malalignment usually presents in infancy or childhood, but we present two cases of acquired malalignment occurring in the teenage years. PMID:27171597

  14. Survival of the anaerobic fungus Orpinomyces sp. strain C1A after prolonged air exposure

    PubMed Central

    Struchtemeyer, Christopher G.; Ranganathan, Abhaya; Couger, M. B.; Liggenstoffer, Audra S.; Youssef, Noha H.; Elshahed, Mostafa S.

    2014-01-01

    Anaerobic fungi are efficient plant biomass degraders and represent promising agents for a variety of biotechnological applications. We evaluated the tolerance of an anaerobic fungal isolate, Orpinomyces sp. strain C1A, to air exposure in liquid media using soluble (cellobiose) and insoluble (dried switchgrass) substrates. Strain C1A grown on cellobiose survived for 11, and 13.5 hours following air exposure when grown under planktonic, and immobilized conditions, respectively. When grown on switchgrass media, strain C1A exhibited significantly enhanced air tolerance and survived for 168 hours. The genome of strain C1A lacked a catalase gene, but contained superoxide dismutase and glutathione peroxidase genes. Real time PCR analysis indicated that superoxide dismutase, but not glutathione peroxidase, exhibits a transient increase in expression level post aeration. Interestingly, the C1A superoxide dismutase gene of strain C1A appears to be most closely related to bacterial SODs, which implies its acquisition from a bacterial donor via cross kingdom horizontal gene transfer during Neocallimastigomycota evolution. We conclude that strain C1A utilizes multiple mechanisms to minimize the deleterious effects of air exposure such as physical protection and the production of oxidative stress enzymes. PMID:25367149

  15. Survival of the anaerobic fungus Orpinomyces sp. strain C1A after prolonged air exposure.

    PubMed

    Struchtemeyer, Christopher G; Ranganathan, Abhaya; Couger, M B; Liggenstoffer, Audra S; Youssef, Noha H; Elshahed, Mostafa S

    2014-01-01

    Anaerobic fungi are efficient plant biomass degraders and represent promising agents for a variety of biotechnological applications. We evaluated the tolerance of an anaerobic fungal isolate, Orpinomyces sp. strain C1A, to air exposure in liquid media using soluble (cellobiose) and insoluble (dried switchgrass) substrates. Strain C1A grown on cellobiose survived for 11, and 13.5 hours following air exposure when grown under planktonic, and immobilized conditions, respectively. When grown on switchgrass media, strain C1A exhibited significantly enhanced air tolerance and survived for 168 hours. The genome of strain C1A lacked a catalase gene, but contained superoxide dismutase and glutathione peroxidase genes. Real time PCR analysis indicated that superoxide dismutase, but not glutathione peroxidase, exhibits a transient increase in expression level post aeration. Interestingly, the C1A superoxide dismutase gene of strain C1A appears to be most closely related to bacterial SODs, which implies its acquisition from a bacterial donor via cross kingdom horizontal gene transfer during Neocallimastigomycota evolution. We conclude that strain C1A utilizes multiple mechanisms to minimize the deleterious effects of air exposure such as physical protection and the production of oxidative stress enzymes. PMID:25367149

  16. Trichinella spiralis Paramyosin Binds Human Complement C1q and Inhibits Classical Complement Activation

    PubMed Central

    Sun, Ran; Zhao, Xi; Wang, Zixia; Yang, Jing; Zhao, Limei; Zhan, Bin; Zhu, Xinping

    2015-01-01

    Background Trichinella spiralis expresses paramyosin (Ts-Pmy) as a defense mechanism. Ts-Pmy is a functional protein with binding activity to human complement C8 and C9 and thus plays a role in evading the attack of the host’s immune system. In the present study, the binding activity of Ts-Pmy to human complement C1q and its ability to inhibit classical complement activation were investigated. Methods and Findings The binding of recombinant and natural Ts-Pmy to human C1q were determined by ELISA, Far Western blotting and immunoprecipitation, respectively. Binding of recombinant Ts-Pmy (rTs-Pmy) to C1q inhibited C1q binding to IgM and consequently inhibited C3 deposition. The lysis of antibody-sensitized erythrocytes (EAs) elicited by the classical complement pathway was also inhibited in the presence of rTs-Pmy. In addition to inhibiting classical complement activation, rTs-Pmy also suppressed C1q binding to THP-1-derived macrophages, thereby reducing C1q-induced macrophages migration. Conclusion Our results suggest that T. spiralis paramyosin plays an important role in immune evasion by interfering with complement activation through binding to C1q in addition to C8 and C9. PMID:26720603

  17. Evolutionary diversification of DYX1C1 transcripts via an HERV-H LTR integration event.

    PubMed

    Kim, Yun-Ji; Huh, Jae-Won; Kim, Dae-Soo; Han, Kyudong; Kim, Hwan-Mook; Kim, Heui-Soo

    2011-01-01

    DYX1C1 is a candidate gene for developmental dyslexia and has three alternative pre-mRNA spliced forms in the human genome. One of the transcripts contains an HERV-H LTR that could affect the expression level of DYX1C1. We speculate that the HERV-H LTR integrated into the DYX1C1 locus in the catarrhine lineage after its divergence from the platyrrhine lineage. Reverse transcription-PCR of the HERV-H LTR-related transcript produced four alternative forms from several human tissues. All of alternative forms were also identified in various rhesus macaque tissues. Through sequencing analysis of various primate DNA samples, we found that a part of the HERV-H LTR sequence was duplicated within the DYX1C1 exon 9 only in catarrhines. However, the duplication event did not cause frameshift mutation of the DYX1C1 transcript. Taken together, this HERV-H LTR insertion into DYX1C1 has contributed to transcript diversification of DYX1C1 during primate evolution. PMID:22214596

  18. Maize anthocyanin regulatory gene pl is a duplicate of c1 that functions in the plant.

    PubMed

    Cone, K C; Cocciolone, S M; Burr, F A; Burr, B

    1993-12-01

    Genetic studies in maize have identified several regulatory genes that control the tissue-specific synthesis of purple anthocyanin pigments in the plant. c1 regulates pigmentation in the aleurone layer of the kernel, whereas pigmentation in the vegetative and floral tissues of the plant body depends on pl. c1 encodes a protein with the structural features of eukaryotic transcription factors and functions to control the accumulation of transcripts for the anthocyanin biosynthetic genes. Previous genetic and molecular observations have prompted the hypothesis that c1 and pl are functionally duplicate, in that they control the same set of anthocyanin structural genes but in distinct parts of the plant. Here, we show that this proposed functional similarity is reflected by DNA sequence homology between c1 and pl. Using a c1 DNA fragment as a hybridization probe, genomic and cDNA clones for pl were isolated. Comparison of pl and c1 cDNA sequences revealed that the genes encode proteins with 90% or more amino acid identity in the amino- and carboxyl-terminal domains that are known to be important for the regulatory function of the C1 protein. Consistent with the idea that the pl gene product also acts as a transcriptional activator is our finding that a functional pl allele is required for the transcription of at least three structural genes in the anthocyanin biosynthetic pathway. PMID:8305872

  19. Synthetic inhibitors of elastase.

    PubMed

    Edwards, P D; Bernstein, P R

    1994-03-01

    For more than two decades investigators around the world, in both academic and industrial institutions, have been developing inhibitors of human neutrophil elastase. A number of very elegant and insightful strategies have been reported. In the case of reversible peptidic inhibitors, this has resulted in the identification of some extremely potent compounds with dissociation constants in the 10(-11) M range. This is quite an accomplishment considering that these low molecular-weight inhibitors are only tri- and tetrapeptides. In the case of the heterocyclic-based inhibitors, the challenge of balancing the heterocycle's inherent reactivity and aqueous stability with the stability of the enzyme-inhibitor adduct has been meet by either using a latent, reactive functionality which is only activated within the enzyme, or by incorporating features which selectively obstruct deacylation but have little effect on the enzyme acylation step. The underlying goal of this research has been the identification of agents to treat diseases associated with HNE. Several animal models have been developed for evaluating the in vivo activity of elastase inhibitors, and compounds have been shown to be effective in all of these models by the intravenous, intratrachael or oral routes of administration. However, only a very small percentage of compounds have possessed all the necessary properties, including lack of toxicity, for progression into the clinic. The peptidyl TFMK ICI 200,880 (25-12) has many of the desired characteristics of a drug to treat the diseases associated with HNE: chemical stability, in vitro and in vivo activity, a long duration of action, and adequate metabolic stability. Currently ICI 200,880 is the only low molecular-weight HNE inhibitor known to be undergoing clinical trials, and may be the compound which finally demonstrates the clinical utility of a synthetic HNE inhibitor. PMID:8189835

  20. Asian elephants acquire inaccessible food by blowing.

    PubMed

    Mizuno, Kaori; Irie, Naoko; Hiraiwa-Hasegawa, Mariko; Kutsukake, Nobuyuki

    2016-01-01

    Many animals acquire otherwise inaccessible food with the aid of sticks and occasionally water. As an exception, some reports suggest that elephants manipulate breathing through their trunks to acquire inaccessible food. Here, we report on two female Asian elephants (Elephas maximus) in Kamine Zoo, Japan, who regularly blew to drive food within their reach. We experimentally investigated this behaviour by placing foods in inaccessible places. The elephants blew the food until it came within accessible range. Once the food was within range, the elephants were increasingly less likely to blow as the distance to the food became shorter. One subject manipulated her blowing duration based on food distance: longer when the food was distant. These results suggest that the elephants used their breath to achieve goals: that is, they used it not only to retrieve the food but also to fine-tune the food position for easy grasping. We also observed individual differences in the elephants' aptitude for this technique, which altered the efficiency of food acquisition. Thus, we added a new example of spontaneous behaviour for achieving a goal in animals. The use of breath to drive food is probably unique to elephants, with their dexterous trunks and familiarity with manipulating the act of blowing, which is commonly employed for self-comfort and acoustic communication. PMID:26541597