bluuebunny/crossref_metadata_2025 huggingface dataset:
Adherence of phosphatidylserine-exposing erythrocytes to endothelial matrix thrombospondin
Authors: Manodori Annamaria B. , Barabino Gilda A. , Lubin Bertram H. , Kuypers Frans A.
Published: October 2019

Phospholipid asymmetry is well maintained in erythrocyte (RBC) membranes with phosphatidylserine (PS) exclusively present in the inner leaflet. The appearance of PS on the surface of the cell can have major physiologic consequences, including increased cell-cell interactions. Because increased adherence of PS-exposing RBCs to endothelial cells (ECs) may be pathologically important in hemoglobinopathies such as sickle cell disease and thalassemia, we studied the role of PS exposure in calcium ionophore-treated normal RBC adherence to human umbilical vein endothelial cell (HUVEC) monolayers. When HUVEC monolayers were incubated with these PS-exposing RBCs, the ECs retracted and the RBCs adhered primarily in the gaps opened between the ECs. A linear correlation was found between the number of PS-exposing RBCs in the population and the number of adhering RBCs to the monolayer. Pretreatment of RBCs with annexin V significantly decreased adherence by shielding PS on the RBCs. Similarly, PS-containing lipid vesicles decreased RBC binding by competing for the PS binding sites in the monolayer. PS-exposing RBCs and PS-containing lipid vesicles adhered to immobilized thrombospondin (TSP) and matrix TSP, respectively, and adherence of PS-exposing RBCs to EC monolayers was reduced by antibodies to TSP and to its EC receptor, vβ3. Together, these results indicate a role for PS and matrix TSP in the adherence of PS-exposing RBCs to EC monolayers, and suggest an important contribution of PS-exposing RBCs in pathologies with reported vascular damage, such as sickle cell anemia.
The IVS4 + 4 A to T mutation of the Fanconi anemia geneFANCC is not associated with a severe phenotype in Japanese patients
Authors: Futaki Makoto , Yamashita Takayuki , Yagasaki Hiroshi , Toda Tatsushi , Yabe Miharu , Kato Shunichi , Asano Shigetaka , Nakahata Tatsutoshi
Published: October 2019

Fanconi anemia (FA) is an autosomal recessive disease characterized by congenital anomalies, aplastic anemia, and a susceptibility to leukemia. There are at least 8 complementation groups (A through H). Extensive analyses of the FA group C gene FANCC in Western countries revealed that 10% to 15% of FA patients have mutations of this gene. The most common mutation is IVS4 + 4 A to T (IVS4), a splice mutation in intron 4, which has been found only in patients of Ashkenazi Jewish ancestry. When we screened 29 Japanese patients (20 unrelated patients and 4 families) using polymerase chain reaction–single strand conformation polymorphism, we found 8 unrelated patients homozygous for IVS4. This is apparently the first non–Ashkenazi-Jewish population for whom this mutation has been detected. The Ashkenazi Jewish patients homozygous for IVS4 have a severe phenotype, in comparison with other FA patients. Our analyses of Japanese patients indicate no significant difference between IVS4 homozygotes and other patients with regard to severity of a clinical phenotype. Thus, ethnic background may have a significant effect on a clinical phenotype in FA patients carrying the same mutation.
Regulation of factor VIIIa by human activated protein C and protein S: inactivation of cofactor in the intrinsic factor Xase
Authors: O'Brien Lynn M. , Mastri Maria , Fay Philip J.
Published: October 2019

Factor VIIIa is a trimer of A1, A2, and A3-C1-C2 subunits. Inactivation of the cofactor by human activated protein C (APC) results from preferential cleavage at Arg336 within the A1 subunit, followed by cleavage at Arg562 bisecting the A2 subunit. In the presence of human protein S, the rate of APC-dependent factor VIIIa inactivation increased several-fold and correlated with an increased rate of cleavage at Arg562. (Active site-modified) factor IXa, blocked cleavage at the A2 site. However, APC-catalyzed inactivation of factor VIIIa proceeded at a similar rate independent of factor IXa, consistent with the location of the preferential cleavage site within the A1 subunit. Addition of protein S failed to increase the rate of cleavage at the A2 site when factor IXa was present. In the presence of factor X, cofactor inactivation was inhibited, due to a reduced rate of cleavage at Arg336. However, inclusion of protein S restored near original rates of factor VIIIa inactivation and cleavage at the A1 site, thus overcoming the factor X-dependent protective effect. These results suggest that in the human system, protein S stimulates APC-catalyzed factor VIIIa inactivation by facilitating cleavage of A2 subunit (an effect retarded in the presence of factor IXa), as well as abrogating protective interactions of the cofactor with factor X.
Single amino acid substitution in human platelet glycoprotein Ibβ is responsible for the formation of the platelet-specific alloantigen Iya
Authors: Sachs Ulrich J. H. , Kiefel Volker , Böhringer Micaela , Afshar-Kharghan Vahid , Kroll Hartmut , Santoso Sentot
Published: October 2019

We recently described a new low-frequency platelet alloantigen on the human platelet glycoprotein (GP) Ib-IX complex, termed Iya, which was implicated in a severe case of neonatal alloimmune thrombocytopenia. Immunoprecipitation studies with trypsin-treated platelets indicated that the Iyaalloantigenic determinants are formed by the membrane-associated remnant moiety of GP Ib (GP Ibr) together with GP Ibβ and GP IX. To elucidate the molecular basis underlying the Iya alloantigen, we amplifiedGPIbr, GPIbβ, andGPIX genes by polymerase chain reaction (PCR). Nucleotide-sequence analysis of these 3 genes showed a G to A transition at position 141 on GPIbβ gene in a subject positive for Iya. This transition resulted in a Gly15Glu dimorphism on the N-terminal domain ofGPIbβ. This finding was confirmed by genotyping analysis of 6 Iya-positive subjects by restriction fragment length polymorphism (RFLP) studies using NarI endonuclease. In 300 randomly selected healthy blood donors, one Iya-positive individual was found. Phenotypes determined by monoclonal antibody-specific immobilization of platelet antigens assay and genotypes determined by RFLP were identical in this population. Analysis of Iya-positive platelets showed that the point mutation affected neither the degree of surface expression nor the function of the GP Ib-GP Ibβ-IX complex on the platelet surface. Transient expression of the GP Ib-IX complex in CHO cells using wild-type GP Ibβ (Gly15) or mutant GP Ibβ (Glu15) allowed us to demonstrate that this single amino acid substitution is sufficient to induce Iya epitope(s).
Vasoactive side effects of intravenous immunoglobulin preparations in a rat model and their treatment with recombinant platelet-activating factor acetylhydrolase
Authors: Bleeker Wim K. , Teeling Jessica L. , Verhoeven Arthur J. , Rigter Gemma M. M. , Agterberg Jacques , Tool Anton T. J. , Koenderman Anky H. L. , Kuijpers Taco W. , Hack C. Erik
Published: October 2019

Previously, we observed in a rat model that intravenous administration of intramuscular immunoglobulin preparations induced a long-lasting hypotension, which appeared to be associated with the presence of IgG polymers and dimers in the preparations, but unrelated to complement activation. We found evidence that this hypotensive response is mediated by platelet-activating factor (PAF) produced by macrophages. In this study, we compared the vasoactive effects of 16 intravenous immunoglobulin (IVIG) products from 10 different manufacturers, in anesthetized rats. Eight of the IVIG preparations showed no hypotensive effects (less than 15% decrease), whereas the other 8 had relatively strong effects (15%-50% decrease). The hypotensive effects correlated with the IgG dimer content of the preparations. Pretreatment of the rats with recombinant PAF acetylhydrolase completely prevented the hypotensive reaction on IVIG infusion, and administration after the onset of hypotension resulted in normalization of the blood pressure. We also observed PAF production on in vitro incubation of human neutrophils with IVIG, which could be blocked by anti-Fcγ receptor antibodies. This indicates that induction of PAF generation may also occur in a human system. Our findings support the hypothesis that the clinical side effects of IVIG in patients may be caused by macrophage and neutrophil activation through interaction of IgG dimers with Fcγ receptors. Because phagocyte activation may also lead to the release of other inflammatory mediators, recombinant PAF acetylhydrolase (rPAF-AH) provides a useful tool to determine whether PAF plays a role in the clinical side effects of IVIG. If so, rPAF-AH can be used for the treatment of those adverse reactions.
Non-MALT marginal zone B-cell lymphomas: a description of clinical presentation and outcome in 124 patients
Authors: Berger Françoise , Felman Pascale , Thieblemont Catherine , Pradier Thierry , Baseggio Lucille , Bryon Paul-Andre , Salles Gilles , Callet-Bauchu Evelyne , Coiffier Bertrand
Published: October 2019

Marginal zone B-cell lymphoma (MZL) is a recently individualized lymphoma that encompasses mucosa-associated lymphoid tissue (MALT) lymphoma, splenic lymphoma with or without villous lymphocytes, and nodal lymphoma with or without monocytoid B-cells. If the clinical description and outcome of MALT lymphoma is well known, this is not the case for the other subtypes. We reviewed 124 patients presenting non-MALT MZL treated in our department to describe the morphologic and clinical presentation and the outcome of these lymphomas. Four clinical subtypes were observed: splenic, 59 patients; nodal, 37 patients; disseminated (splenic and nodal), 20 patients; and leukemic (not splenic nor nodal), 8 patients. These lymphomas were usually CD5-, CD10-, CD23-, and CD43-, but the detection of one or, rarely, two of these antigens may be observed. Bone marrow and blood infiltrations were frequent, except in the nodal subtype, but these locations were not associated with a poorer outcome. Splenic and leukemic subtypes were associated with a median time to progression (TTP) longer than 5 years, even in the absence of treatment or of complete response to therapy. Nodal and disseminated subtypes were associated with a median TTP of 1 year. However, in all these subtypes, survival was good with a median survival of 9 years, allowing these lymphomas to be classified as indolent. Because of the retrospective nature of this analysis, no conclusion may be drawn on the therapeutic aspects, but conservative treatments seem recommended for leukemic and splenic subtypes.
Role of SUMO-1–modified PML in nuclear body formation
Authors: Zhong Sue , Müller Stefan , Ronchetti Simona , Freemont Paul S. , Dejean Anne , Pandolfi Pier Paolo
Published: October 2019

The tumor-suppressive promyelocytic leukemia (PML) protein of acute promyelocytic leukemia (APL) has served as one of the defining components of a class of distinctive nuclear bodies (NBs). PML is delocalized from NBs in APL cells and is degraded in cells infected by several viruses. In these cells, NBs are disrupted, leading to the aberrant localization of NB proteins. These results have suggested a critical role for the NB in immune response and tumor suppression and raised the question of whether PML is crucial for the formation or stability of NB. In addition, PML is, among other proteins, covalently modified by SUMO-1. However, the functional relevance of this modification is unclear. Here, we show in primary PML−/− cells of various histologic origins, that in the absence of PML, several NB proteins such as Sp100, CBP, ISG20, Daxx, and SUMO-1 fail to accumulate in the NB and acquire aberrant localization patterns. Transfection of PML in PML−/−cells causes the relocalization of NB proteins. By contrast, a PML mutant that can no longer be modified by SUMO-1 fails to do so and displays an aberrant nuclear localization pattern. Therefore, PML is required for the proper formation of the NB. Conjugation to SUMO-1 is a prerequisite for PML to exert this function. These data shed new light on both the mechanisms underlying the formation of the NBs and the pathogenesis of APL.
HTLV-II down-regulates HIV-1 replication in IL-2–stimulated primary PBMC of coinfected individuals through expression of MIP-1α
Authors: Casoli Claudio , Vicenzi Elisa , Cimarelli Andrea , Magnani Giacomo , Ciancianaini Paolo , Cattaneo Ercole , Dall'Aglio PierPaolo , Poli Guido , Bertazzoni Umberto
Published: October 2019

The influence of human T-cell leukemia/lymphoma virus type II (HTLV-II) in individuals also infected with HIV-1 is poorly understood. To evaluate the reciprocal influence of HTLV-II and HIV-1 infection, primary peripheral blood mononuclear cell (PBMC) cultures from coinfected individuals were established in the presence of interleukin 2 (IL-2). In these cultures, the kinetics of HTLV-II replication always preceded those of HIV-1. Noteworthy, the kinetics of HIV-1 production were inversely correlated to the HTLV-II proviral load in vivo and its replication ex vivo. These observations suggested a potential interaction between the 2 retroviruses. In this regard, the levels of IL-2, IL-6, and tumor necrosis factor- (TNF-) were measured in the same coinfected PBMC cultures. Endogenous IL-2 was not produced, whereas IL-6 and TNF- were secreted at levels compatible with their known ability to up-regulate HIV-1 expression. The HIV-suppressive CC-chemokines RANTES, macrophage inflammatory protein-1 (MIP-1), and MIP-1β were also determined in IL-2–stimulated PBMC cultures. Of interest, their kinetics and concentrations were inversely related to those of HIV-1 replication. Experiments were performed in which CD8+ T cells or PBMCs from HTLV-II monoinfected individuals were cocultivated with CD4+ T cells from HIV-1 monoinfected individuals separated by a semipermeable membrane in the presence or absence of antichemokine neutralizing antibodies. The results indicate that HTLV-II can interfere with the replicative potential of HIV-1 by up-regulating viral suppressive CC-chemokines and, in particular, MIP-1. This study is the first report indicating that HTLV-II can influence HIV replication, at least in vitro, via up-regulation of HIV-suppressive chemokines.
Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload
Authors: Franchini Massimo , Gandini Giorgio , de Gironcoli Marzia , Vassanelli Aurora , Borgna-Pignatti Caterina , Aprili Giuseppe
Published: October 2019

We compared 48-hour urinary iron excretion after a twice-daily subcutaneous bolus injection of deferoxamine and after 12 hours of subcutaneous continuous infusion of the drug in 27 patients with iron overload (mean age, 55.7 years). In most patients, the iron overload was due to multiple transfusions administered during chemotherapy or as part of supportive care for a hematologic or oncologic disorder. One patient had sickle cell anemia and 1 had hereditary hemochromatosis and spherocytosis. Similar urinary iron excretion was observed with the 2 methods of administration; mean ± SD values were 6935.3 ± 3832.3 μg/48 hours with subcutaneous bolus injection and 6630.4 ± 3606.9 μg/48 hours with subcutaneous continuous infusion (P = .3). Twenty-six patients (96.3%) chose to continue therapy with bolus injection. The long-term efficacy of bolus injection was evaluated by measuring the serum ferritin concentration at regular intervals for a follow-up time of 20.1 ± 4.5 months. Ferritin concentration decreased to below 1000 μg/L in 73% of the patients and to below 500 μg/L in 42% and became normal in 26%. Best results were obtained in patients who were no longer receiving blood transfusions when chelation therapy was initiated. Three of 26 patients (11.5%) had mild, transient side effects after bolus injection. Larger prospective, randomized studies must be conducted before deferoxamine bolus injection can be routinely recommended for patients with iron overload.
Linkage analysis demonstrates that the prothrombin G20210A mutation jointly influences plasma prothrombin levels and risk of thrombosis
Authors: Soria José Manuel , Almasy Laura , Souto Juan Carlos , Tirado Isabel , Borell Montserrat , Mateo José , Slifer Susan , Stone William , Blangero John , Fontcuberta Jordi
Published: October 2019

Association studies suggest that the G20210A mutation (G to A substitution at nucleotide position 20210) in the prothrombin gene (PT) is associated with increased plasma prothrombin activity and with increased risk for venous thromboembolism. To test directly for linkage between this PT variant and plasma prothrombin activity we performed a family-based study. The G20210A genotypes and plasma prothrombin activity levels were determined in 435 individuals belonging to 22 extended Spanish families. The sample was composed of 388 homozygous (G/G) normal individuals and 43 heterozygote (G/A) and 4 homozygote (A/A) carriers for the G20210A mutation. The results of variance-component linkage analysis yielded a highly significant lod score of 3.6 (P = 2.4 × 10−5) between this mutation and a quantitative trait locus (QTL) that influences prothrombin activity. Importantly, a conditional linkage analysis that simultaneously accounted for association with the G20210A variant completely eliminated the linkage signal, which indicates that this mutation affects the function of the prothrombin gene. Additionally, a bivariate linkage analysis of plasma prothrombin activity and thrombosis significantly improved the linkage signal for prothrombin activity (lod score = 4.7;P = 1.5 × 10−6) and provided strong evidence that this QTL has a pleiotropic effect on the risk of thrombosis (lod score = 2.43; P = .0004). These results represent the first direct genetic evidence that a QTL in thePT gene influences prothrombin activity levels and susceptibility to thrombosis and strongly support the conclusion that G20210A is a functional polymorphism.
Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features
Authors: Mauro Francesca R. , Foa Robert , Cerretti Raffaella , Giannarelli Diana , Coluzzi Serelina , Mandelli Franco , Girelli Gabriella
Published: October 2019

Fifty-two cases of autoimmune hemolytic anemia (AHA) were observed within a series of 1203 patients (4.3%) with chronic lymphocytic leukemia (CLL) followed at a single institution. Nineteen were observed at the time of CLL diagnosis and 33 during the clinical follow-up. Ninety percent of the patients with CLL/AHA showed active CLL and 25% had been treated previously. The antierythrocyte autoantibody (AeAb) was an IgG in 87% of cases and an IgM in 13%. A lymphocyte count more than 60 × 109/L (P < .00001), age above 65 years (P < .01), and male gender (P < .01) emerged as independent parameters that correlated significantly with an increased rate of AHA at CLL diagnosis. Patients previously treated with chlorambucil (CB) plus prednisone (PDN) and with fludarabine plus PDN showed a similar rate of AHA (1.8% and 2.5%, respectively). After steroid therapy associated with CB in case of active CLL, 70% of patients achieved the complete disappearance of the AeAb. The actuarial AHA relapse-free survival probability was 54% at 5 years and the median survival probability after AHA was 41 months. Infections represented the main cause of morbidity and mortality. IgG AHA and the occurrence of AHA at the same time of CLL diagnosis emerged as independent factors significantly correlated with a better survival probability of AHA/CLL patients. Taken together, this study indicates that in CLL, AHA is a rare event with no independent effect on survival for which steroids, associated with CB if required, and a careful management of infections may successfully control the 2 conditions. Cooperative studies are needed to better define the optimal steroid schedule and the therapeutic role of other immunosuppressive agents and splenectomy.
Nonsteroidal anti-estrogens inhibit the functional differentiation of human monocyte-derived dendritic cells
Authors: Komi Janne , Lassila Olli
Published: October 2019

Dendritic cells (DC) are professional antigen-presenting cells with a unique capacity to initiate and regulate immune responses. Immature CD1a+ DC can be cultured from CD14+monocytes in the presence of interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in vitro. Results of this study show that the nonsteroidal anti-estrogens toremifene and tamoxifen inhibit this differentiation. In the presence of anti-estrogens the cells lose CD14 expression, but remain CD1a− and clearly have less dendritic processes than immature DC. Functionally, anti-estrogen-treated cells are inferior to immature DC in inducing proliferation of allogeneic T cells and in producing IL-12 p70 protein after CD40 ligation. The expression of the costimulatory molecules CD80 and CD86 is differentially regulated by anti-estrogens during DC differentiation. Furthermore, anti-estrogens are also able to inhibit the terminal maturation of DC. By inhibiting the functional differentiation of DC, anti-estrogens may have a role in the treatment and prevention of autoimmune diseases.
Variable heavy chain gene analysis of follicular lymphomas: correlation between heavy chain isotype expression and somatic mutation load
Authors: Aarts Wilhelmina M. , Bende Richard J. , Steenbergen Eric J. , Kluin Philip M. , Ooms Engelbert C. M. , Pals Steven T. , van Noesel Carel J. M.
Published: October 2019

The expansion of follicular lymphomas (FLs) resembles, both morphologically and functionally, normal germinal center B-cell growth. The tumor cells proliferate in networks of follicular dendritic cells and are believed to be capable of somatic hypermutation and isotype switching. To investigate the relation between somatic mutation and heavy chain isotype expression, we analyzed the variable heavy (VH) chain genes of 30 FL samples of different isotypes. The VH genes of the FLs were heavily mutated (29.3 mutations on average). In addition, isotype-switched lymphomas contained more somatic mutations than immunoglobulin M–positive lymphomas (33.8 mutations per VH gene versus 23.0, respectively). In all but one of the FLs, the ratios of replacement versus silent mutations in the framework regions were low, independent of the absolute number of somatic mutations and the level of intraclonal variation. Analysis of relapse samples of 4 FLs showed no obvious increase in somatic mutation load in most FLs and a decrease in intraclonal variation in time. In 3 of 4 cases, we obtained evidence for selection of certain subclones, rather than clonal evolution. Our findings question if intraclonal variation is always a reflection of ongoing somatic hypermutation. This may have implications for the concept of antigen-driven lymphomagenesis.
Intracellular iron status as a hallmark of mammalian cell susceptibility to oxidative stress: a study of L5178Y mouse lymphoma cell lines differentially sensitive to H2O2
Authors: Lipiński Pawel , Drapier Jean-Claude , Oliveira Leonor , Retmańska Hanna , Sochanowicz Barbara , Kruszewski Marcin
Published: October 2019

The redox properties of iron make this metal a key participant in oxygen-mediated toxicity. Accordingly, L5178Y (LY) mouse lymphoma cell lines, which display a unique inverse cross-sensitivity to ionizing radiation (IR) and hydrogen peroxide (H2O2), are a suitable model for the study of possible differences in the constitutive control of intracellular iron availability. We report here that the level of iron in the cytosolic labile iron pool (LIP), ie, potentially active in the Fenton reaction, is more than 3-fold higher in IR-resistant, H2O2-sensitive (LY-R) cells than in IR-sensitive, H2O2-resistant (LY-S) cells. This difference is associated with markedly greater content of ferritin H-subunits (H-Ft) in LY-S than in LY-R cells. Our results show that different expression of H-Ft in LY cells is a consequence of an up-regulation of H-Ft mRNA in the LY-S mutant cell line. In contrast, posttranscriptional control of iron metabolism mediated by iron-responsive element–iron regulatory proteins (IRPs) interaction is similar in the 2 cell lines, although IRP1 protein levels in iron-rich LY-R cells are twice those in iron-deficient LY-S cells. In showing that LY cell lines exhibit 2 different patterns of intracellular iron regulation, our results highlight both the role of high LIP in the establishment of pro-oxidant status in mammalian cells and the antioxidant role of ferritin.
Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites
Authors: Riemersma Sietske A. , Jordanova Ekaterina S. , Schop Roelandt F. J. , Philippo Katja , Looijenga Leendert H. J. , Schuuring Ed , Kluin Philip M.
Published: October 2019

In B-cell lymphomas, loss of human leukocyte antigen (HLA) class I and II molecules might contribute to immune escape from CD8+ and CD4+ cytotoxic T cells, especially because B cells can present their own idiotype. Loss of HLA expression and the possible underlying genomic alterations were studied in 28 testicular, 11 central nervous system, and 21 nodal diffuse large B-cell lymphomas (DLCLs), the first two sites are considered as immune-privileged sites. The analysis included immunohistochemistry, loss of heterozygosity analysis, and fluorescent in situ hybridization (FISH) on interphase cells and isolated DNA fibers. Total loss of HLA-A expression was found in 60% of the extranodal cases and in 10% of the nodal cases (P < .01), whereas loss of HLA-DR expression was found in 56% and 5%, respectively (P < .01). This was accompanied by extensive loss of heterozygosity within the HLA region in the extranodal DLCLs. In 3 cases, retention of heterozygosity for D6S1666 in the class II region suggested a homozygous deletion. This finding was confirmed by interphase FISH that showed homozygous deletions in the class II genes in 11 of the 18 extranodal lymphomas but in none of the 7 nodal DLCLs (P < .001). Mapping by fiber FISH showed variable deletions that always included HLA-DQ and HLA-DR genes. Hemizygous deletions and mitotic recombinations often involving all HLA genes were found in 13 of 18 extranodal and 2 of 7 nodal lymphomas. In conclusion, a structural loss of HLA class I and II expression might help the B-cell lymphoma cells to escape from immune attack.
The immunophenotype of 177 adults with acute myeloid leukemia: proposal of a prognostic score
Authors: Legrand Ollivier , Perrot Jean-Yves , Baudard Marion , Cordier Annie , Lautier Régine , Simonin Ghislaine , Zittoun Robert , Casadevall Nicole , Marie Jean-Pierre
Published: October 2019

In acute myeloid leukemia (AML) patients, a variety of clinical and biologic parameters, including phenotype, have been examined for potential value in predicting treatment response and survival. The European Group for the Immunological Classification of Leukaemias (EGIL) has proposed that AML be defined immunologically by the expression of 2 or more of the following myeloid markers: myeloperoxidase, CD13, CD33, CDw65, and CD117. With regard to this classification, the prognostic significance of 21 antigens taken separately and with immunophenotypic subgroups were evaluated and compared with other clinical and biological variables in 177 adult AML patients. None of the antigens tested were associated with treatment outcome. In contrast, patients with blasts disclosing a full expression of panmyeloid phenotype (defined by the expression of all 5 myeloid markers) had a higher complete remission rate (P < .0001) and differed significantly in disease-free survival (P = .02) and overall survival (P = .008) than patients whose cells expressed fewer than 5 of these markers. In multivariate analysis, only age, panmyeloid phenotype, performance status, and permeability glycoprotein activity influence treatment outcome. Cytogenetics was significant in univariate analysis but not in multivariate analysis, most likely because of the redundancy with panmyeloid phenotype and a higher sensitivity of immunophenotyping. Patients whose cells exhibit the panmyeloid phenotype appear to define a relatively homogeneous biological subset of AML. The 4 independent prognostic factors were used to create a prognostic score, defined by the number of factors present. This score permitted a stratification of patients with AML, thereby allowing for the consideration of innovative therapies to improve outcome in the poorer outcome groups.
Autocrine production of epithelial cell–derived neutrophil attractant-78 induced by granulocyte colony-stimulating factor in neutrophils
Authors: Suzuki Sachiko , Kobayashi Masanobu , Chiba Kouji , Horiuchi Iori , Wang Jingxin , Kondoh Takeshi , Hashino Satoshi , Tanaka Junji , Hosokawa Masuo , Asaka Masahiro
Published: October 2019

Whereas mobilization to inflammatory sites is an important function of neutrophils, it remains to be determined whether granulocyte colony-stimulating factor (G-CSF) stimulates the mobilization of neutrophils to the inflammatory sites. This study compared the expression of more than 9000 genes in neutrophils treated with and without G-CSF with the use of a DNA microarray system to determine the effects of G-CSF on the function of neutrophils. It was found that messenger RNA expression of epithelial cell–derived neutrophil attractant-78 (ENA-78), which has been reported to be a chemotactic factor for neutrophils, was induced by G-CSF in neutrophils. The study demonstrated that the supernatant of G-CSF–treated neutrophils induced the chemotaxis of neutrophils and that anti–ENA-78 antibody and anti–CXCR-2 antibody inhibited the chemotaxis. These data suggest that G-CSF may enhance the mobilization of neutrophils and consequently augment the accumulation of neutrophils in the inflammatory sites through the secretion of ENA-78.
TetR-family transcription factors in Gram-negative bacteria: conservation, variation and implications for efflux-mediated antimicrobial resistance
Authors: Colclough A. L. , Scadden J. , Blair J. M. A.
Published: October 2019

Background

TetR-family transcriptional regulators (TFTRs) are DNA binding factors that regulate gene expression in bacteria. Well-studied TFTRs, such as AcrR, which regulates efflux pump expression, are usually encoded alongside target operons. Recently, it has emerged that there are many TFTRs which act as global multi-target regulators. Our classical view of TFTRs as simple, single-target regulators therefore needs to be reconsidered. As some TFTRs regulate essential processes (e.g. metabolism) or processes which are important determinants of resistance and virulence (e.g. biofilm formation and efflux gene expression) and as TFTRs are present throughout pathogenic bacteria, they may be good drug discovery targets for tackling antimicrobial resistant infections. However, the prevalence and conservation of individual TFTR genes in Gram-negative species, has to our knowledge, not yet been studied.

Results

Here, a wide-scale search for TFTRs in available proteomes of clinically relevant pathogensSalmonellaandEscherichiaspecies was performed and these regulators further characterised. The majority of identified TFTRs are involved in efflux regulation in bothEscherichiaandSalmonella. The percentage variance in TFTR genes of these genera was found to be higher in those regulating genes involved in efflux, bleach survival or biofilm formation than those regulating more constrained processes. Some TFTRs were found to be present in all strains and species of these two genera, whereas others (i.e. TetR) are only present in some strains and some (i.e. RamR) are genera-specific. Two further pathogens on the WHO priority pathogen list (K. pneumoniaeandP. aeruginosa) were then searched for the presence of the TFTRs conserved inEscherichiaandSalmonella.

Conclusions

Through bioinformatics and literature analyses, we present that TFTRs are a varied and heterogeneous family of proteins required for the regulation of numerous important processes, with consequences to antimicrobial resistance and virulence, and that the roles and responses of these proteins are frequently underestimated.
Transcriptomic analysis of Eruca vesicaria subs. sativa lines with contrasting tolerance to polyethylene glycol-simulated drought stress
Authors: Huang Bang-Lian , Li Xuan , Liu Pei , Ma Lan , Wu Wenhua , Zhang Xuekun , Li Zaiyun , Huang Bangquan
Published: October 2019

Background

Eruca vesicaria subsp. sativais one of the Cruciferae species most tolerant to drought stress. In our previous study some extremely drought-tolerant/sensitiveErucalines were obtained. However little is known about the mechanism for drought tolerance inEruca.

Methods

In this study twoE. vesicariasubs.sativalines with contrasting drought tolerance were treated with liquid MS/PEG solution. Total RNA was isolated from 7-day old whole seedlings and then applied to Illumina sequencing platform for high-throughput transcriptional sequencing.

Results

KEGG pathway analysis indicated that differentially expressed genes (DEGs) involved in alpha-Linolenic acid metabolism, Tyrosine metabolism, Phenylalanine, Tyrosine and tryptophan biosynthesis, Galactose metabolism, Isoquinoline alkaloid biosynthesis, Tropane, Piperidine and pyridine alkaloid biosynthesis, Mineral absorption, were all up-regulated specifically in drought-tolerant (DT)Erucaline under drought stress, while DEGs involved in ribosome, ribosome biogenesis, Pyrimidine metabolism, RNA degradation, Glyoxylate and dicarboxylate metabolism, Aminoacyl-tRNA biosynthesis, Citrate cycle, Methane metabolism, Carbon fixation in photosynthetic organisms, were all down-regulated. 51 DEGs were found to be most significantly up-regulated (log2ratio ≥ 8) specifically in the DT line under PEG treatment, including those for ethylene-responsive transcription factors, WRKY and bHLH transcription factors, calmodulin-binding transcription activator, cysteine-rich receptor-like protein kinase, mitogen-activated protein kinase kinase, WD repeat-containing protein, OPDA reductase, allene oxide cyclase, aquaporin, O-acyltransferase WSD1, C-5 sterol desaturase, sugar transporter ERD6-like 12, trehalose-phosphate phosphatase and galactinol synthase 4. Eight of these 51 DEGs wre enriched in 8 COG and 17 KEGG pathways.

Conclusions

DEGs that were found to be most significantly up-regulated specifically in the DT line under PEG treatment, up-regulation of DEGs involved in Arginine and proline metabolism, alpha-linolenic acid metabolism and down-regulation of carbon fixation and protein synthesis might be critical for the drought tolerance inEruca. These results will be valuable for revealing mechanism of drought tolerance inErucaand also for genetic engineering to improve drought tolerance in crops.
Effects of depression, dementia and delirium on activities of daily living in elderly patients after discharge
Authors: Weng Ching-Fu , Lin Kun-Pei , Lu Feng-Ping , Chen Jen-Hau , Wen Chiung-Jung , Peng Jui-Hua , Tseng Ailun Heather , Chan Ding-Cheng
Published: October 2019

Background

The three geriatric conditions, depression, dementia and delirium (3D’s), are common among hospitalized older patients and often lead to impairments of activities of daily living. The aim of this study is to explore the impact of depression, dementia and delirium on activities of daily living (ADLs) during and after hospitalization.

Methods

A prospective cohort study was conducted between 2012 and 2013 in a tertiary medical center in Taiwan. Patients who aged over 65 years and admitted to the geriatric ward were invited to this study. Geriatric Depression Scale Short Form, Mini-Mental State and Confusion Assessment Method were used to identify patients with depression, dementia and delirium on admission, respectively. Barthel Index (BI) was used to evaluate patients’ functional status on admission, at discharge, 30-day, 90-day and 180-day after discharge. Generalized Estimating Equation (GEE) was used to calculate the associations between 3 D’s and BI.

Results

One-hundred-and-forty-nine patients were included in this study. Twenty-seven patients (18.1%) had depression, 37 (24.8%) had dementia, and 85 (57.0%) had delirium. The study demonstrated that all the geriatric patients with functional decline presented gradual improvements of physical function up to 180 days after discharge. Whether depression exists did not substantially affect functional recovery after discharge, whilst either dementia or delirium could impede elder people functional status. The recovery of functional improvement in delirium or dementia was relatively irreversible when comparing with depression. Once delirium or dementia was diagnosed, poorer functional restore was expected. In brief, intensive work and strategies on modifying delirium or dementia should be put more effort as early as possible.

Conclusions

Old hospitalized patients with depression can recover well after adequate intervention. We emphasize that early detection of dementia and delirium is imperative in subsequent functional outcome, even if at or before admission. Comprehensive plan must be implemented timely.
Moraxella nonliquefaciens bloodstream infection and sepsis in a pediatric cancer patient: case report and literature review
Authors: Correa-Martínez Carlos L. , Rauwolf Kerstin K. , Schuler Franziska , Füller Miriam , Kampmeier Stefanie , Groll Andreas H.
Published: October 2019

Background

Moraxella nonliquefaciens is a usually non-pathogenic biofilm-producing Gram-negative coccobacillus which may colonize the upper respiratory tract, rarely causing invasive disease. Although very rare, bloodstream infections caused by this organism have been described, showing often a fatal outcome. Here, we report the case of a pediatric cancer patient with bloodstream infection and sepsis due to M. nonliquefaciens showing full recovery after appropriate antibiotic treatment.

Case presentation

A three-year-old boy with stage IV neuroblastoma was admitted for high-dose chemotherapy with autologous stem cell rescue after standard neuroblastoma treatment. Despite receiving antimicrobial prophylaxis with trimethoprim/sulfamethoxazole, acyclovir and amphothericin B, the patient presented with fever of up to 39.5 °C and neutropenia. Besides a chemotherapy-related mucositis and an indwelling Broviac catheter (removed), no infection focus was identified on physical examination. Moraxella nonliquafaciens was identified in blood cultures. After antibiotic treatment and neutrophil recovery, the patient was fit for discharge.

Conclusions

The case described highlights the importance of an otherwise non-pathogenic microorganism, especially in immunosupressed cancer patients. It should be kept in mind that, although very infrequently, Moraxella nonliquefaciens may cause bloodstream infections that can be successfully treated with prompt focus identification and antibiotic therapy.
IKZF1 genetic variants rs4132601 and rs11978267 and acute lymphoblastic leukemia risk in Tunisian children: a case-control study
Authors: Mahjoub Sana , Chayeb Vera , Zitouni Hedia , Ghali Rabeb M. , Regaieg Haifa , Almawi Wassim Y. , Mahjoub Touhami
Published: October 2019

Background

Associations betweenIKZF1gene variants and Acute Lymphoblastic Leukemia (ALL) was recently reported. We examined whether the commonIKZF1polymorphisms rs4132601 T/G and rs111978267 A/G are associated with ALL among a Tunisian pediatric cohort.

Methods

This case-control study involved 170 patients with ALL and 150 control subjects. SNP genotyping was performed by TaqMan® SNP Genotyping Assay.

Results

The minor allele G ofIKZF1gene polymorphism rs4132601 T/G was significantly higher in ALL cases than in control subjects (P = 0.029), with 1.54-fold increased risk of ALL. The association of rs4132601 with ALL was seen under co-dominant (P = 0.009), recessive (P = 0.006), and additive (P = 0.027) genetic models, of which the co-dominant (P = 0.027) and recessive (P = 0.027) association remained significant after adjusting for covariates, and False Discovery Rate correction. In contrast, no association was noted for rs111978267 variant. Two-locus (rs4132601-rs11978267)IKZF1haplotype analysis demonstrated association of GA (P = 0.053), with increased ALL risk [OR (95% CI) = 1.58 (1.00–2.51)], which remained significant after controlling for key covariates [aP = 0.046; aOR (95% CI) = 1.61 (1.01–2.57)].

Conclusion

We demonstrated the association ofIKZF1polymorphism rs4132601 T/G with increased risk of ALL among Tunisian pediatric cohort, with altered phenotypic changes among ALL patients.
Mothers’ utilization and associated factors in preconception care in northern Ethiopia: a community based cross sectional study
Authors: Asresu Tsrity Tadese , Hailu Desta , Girmay Berhe , Abrha Mulugeta Woldu , Weldearegay Haftom Gebrehiwot
Published: October 2019

Background

Adverse pregnancy outcomes remain a prevalent health problem in Ethiopia. Mothers’ use of preconception care service has the potential to avert many of the adverse outcomes. However, the use of this service and its determinants is not well investigated. Therefore, this study was conducted to assess the utilization and determinants of preconception care among recently delivered mothers.

Methods

A community based cross-sectional design was conducted among 564 recently delivered mothers in Mekelle City, Northern Ethiopia. A multi stage cluster sampling technique was employed. Data was collected using a pre-tested, structured interviewer questionnaire and was entered in to Epi-Info™ Version 7 and analyzed using SPSS™ Version 20.0. Descriptive, bivariable and multivariable logistic regression was used to identify the association.

Results

This study revealed that, 102(18.2%) of the mothers had utilized preconception care. Mothers’ knowledge on preconception care (AOR: 2.21; 95% CI: 1.03, 4.73), prior experience of adverse birth outcomes (AOR: 5.10; 95% CI: 2.31, 11.24), history of chronic health problems (AOR: 5.69; 95% CI: 2.06, 15.72), husband’s support (AOR: 13.84; 95% CI: 6.02, 31.79), and challenges in accessing a health facility (AOR: 0.24; 95% CI: 0.16, 0.48) were significantly associated with preconception care service utilization.

Conclusion

Mothers’ utilization of preconception care is low. Mothers knowledge on preconception care, experience of adverse birth outcome, having chronic health problems and husband support increases utilization of preconception care. However, mothers who experienced challenges in visiting a health facility showed decrease preconception care utilization. Therefore, increased efforts are need in terms of advocating for involvement of husband’s and awareness creation respecting preconception care services for all women.
Prevalence of gestational diabetes according to commonly used data sources: an observational study
Authors: Lawrence Robyn L. , Wall Clare R. , Bloomfield Frank H.
Published: October 2019

Background

It is well recognized that prevalence of gestational diabetes mellitus (GDM) varies depending on the population studied and the diagnostic criteria used. The data source used also can lead to substantial differences in the reporting of GDM prevalence but is considered less frequently. Accurate estimation of GDM prevalence is important for service planning and evaluation, policy development, and research. We aimed to determine the prevalence of GDM in a cohort of New Zealand women using a variety of data sources and to evaluate the agreement between different data sources.

Methods

A retrospective analysis of prospectively collected data from the Growing Up in New Zealand Study, consisting of a cohort of 6822 pregnant women residing in a geographical area defined by three regional health boards in New Zealand. Prevalence of GDM was estimated using four commonly used data sources. Coded clinical data on diabetes status were collected from regional health boards and the Ministry of Health’s National Minimum Dataset, plasma glucose results were collected from laboratories servicing the recruitment catchment area and coded according to the New Zealand Society for the Study of Diabetes diagnostic criteria, and self-reported diabetes status collected via interview administered questionnaires. Agreement between data sources was calculated using the proportion of agreement with 95% confidence intervals for both a positive and negative diagnosis of GDM.

Results

Prevalence of GDM combining data from all sources in the Growing Up in New Zealand cohort was 6.2%. Estimates varied from 3.8 to 6.9% depending on the data source. The proportion of agreement between data sources for presence of GDM was 0.70 (95% CI 0.65, 0.75). A third of women who had a diagnosis of GDM according to medical data reported having no diabetes in interview administered questionnaires.

Conclusion

Prevalence of GDM varies considerably depending on the data source used. Health services need to be aware of this and to understand the limitations of local data sources to ensure service planning and evaluation, policy development and research are appropriate for the local prevalence. Improved communication of the diagnosis may assist women’s self-management of GDM.
The relationship between peripheral neuropathy and efficacy in second-line chemotherapy for unresectable advanced gastric cancer: a prospective observational multicenter study protocol (IVY)
Authors: Tanioka Hiroaki , Nagasaka Takeshi , Uno Futoshi , Inoue Masafumi , Okita Hiroyuki , Katata Yosuke , Kanzaki Hiromitsu , Kuramochi Hidekazu , Satake Hironaga , Shindo Yoshiaki , Doi Akira , Nasu Jyunichiro , Yamashita Haruhiro , Yamaguchi Yoshiyuki
Published: October 2019

Background

Paclitaxel is used in second-line conventional chemotherapies to manage patients with unresectable advanced gastric cancer (GC). Paclitaxel-induced peripheral neuropathy is a known adverse event leading to treatment discontinuation. Additionally, oxaliplatin which causes irreversible peripheral neuropathy is now commonly used in first-line chemotherapy for advanced GC in Japan. Thus, examining the incidence of peripheral neuropathy with paclitaxel after oxaliplatin is necessary to improve the quality of life and outcomes of patients with advanced GC in the second-line treatment setting.

Methods

This prospective observational multicenter study, (which we named IVY study), will evaluate the degree of chemotherapy-induced peripheral neuropathy (CIPN) and the efficacy of second-line chemotherapy for unresectable advanced GC. A patient neurotoxicity questionnaire (PNQ) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) will be used to assess CIPN during the second-line treatment. The key eligibility criteria are as follows: 1) unresectable or recurrent GC histologically confirmed to be primary adenocarcinoma of the stomach, 2) age over 20 years, 3) Eastern Cooperative Oncology Group performance status score of 0–2, 4) written informed consent following full study information is provided to the patient, 5) progression or intolerance for first-line chemotherapy comprising fluorinated pyrimidine and platinum anticancer drugs (cisplatin or oxaliplatin) for advanced GC. 6) presence of evaluable lesions as confirmed using a computed tomography (CT) or magnetic resonance imaging. A total of 200 patients is considered to be appropriate for inclusion in this study.

Discussion

The results of this study will provide some information on CIPN with the sequential usage of oxaliplatin as first-line chemotherapy to paclitaxel as second-line chemotherapy in clinical practice.

Trial registration

This trial is registered in the University Hospital Medical Information Network’s Clinical Trials Registry with the registration number UMIN000033376 (Registered 11 July 2018).