Expression of the transcription factor Evi-1 in human erythroleukemia cell lines and in leukemias.

PubMed

Fontenay-Roupie, M; Bouscary, D; Melle, J; Viguié, F; Picard, F; Guesnu, M; Dreyfus, F

1997-02-01

The Evi-1 proto-oncogene is a zinc finger DNA binding protein. Although activation of the Evi-1 gene has been associated with chromosomal rearrangements of the 3q25-q28 region, ectopic expression of Evi-1 could also be observed in acute myelogenous leukemias and myelodysplastic syndromes without cytogenetic abnormalities of the 3q26 locus. In this study, human erythroleukemic cell lines were screened for the expression of Evi-1 mRNA by northern blotting. Evi-1 was expressed in all the erythroid cell lines, whether undifferentiated (K 562, HEL, LAMA 84) or exhibiting spontaneous terminal erythroid differentiation (KU 812, JK-1). Evi-1 mRNA levels were constant or elevated in hemoglobin-synthesizing KU 812 or K 562 cells in response to erythropoietin or hemin treatment, respectively. In human acute myeloblastic leukemias (AML), 11/30 expressed Evi-1 by RT-PCR. Among these cases, 4/6 erythroleukemias without abnormalities of the 3q25-q28 region were found positive. The presence of acidophilic erythroblasts (15-47% of bone marrow cells) accounted for the existence of a terminal erythroid differentiation in all Evi-1-positive AML M6, whereas one negative case was poorly differentiated and referred to as AML M6 variant. These results suggest that Evi-1 mRNA expression can coexist with erythroid differentiation.

Trebananib With or Without Low-Dose Cytarabine in Treating Patients With Acute Myeloid Leukemia

ClinicalTrials.gov

2017-02-14

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Azacitidine, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With High-Risk Acute Myeloid Leukemia

ClinicalTrials.gov

2018-01-02

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Vorinostat and Gemtuzumab Ozogamicin in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia

ClinicalTrials.gov

2017-05-30

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Untreated Adult Acute Myeloid Leukemia

Differential stability of host mRNAs in Friend erythroleukemia cells infected with herpes simplex virus type 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mayman, B.A.; Nishioka, Y.

1985-01-01

The consequences of herpes simplex virus type 1 infection on cellular macromolecules were investigated in Friend erythroleukemia cells. The patterns of protein synthesis, examined by polyacrylamide gel electrophoresis, demonstrated that by 4 h postinfection the synthesis of many host proteins, with the exception of histones, was inhibited. Examination of the steady-state level of histone H3 mRNA by molecular hybridization of total RNA to a cloned mouse histone H3 complementary DNA probe demonstrated that the ratio of histone H3 mRNA to total RNA remained unchanged for the first 4 h postinfection. In contrast, the steady-state levels of globin and actin mRNAsmore » decreased progressively at early intervals postinfection. Studies on RNA synthesis in isolated nuclei demonstrated that the transcription of the histone H3 gene was inhibited to approximately the same extent as that of actin gene. It was concluded that the stabilization of preexisting histone H3 mRNA was responsible for the persistence of H3 mRNA and histone protein synthesis in herpes simplex virus type 1-infected Friend erythroleukemia cells. The possible mechanisms influencing the differential stability of host mRNAs during the course of productive infection with herpes simplex virus type 1 are discussed.« less

Identification of de Novo Fanconi Anemia in Younger Patients With Newly Diagnosed Acute Myeloid Leukemia

ClinicalTrials.gov

2016-05-13

Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Fanconi Anemia; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Secondary Myelodysplastic Syndromes; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Choline Magnesium Trisalicylate and Combination Chemotherapy in Treating Patients With Acute Myeloid Leukemia

ClinicalTrials.gov

2017-02-01

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Children With Acute Myelogenous Leukemia or Myelodysplastic Syndrome

ClinicalTrials.gov

2013-01-15

Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Secondary Myelodysplastic Syndromes; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Omacetaxine Mepesuccinate, Cytarabine, and Decitabine in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia

ClinicalTrials.gov

2016-04-05

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Cyclosporine, Pravastatin Sodium, Etoposide, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

ClinicalTrials.gov

2017-06-27

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia

Tanespimycin and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, Chronic Myelomonocytic Leukemia, or Myelodysplastic Syndromes

ClinicalTrials.gov

2013-09-27

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

Alvocidib, Cytarabine, and Mitoxantrone Hydrochloride or Cytarabine and Daunorubicin Hydrochloride in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

ClinicalTrials.gov

2017-07-03

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Idarubicin, Cytarabine, and Pravastatin Sodium in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

ClinicalTrials.gov

2017-10-16

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Refractory Anemia With Excess Blasts; Untreated Adult Acute Myeloid Leukemia

MS-275 and GM-CSF in Treating Patients With Myelodysplastic Syndrome and/or Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphocytic Leukemia

ClinicalTrials.gov

2017-06-16

Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

Early Discharge and Outpatients Care in Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia Previously Treated With Intensive Chemotherapy

ClinicalTrials.gov

2015-02-05

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia

Reduced Intensity Donor Peripheral Blood Stem Cell Transplant in Treating Patients With De Novo or Secondary Acute Myeloid Leukemia in Remission

ClinicalTrials.gov

2018-05-24

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia

Clofarabine or Daunorubicin Hydrochloride and Cytarabine Followed By Decitabine or Observation in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia

ClinicalTrials.gov

2017-12-07

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Idarubicin, Cytarabine, and Tipifarnib in Treating Patients With Newly Diagnosed Myelodysplastic Syndromes or Acute Myeloid Leukemia

ClinicalTrials.gov

2014-05-09

Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

Acute erythroid leukemia.

PubMed

Zuo, Zhuang; Polski, Jacek M; Kasyan, Armen; Medeiros, L Jeffrey

2010-09-01

Acute erythroid leukemia (AEL) is an uncommon type of acute myeloid leukemia (AML), representing less than 5% of all cases. Acute erythroid leukemia is characterized by a predominant erythroid proliferation, and in the current World Health Organization (WHO) classification scheme there are 2 subtypes: erythroleukemia (erythroid/myeloid leukemia) and pure erythroid leukemia. Morphologic findings are most important for establishing the diagnosis. The erythroleukemia subtype, which is most common, is defined as the presence of 50% or more erythroid precursors and 20% or more blasts in the nonerythroid component. The pure erythroid leukemia subtype is composed of 80% or more immature erythroblasts. Although these morphologic criteria appear straightforward, AEL overlaps with other types of AML and myelodysplastic syndrome that are erythroid rich. To provide an update of AEL, including clinical presentation, morphologic features, immunophenotype, and cytogenetic and molecular data. As the erythroleukemia subtype is most common, the literature and this review are biased towards this subtype of AEL. Clinicopathologic, cytogenetic, and molecular information were extracted from our review of pertinent literature and a subset of AEL cases in the files of The University of Texas M. D. Anderson Cancer Center (Houston) and University of South Alabama (Mobile). The current WHO criteria for establishing the diagnosis of AEL reduce the frequency of this entity, as cases once classified as the erythroleukemia subtype are now reclassified as other types of AML, particularly AML with myelodysplasia-related changes and therapy-related AML. This reclassification also may have prognostic significance for patients with the erythroleukemia subtype of AEL. In contrast, the current WHO criteria appear to have little impact on the frequency and poor prognosis of patients with the pure erythroid leukemia subtype of AEL. Molecular studies, preferably using high-throughput methods, are needed

Erythroleukemia shares biological features and outcome with myelodysplastic syndromes with excess blasts: a rationale for its inclusion into future classifications of myelodysplastic syndromes.

PubMed

Calvo, Xavier; Arenillas, Leonor; Luño, Elisa; Senent, Leonor; Arnan, Montserrat; Ramos, Fernando; Ardanaz, María Teresa; Pedro, Carme; Tormo, Mar; Montoro, Julia; Díez-Campelo, María; Arrizabalaga, Beatriz; Xicoy, Blanca; Bonanad, Santiago; Jerez, Andrés; Nomdedeu, Benet; Ferrer, Ana; Sanz, Guillermo F; Florensa, Lourdes

2016-12-01

Erythroleukemia was considered an acute myeloid leukemia in the 2008 World Health Organization (WHO) classification and is defined by the presence of ≥50% bone marrow erythroblasts, having <20% bone marrow blasts from total nucleated cells but ≥20% bone marrow myeloblasts from nonerythroid cells. Erythroleukemia shares clinicopathologic features with myelodysplastic syndromes, especially with erythroid-predominant myelodysplastic syndromes (≥50% bone marrow erythroblasts). The upcoming WHO revision proposes to eliminate the nonerythroid blast cell count rule and to move erythroleukemia patients into the appropriate myelodysplastic syndrome category on the basis of the absolute blast cell count. We conducted a retrospective study of patients with de novo erythroleukemia and compared their clinico-biological features and outcome with those of de novo myelodysplastic syndromes, focusing on erythroid-predominant myelodysplastic syndromes. Median overall survival of 405 erythroid-predominant myelodysplastic syndromes without excess blasts was significantly longer than that observed in 57 erythroid-predominant refractory anemias with excess blasts-1 and in 59 erythroleukemias, but no significant difference was observed between erythroid-predominant refractory anemias with excess blasts-1 and erythroleukemias. In this subset of patients with ≥50% bone marrow erythroblasts and excess blasts, the presence of a high-risk karyotype defined by the International Prognostic Scoring System or by the Revised International Prognostic Scoring System was the main prognostic factor. In the same way, the survival of 459 refractory anemias with excess blasts-2, independently of having ≥20% bone marrow blasts from nonerythroid cells or not, was almost identical to the observed in 59 erythroleukemias. Interestingly, 11 low-blast count erythroleukemias with 5 to <10% bone marrow blasts from total nucleated cells showed similar survival than the rest of erythroleukemias. Our data

Clofarabine, Cytarabine, and Filgrastim Followed by Infusion of Non-HLA Matched Ex Vivo Expanded Cord Blood Progenitors in Treating Patients With Acute Myeloid Leukemia

ClinicalTrials.gov

2014-08-13

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

SB-715992 in Treating Patients With Acute Leukemia, Chronic Myelogenous Leukemia, or Advanced Myelodysplastic Syndromes

ClinicalTrials.gov

2013-01-10

Acute Undifferentiated Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia

ClinicalTrials.gov

2018-05-21

Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myelomonocytic Leukemia (M4); Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

Acute erythremic myelosis (true erythroleukaemia): a variant of AML FAB-M6.

PubMed

Hasserjian, R P; Howard, J; Wood, A; Henry, K; Bain, B

2001-03-01

Classic erythroleukaemia (acute myeloid leukaemia M6, or M6 AML) is defined as an excess of myeloblasts in an erythroid predominant background. Leukaemia variants in which the primitive blast cells are demonstrably erythroid are extremely rare and poorly characterised. Variably referred to as "true erythroleukaemia" or "acute erythremic myelosis", they are often included within the M6 AML category even though they do not meet strict criteria for this type of AML. Two cases of acute erythroid neoplasia are presented with clinical, morphological, immunophenotypic, and cytogenetic analysis. Both patients presented with profound anaemia, one in a setting of long standing myelodysplasia. Bone marrow examination revealed a predominant population of highly dysplastic erythroid cells in both cases. In one case, the liver was infiltrated by neoplastic erythroid cells. Both patients died within four months of diagnosis. This report illustrates that cases of acute leukaemia occur in which the dominant neoplastic cell is a primitive erythroid cell without an accompanying increase in myeloblasts. This does not preclude the neoplastic clone originating in a multipotent haemopoietic stem cell, as suggested by cases arising in patients with myelodysplasia. Acute erythremic myelosis should be recognised as a distinct variant of M6 AML.

7-Hydroxystaurosporine and Perifosine in Treating Patients With Relapsed or Refractory Acute Leukemia, Chronic Myelogenous Leukemia or High Risk Myelodysplastic Syndromes

ClinicalTrials.gov

2013-09-27

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasms; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

Vorinostat, Cytarabine, and Etoposide in Treating Patients With Relapsed and/or Refractory Acute Leukemia or Myelodysplastic Syndromes or Myeloproliferative Disorders

ClinicalTrials.gov

2013-05-01

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

Acute erythroid neoplastic proliferations. A biological study based on 62 patients.

PubMed

Domingo-Claros, Alicia; Larriba, Itziar; Rozman, Maruja; Irriguible, Dolors; Vallespí, Teresa; Aventin, Anna; Ayats, Ramon; Millá, Fuensanta; Solé, Francesc; Florensa, Lourdes; Gallart, Miquel; Tuset, Esperanza; Lopez, Carmen; Woessner, Soledad

2002-02-01

The terms acute erythroleukemia and AML-M6 are defined in the FAB classification as proliferations of dysplastic erythroid elements mixed with blasts of myeloid origin, but pure erythroid leukemias are not included. The recent WHO classification has a category of acute myeloid leukemia not otherwise categorized, which includes acute erythroid leukemia (M6) of two subtypes: M6a-erythroleukemia (erythroid/myeloid) and M6b-pure erythroid leukemia. The aims of this co-operative study were to discover the incidences of these different subtypes, and pay special attention to the morphology of these entities. We reviewed a series of 62 patients with erythroid neoplastic proliferations. Previous medical history, age, sex, peripheral blood and bone marrow cell counts, cytochemical stains, immunophenotype, and cytogenetics were evaluated at presentation. We analyzed the incidence of erythrocyte, leukocyte and platelet abnormalities in the peripheral blood. In bone marrow we analyzed dysplastic features of erythroblasts, granulocytic elements and the megakaryocytic lineage. Fifty-three patients met the criteria of M6a subtype of the WHO classification, and 2 were classified as having pure erythremia (M6b); 7 cases could not be classified according to the WHO criteria. Fifty-five patients presented with de novo acute leukemia, and seven patients had secondary acute leukemia. The most frequent dysplastic features in blood smears were: schistocytes, tear-drop and pincered cells in erythrocytes; hypogranulation and hyposegmentation in leukocytes; gigantism and hypogranulation in platelets. In bone marrow, megaloblastic changes, multinuclearity, karyorrhexis and basophilic stippling in erythroblasts; hypogranulation and gigantism in granulocytic series, and micromegakaryocytes and unconnected nuclei in megakarocytes were the most dysplastic features. A positive PAS reaction and increase of bone marrow iron with ring sideroblasts were common features. Trilineage dysplasia was

Erythroleukemia cells acquire an alternative mitophagy capability.

PubMed

Wang, Jian; Fang, Yixuan; Yan, Lili; Yuan, Na; Zhang, Suping; Xu, Li; Nie, Meilan; Zhang, Xiaoying; Wang, Jianrong

2016-04-19

Leukemia cells are superior to hematopoietic cells with a normal differentiation potential in buffering cellular stresses, but the underlying mechanisms for this leukemic advantage are not fully understood. Using CRISPR/Cas9 deletion of the canonical autophagy-essential gene Atg7, we found that erythroleukemia K562 cells are armed with two sets of autophagic machinery. Alternative mitophagy is functional regardless of whether the canonical autophagic mechanism is intact or disrupted. Although canonical autophagy defects attenuated cell cycling, proliferation and differentiation potential, the leukemia cells retained their abilities for mitochondrial clearance and for maintaining low levels of reactive oxygen species (ROS) and apoptosis. Treatment with a specific inducer of mitophagy revealed that the canonical autophagy-defective erythroleukemia cells preserved a mitophagic response. Selective induction of mitophagy was associated with the upregulation and localization of RAB9A on the mitochondrial membrane in both wild-type and Atg7(-/-) leukemia cells. When the leukemia cells were treated with the alternative autophagy inhibitor brefeldin A or when the RAB9A was knocked down, this mitophagy was prohibited. This was accompanied by elevated ROS levels and apoptosis as well as reduced DNA damage repair. Therefore, the results suggest that erythroleukemia K562 cells possess an ATG7-independent alternative mitophagic mechanism that functions even when the canonical autophagic process is impaired, thereby maintaining the ability to respond to stresses such as excessive ROS and DNA damage.

Translocation (3;5)(q21;q34) in erythroleukemia: a molecular and in situ hybridization study.

PubMed

Kwong, Y L

1998-05-01

Translocation (3;5) is an uncommon karyotypic aberration in acute myeloid leukemia (AML). With the exception of M3, t(3;5) has been reported in every other subtype of AML, being most frequently associated with AML M6. Although a variety of breakpoints have been described, it has been suggested that the breakpoints in t(3;5) of all the reported cases should be assigned to 3q25.1 and 5q34. Recently, the breakpoints in three pediatric cases of AML M2 with t(3;5) were cloned and shown to involve the myelodysplasia/myeloid leukemia factor I (MLF1) gene on 3q25.1 and the nucleophosmin (NPM) gene on 5q34, generating a chimeric NPM/MLF1 transcript. An adult case of indolent erythroleukemia was found on karyotypic analysis to have t(3;5)(q21;q34). In about 60% of cells, the translocation was unbalanced, resulting in loss of the der(3) chromosome, implying that the critical leukemogenic sequence might reside on the der(5) chromosome. Molecular analysis of this case, however, failed to show rearrangement of the NPM gene and an MLF1/NPM transcript. A review of other reported cases of AML M6 with t(3;5) showed that the commonest breakpoint on chromosome 3 was also assigned to 3q21, as in our case. The considerable clinical, pathologic, cytogenetic and molecular differences observed in AML with t(3;5) suggest that these cases might be heterogeneous.

Acute guttate psoriasis patients have positive streptococcus hemolyticus throat cultures and elevated antistreptococcal M6 protein titers.

PubMed

Zhao, Guang; Feng, Xiaoling; Na, Aihua; Yongqiang, Jiang; Cai, Qing; Kong, Jian; Ma, Huijun

2005-02-01

To further study the role of Streptococci hemolyticus infection and streptococcal M6 protein in the pathogenesis of acute guttate psoriasis, streptococcal cultures were taken from the throats of 68 patients with acute guttate psoriasis. PCR technique was applied to detect M6 protein encoding DNA from those cultured streptococci. Pure M6 protein was obtained by Sephacry/S-200HR and Mono-Q chromatography from proliferated Streptococcus hemolyticus. Antistreptococcal M6 protein titers were measured in the serum of patients with acute guttate psoriasis, plaque psoriasis and healthy controls by ELISA. A high incidence of Streptococcus hemolyticus culture was observed in the guttate psoriatic group compared with the plaque psoriasis and control groups. Fourteen strains of Streptococcus hemolyticus were cultured from the throats of 68 acute guttate psoriasis patients. Of these, 5 strains contain DNA encoding the M6 protein gene as confirmed by PCR technique. More than 85% purification of M6 protein was obtained from Streptococcus pyogenes. Applying our pure M6 protein with the ELISA methods, we found that the titer of antistreptococcal M6 protein was significantly higher in the serum of guttate psoriasis patients than in the control or plaque psoriasis groups (P < 0.01). We verified that patients of acute guttate psoriasis have a high incidence of Streptococcus hemolyticus in their throats and raised titers of antistreptococcal M6 protein in their sera.

Acute erythroid leukemia as defined in the World Health Organization classification is a rare and pathogenetically heterogeneous disease.

PubMed

Kasyan, Armen; Medeiros, L Jeffrey; Zuo, Zhuang; Santos, Favio P; Ravandi-Kashani, Farhad; Miranda, Roberto; Vadhan-Raj, Saroj; Koeppen, Hartmut; Bueso-Ramos, Carlos E

2010-08-01

The diagnostic criteria for acute erythroid leukemia have been controversial since this disease was initially described. Using the current World Health Organization classification criteria, we retrospectively reviewed cases of acute myeloid leukemia or myelodysplastic syndrome in which erythroid precursors were >or=50% of the bone marrow nucleated cell population and the diagnosis of erythroleukemia was considered using older classification schemes. We collected 90 cases and separated them into four diagnostic groups: acute erythroid leukemia, erythroleukemia or erythroid/myeloid type (n=20); acute myeloid leukemia with myelodysplasia-related changes (n=22); therapy-related acute myeloid leukemia (n=32); and refractory anemia with excess blasts and preceding or concurrent history of erythropoietin therapy for anemia (n=16). Patients with acute erythroid leukemia were the youngest patient group and had the best overall survival. There was a statistically significant difference in overall survival between patients with acute erythroid leukemia versus acute myeloid leukemia with myelodysplasia-related changes (P=0.003) and between patients with acute erythroid leukemia versus therapy-related acute myeloid leukemia (P<0.0001). The presence of complex cytogenetic abnormalities (>3) was the only statistically significant independent variable that adversely affected survival in the acute erythroid leukemia group. Monosomy 5/del(5q) and monosomy 7/del(7q) were overrepresented in the context of complex chromosomal abnormalities. Our data suggest that acute erythroid leukemia, as currently defined in the World Health Organization classification, has become a rare disease. A majority of the cases reported previously as erythroleukemia are now classified as other entities. In addition, our data suggest that the current definition of acute erythroid leukemia, erythroleukemia type remains heterogeneous. One subset of acute erythroid leukemia patients has relatively low blast

Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin for Older Patients With Relapsed or Refractory AML

ClinicalTrials.gov

2015-01-22

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia

Decitabine Followed by Idarubicin and Cytarabine in Treating Patients With Relapsed or Refractory AML and MDS

ClinicalTrials.gov

2017-02-14

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts

Successful treatment of congenital acute myeloid leukemia (AML-M6) in a premature infant.

PubMed

van Dongen, Joyce C A; Dalinghaus, Michiel; Kroon, Andre A; de Vries, Andrica C H; van den Heuvel-Eibrink, Marry M

2009-11-01

Congenital acute myeloid leukemia (AML), and especially AML-M6 is a rare disease with a poor prognosis. Moreover, reports of treatment outcome of congenital AML-M6 in premature infants are not available. We report the first treated case of congenital AML-M6 in a premature girl, who received a full AML protocol. She presented with blueberry-muffin spots, anemia, high white blood cell count, and serious cardiopulmonary distress. Peripheral blood smears showed AML-M6 blasts. After treatment with a sequential low-dose cytarabine after birth and full-dose AML treatment according to the MRC-12 protocol at the age of 2 months, she now is in continuous complete remission for 4 years.

AML Therapy With Irradiated Allogeneic Cells

ClinicalTrials.gov

2017-02-01

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Genetic alterations of m6A regulators predict poorer survival in acute myeloid leukemia.

PubMed

Kwok, Chau-To; Marshall, Amy D; Rasko, John E J; Wong, Justin J L

2017-02-02

Methylation of N 6 adenosine (m 6 A) is known to be important for diverse biological processes including gene expression control, translation of protein, and messenger RNA (mRNA) splicing. However, its role in the development of human cancers is poorly understood. By analyzing datasets from the Cancer Genome Atlas Research Network (TCGA) acute myeloid leukemia (AML) study, we discover that mutations and/or copy number variations of m 6 A regulatory genes are strongly associated with the presence of TP53 mutations in AML patients. Further, our analyses reveal that alterations in m 6 A regulatory genes confer a worse survival in AML. Our work indicates that genetic alterations of m 6 A regulatory genes may cooperate with TP53 and/or its regulator/downstream targets in the pathogenesis and/or maintenance of AML.

Pure erythroid leukemia following precursor B-cell lymphoblastic leukemia.

PubMed

Xu, Min; Finn, Laura S; Tsuchiya, Karen D; Thomson, Blythe; Pollard, Jessica; Rutledge, Joe

2012-01-01

Therapy-related acute myeloid leukemia is an unfortunate sequel to current multimodal intensive chemotherapy. The patient described was diagnosed with pure erythroleukemia, AML-M6b, during therapy for precursor B-cell acute lymphoblastic leukemia. To the best of our knowledge, this is the first report of this unusual association.

Specific binding of sup 125 I-rErythropoietin to Friend polycythemia virus-transformed erythroleukemia cells purified by centrifugal elutriation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Correa, P.N.; Bard, V.; Axelrad, A.A.

1990-01-01

We have used countercurrent centrifugal elutriation (CCE) to determine the distribution of cells with respect to cell volume and buoyant density for an erythroleukemia cell line (JG6) transformed by the polycythemia strain of Friend virus (FV-P), and to determine the effect of inducing the cells to differentiate with dimethylsulfoxide (DMSO) on this distribution. CCE made it possible to obtain suspensions of modal JG6 populations virtually free of dead cells and uniform with respect to volume and buoyant density. These modal populations were assayed for specific binding of erythropoietin (Epo). Between 500 and 550 Epo receptors per cell were detected. Thesemore » belonged to a single class having a dissociation constant of 0.36 nM. DMSO induction of differentiation of the JG6 cells had no effect on the number of Epo receptors expressed.« less

Metformin+Cytarabine for the Treatment of Relapsed/Refractory AML

ClinicalTrials.gov

2017-09-12

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Treatment for Relapsed/Refractory AML Based on a High Throughput Drug Sensitivity Assay

ClinicalTrials.gov

2018-04-11

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Chronic Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts

Tipifarnib in Treating Older Patients With Acute Myeloid Leukemia

ClinicalTrials.gov

2015-03-19

Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Cyclophosphamide for Prevention of Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation in Patients With Hematological Malignancies

ClinicalTrials.gov

2017-05-17

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Myeloid Leukemia in Remission; Adult Erythroleukemia (M6a); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Pure Erythroid Leukemia (M6b); Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell

Azacitidine and Gemtuzumab Ozogamicin in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia

ClinicalTrials.gov

2018-04-20

Acute Myeloid Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Tipifarnib in Treating Patients With Acute Myeloid Leukemia in Remission

ClinicalTrials.gov

2018-03-20

Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Myelodysplastic Syndrome With Excess Blasts; Recurrent Adult Acute Myeloid Leukemia

High-Dose Busulfan and High-Dose Cyclophosphamide Followed By Donor Bone Marrow Transplant in Treating Patients With Leukemia, Myelodysplastic Syndrome, Multiple Myeloma, or Recurrent Hodgkin or Non-Hodgkin Lymphoma

ClinicalTrials.gov

2010-08-05

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With T(15;17)(q22;q12); Adult Acute Myeloid Leukemia With T(16;16)(p13;q22); Adult Acute Myeloid Leukemia With T(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Pure Erythroid Leukemia (M6b); Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Burkitt Lymphoma; Childhood Acute Erythroleukemia (M6); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myeloid Leukemia in Remission; Childhood Acute Myelomonocytic Leukemia (M4); Childhood Acute Promyelocytic Leukemia (M3); Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; De Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-Cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent

Cytarabine With or Without SCH 900776 in Treating Adult Patients With Relapsed Acute Myeloid Leukemia

ClinicalTrials.gov

2016-07-20

Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia

Donor Umbilical Cord Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

ClinicalTrials.gov

2015-12-18

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Erythroleukemia (M6a); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Pure Erythroid Leukemia (M6b); B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Burkitt Lymphoma; Childhood Acute Erythroleukemia (M6); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Juvenile Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult

Adsorption and transport of charged vs. neutral hydrophobic molecules at the membrane of murine erythroleukemia (MEL) cells.

PubMed

Zeng, Jia; Eckenrode, Heather M; Dai, Hai-Lung; Wilhelm, Michael J

2015-03-01

The adsorption and transport of hydrophobic molecules at the membrane surface of pre- and post-DMSO induced differentiated murine erythroleukemia (MEL) cells were examined by time- and wavelength-resolved second harmonic light scattering. Two medium (<600 Da) hydrophobic molecules, cationic malachite green (MG) and neutral bromocresol purple (BCP), were investigated. While it was observed that the MG cation adsorbs onto the surface of the MEL cell, neutral BCP does not. It is suggested that an electrostatic interaction between the opposite charges of the cation and the MEL cell surface is the primary driving force for adsorption. Comparisons of adsorption density and free energy, measured at different pH and cell morphology, indicate that the interaction is predominantly through sialic acid carboxyl groups. MG cation adsorption densities have been determined as (0.6±0.3)×10(6) μm(-2) on the surface of undifferentiated MEL cells, and (1.8±0.5)×10(7) μm(-2) on differentiated MEL cells, while the deduced adsorption free energies are effectively identical (ca. -10.9±0.1 and -10.8±0.1 kcal mol(-1), respectively). The measured MG densities indicate that the total number of surface carboxyl groups is largely conserved following differentiation, and therefore the density of carboxylic groups is much larger on the differentiated cell surface than the undifferentiated one. Finally, in contrast to synthetic liposomes and bacterial membranes, surface adsorbed MG cations are unable to traverse the MEL cell membrane. Copyright © 2015 Elsevier B.V. All rights reserved.

Curcumin-Loaded Blood-Stable Polymeric Micelles for Enhancing Therapeutic Effect on Erythroleukemia.

PubMed

Gong, Feirong; Chen, Dan; Teng, Xin; Ge, Junhua; Ning, Xianfeng; Shen, Ya-Ling; Li, Jian; Wang, Shanfeng

2017-08-07

Curcumin has high potential in suppressing many types of cancer and overcoming multidrug resistance in a multifaceted manner by targeting diverse molecular targets. However, the rather low systemic bioavailability resulted from its poor solubility in water and fast metabolism/excretion in vivo has hampered its applications in cancer therapy. To increase the aqueous solubility of curcumin while retaining the stability in blood circulation, here we report curcumin-loaded copolymer micelles with excellent in vitro and in vivo stability and antitumor efficacy. The two copolymers used for comparison were methoxy-poly(ethylene glycol)-block-poly(ε-caprolactone) (mPEG-PCL) and N-(tert-butoxycarbonyl)-l-phenylalanine end-capped mPEG-PCL (mPEG-PCL-Phe(Boc)). In vitro cytotoxicity evaluation against human pancreatic SW1990 cell line showed that the delivery of curcumin in mPEG-PCL-Phe(Boc) micelles to cancer cells was efficient and dosage-dependent. The pharmacokinetics in ICR mice indicated that intravenous (i.v.) administration of curcumin/mPEG-PCL-Phe(Boc) micelles could retain curcumin in plasma much better than curcumin/mPEG-PCL micelles. Biodistribution results in Sprague-Dawley rats also showed higher uptake and slower elimination of curcumin into liver, lung, kidney, and brain, and lower uptake into heart and spleen of mPEG-PCL-Phe(Boc) micelles, as compared with mPEG-PCL micelles. Further in vivo efficacy evaluation in multidrug-resistant human erythroleukemia K562/ADR xenograft model revealed that i.v. administration of curcumin-loaded mPEG-PCL-Phe(Boc) micelles significantly delayed tumor growth, which was attributed to the improved stability of curcumin in the bloodstream and increased systemic bioavailability. The mPEG-PCL-Phe(Boc) micellar system is promising in overcoming the key challenge of curcumin's to promote its applications in cancer therapy.

17-N-Allylamino-17-Demethoxygeldanamycin and Bortezomib in Treating Patients With Relapsed or Refractory Hematologic Cancer

ClinicalTrials.gov

2013-06-03

Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

Osteolytic Bone Lesions - A Rare Presentation of AML M6.

PubMed

Geetha, N; Sreelesh, K P; Priya, M J; Lali, V S; Rekha, N

2015-01-01

Acute myeloid leukemia (AML) M6 is a rare form of AML accounting for < 5 % of all AML. Extramedullary involvement is very rarely seen in this entity. Skeletal lesion has not been described in AML M6 before. We discuss the case of a 17 year old boy with AML M6, who presented with osteolytic lesion of right humerus. He was treated with induction and consolidation chemotherapy. The present case is the first report in literature of AML M6 presenting with skeletal lesions.

Cyclopamine and jervine induce COX-2 overexpression in human erythroleukemia cells but only cyclopamine has a pro-apoptotic effect

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ghezali, Lamia; Leger, David Yannick; Limami, Youness

2013-04-15

Erythroleukemia is generally associated with a very poor response and survival to current available therapeutic agents. Cyclooxygenase-2 (COX-2) has been described to play a crucial role in the proliferation and differentiation of leukemia cells, this enzyme seems to play an important role in chemoresistance in different cancer types. Previously, we demonstrated that diosgenin, a plant steroid, induced apoptosis in HEL cells with concomitant COX-2 overexpression. In this study, we investigated the antiproliferative and apoptotic effects of cyclopamine and jervine, two steroidal alkaloids with similar structures, on HEL and TF1a human erythroleukemia cell lines and, for the first time, their effectmore » on COX-2 expression. Cyclopamine, but not jervine, inhibited cell proliferation and induced apoptosis in these cells. Both compounds induced COX-2 overexpression which was responsible for apoptosis resistance. In jervine-treated cells, COX-2 overexpression was NF-κB dependent. Inhibition of NF-κB reduced COX-2 overexpression and induced apoptosis. In addition, cyclopamine induced apoptosis and COX-2 overexpression via PKC activation. Inhibition of the PKC pathway reduced both apoptosis and COX-2 overexpression in both cell lines. Furthermore, we demonstrated that the p38/COX-2 pathway was involved in resistance to cyclopamine-induced apoptosis since p38 inhibition reduced COX-2 overexpression and increased apoptosis in both cell lines. - Highlights: ► Cyclopamine alone but not jervine induces apoptosis in human erythroleukemia cells. ► Cyclopamine and jervine induce COX-2 overexpression. ► COX-2 overexpression is implicated in resistance to cyclopamine-induced apoptosis. ► Apoptotic potential of jervine is restrained by NF-κB pathway activation. ► PKC is involved in cyclopamine-induced apoptosis and COX-2 overexpression.« less

Evidence That Ly6C(hi) Monocytes are Protective in Acute Ischemic Stroke by Promoting M2 Macrophage Polarization.

PubMed

Chu, Hannah X; Broughton, Brad R S; Kim, Hyun Ah; Lee, Seyoung; Drummond, Grant R; Sobey, Christopher G

2015-07-01

Ly6C(hi) monocytes are generally thought to exert a proinflammatory role in acute tissue injury, although their impact after injuries to the central nervous system is poorly defined. CC chemokine receptor 2 is expressed on Ly6C(hi) monocytes and plays an essential role in their extravasation and transmigration into the brain after cerebral ischemia. We used a selective CC chemokine receptor 2 antagonist, INCB3344, to assess the effect of Ly6C(hi) monocytes recruited into the brain early after ischemic stroke. Male C57Bl/6J mice underwent occlusion of the middle cerebral artery for 1 hour followed by 23 hours of reperfusion. Mice were administered either vehicle (dimethyl sulfoxide/carboxymethylcellulose) or INCB3344 (10, 30 or 100 mg/kg IP) 1 hour before ischemia and at 2 and 6 hours after ischemia. At 24 hours, we assessed functional outcomes, infarct volume, and quantified the immune cells in blood and brain by flow cytometry or immunofluorescence. Gene expression of selected inflammatory markers was assessed by quantitative polymerase chain reaction. Ly6C(hi) monocytes were increased 3-fold in the blood and 10-fold in the brain after stroke, and these increases were selectively prevented by INCB3344 in a dose-dependent manner. Mice treated with INCB3344 exhibited markedly worse functional outcomes and larger infarct volumes, in association with reduced M2 polarization and increased peroxynitrite production in macrophages, compared with vehicle-treated mice. Our data suggest that Ly6C(hi) monocytes exert an acute protective effect after ischemic stroke to limit brain injury and functional deficit that involves promotion of M2 macrophage polarization. © 2015 American Heart Association, Inc.

Further considerations on the thermal stabilization of the nuclear matrix in mouse erythroleukemia cells.

PubMed

Martelli, A M; Falcieri, E; Gobbi, P; Manzoli, L; Cataldi, A; Rana, R A; Cocco, L

1992-04-01

The morphology and the polypeptide composition of the nuclear matrix obtained from 37 degrees C incubated nuclei has been studied in mouse erythroleukemia cells. From a structural point of view, in the absence of heat treatment, the matrix lacked identifiable nucleolar remnants and the internal fibrogranular meshwork whereas a peripheral lamina was seen. On the contrary, the matrix obtained from heat exposed nuclei displayed very electrondense nucleolar remnants and an abundant inner network. These results were obtained irrespective of the type of extracting agent (2M NaCl or 0.2 M (NH4)2SO4) used to remove histones and other soluble proteins. The heat stabilization of the matrix could not be prevented by sulfhydryl blocking chemicals such as iodoacetamide and n-ethylmaleimide, thus suggesting that heat does not stabilize the matrix by inducing the formation of disulfide bonds. Only limited differences in the polypeptide pattern of matrix isolated under different conditions were seen using one-dimensional pore gradient polyacrylamide gels stained with both Coomassie Brilliant Blue and silver despite the fact that the matrix fraction from heat treated nuclei retained about three fold more protein in comparison with controls. The same results were obtained also by means of two-dimensional non-equilibrium gel electrophoresis.

Importance of interferon alpha in the resistance of allogeneic C57B1/6 mice to the multiplication of Friend erythroleukemia cells in the liver.

PubMed

Gresser, I; Maury, C; Bandu, M T; Belardelli, F

1990-02-15

Friend erythroleukemia cells (FLC) (H-2d) injected intravenously multiply extensively in the livers of syngeneic DBA/2 mice and not at all in the livers of allogeneic C57B1/6 mice. Our results indicate that interferon alpha (IFN-alpha) is an important factor in the resistance of allogeneic mice to the multiplication of FLC in the liver. (a) After i.v. inoculation of FLC there was an inverse correlation between the presence of IFN-alpha in the serum and the capacity of FLC to multiply in the liver. Thus, all 44 FLC-injected adult C57B1/6 mice had circulating IFN-alpha and FLC did not multiply in the liver of any of the mice. Interferon was not detected in the serum of 83% of 41 FLC-injected DBA/2 mice (and was found only at a low titer in 17% of the mice) and FLC multiplied in the liver of all mice. (b) FLC did multiply in the livers of newborn C57B1/6 mice and in the livers of irradiated adult C57B1/6 mice, and IFN-alpha was not detected in their sera. In contrast, after i.v. inoculation of FLC, IFN-alpha was detected in the sera of 3-week-old and athymic nu/nu adult C57B1/6 mice while FLC failed to multiply in the liver. (c) FLC also induced IFN-alpha in congenic B10.D2 (H-2d) mice and FLC did not multiply in the liver. We suggest that, depending on the site of tumor implantation, different host mechanisms have various degrees of importance in controlling the growth and/or rejection of allogeneic tumor cells, and that IFN-alpha is particularly important when FLC are injected i.v.

Acute myotube protein synthesis regulation by IL-6-related cytokines.

PubMed

Gao, Song; Durstine, J Larry; Koh, Ho-Jin; Carver, Wayne E; Frizzell, Norma; Carson, James A

2017-11-01

IL-6 and leukemia inhibitory factor (LIF), members of the IL-6 family of cytokines, play recognized paradoxical roles in skeletal muscle mass regulation, being associated with both growth and atrophy. Overload or muscle contractions can induce a transient increase in muscle IL-6 and LIF expression, which has a regulatory role in muscle hypertrophy. However, the cellular mechanisms involved in this regulation have not been completely identified. The induction of mammalian target of rapamycin complex 1 (mTORC1)-dependent myofiber protein synthesis is an established regulator of muscle hypertrophy, but the involvement of the IL-6 family of cytokines in this process is poorly understood. Therefore, we investigated the acute effects of IL-6 and LIF administration on mTORC1 signaling and protein synthesis in C2C12 myotubes. The role of glycoprotein 130 (gp130) receptor and downstream signaling pathways, including phosphoinositide 3-kinase (PI3K)-Akt-mTORC1 and signal transducer and activator of transcription 3 (STAT3)-suppressor of cytokine signaling 3 (SOCS3), was investigated by administration of specific siRNA or pharmaceutical inhibitors. Acute administration of IL-6 and LIF induced protein synthesis, which was accompanied by STAT3 activation, Akt-mTORC1 activation, and increased SOCS3 expression. This induction of protein synthesis was blocked by both gp130 siRNA knockdown and Akt inhibition. Interestingly, STAT3 inhibition or Akt downstream mTORC1 signaling inhibition did not fully block the IL-6 or LIF induction of protein synthesis. SOCS3 siRNA knockdown increased basal protein synthesis and extended the duration of the protein synthesis induction by IL-6 and LIF. These results demonstrate that either IL-6 or LIF can activate gp130-Akt signaling axis, which induces protein synthesis via mTORC1-independent mechanisms in cultured myotubes. However, IL-6- or LIF-induced SOCS3 negatively regulates the activation of myotube protein synthesis. Copyright © 2017 the

Ptpmt1 induced by HIF-2α regulates the proliferation and glucose metabolism in erythroleukemia cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Qin-Qin; Qinghai Provincial People's Hospital, Xining; Xiao, Feng-Jun

Hypoxia provokes metabolism misbalance, mitochondrial dysfunction and oxidative stress in both human and animal cells. However, the mechanisms which hypoxia causes mitochondrial dysfunction and energy metabolism misbalance still remain unclear. In this study, we presented evidence that mitochondrial phosphatase Ptpmt1 is a hypoxia response molecule that regulates cell proliferation, survival and glucose metabolism in human erythroleukemia TF-1 cells. Exposure to hypoxia or DFO treatment results in upregulation of HIF1-α, HIF-2α and Ptpmt1. Only inhibition of HIF-2α by shRNA transduction reduces Ptpmt1 expression in TF-1 cells under hypoxia. Ptpmt1 inhibitor suppresses the growth and induces apoptosis of TF-1 cells. Furthermore, we demonstrated that Ptpmt1more » inhibition reduces the Glut1 and Glut3 expression and decreases the glucose consumption in TF-1 cells. In additional, Ptpmt1 knockdown also results in the mitochondrial dysfunction determined by JC1 staining. These results delineate a key role for HIF-2α-induced Ptpmt1 upregulation in proliferation, survival and glucose metabolism of erythroleukemia cells. It is indicated that Ptpmt1 plays important roles in hypoxia-induced cell metabolism and mitochondrial dysfunction. - Highlights: • Hypoxia induces upregulation of HIF-1α, HIF-2α and Ptpmt1; HIF-2a induces Ptpmt1 upregulation in TF-1 cells. • PTPMT-1 inhibition reduces growth and induces apoptosis of TF-1 cells. • PTPMT1 inhibition downregulates Glut-1, Glut-3 expression and reduces glucose consumption.« less

SIRS score on admission and initial concentration of IL-6 as severe acute pancreatitis outcome predictors.

PubMed

Gregoric, Pavle; Pavle, Gregoric; Sijacki, Ana; Ana, Sijacki; Stankovic, Sanja; Sanja, Stankovic; Radenkovic, Dejan; Dejan, Radenkovic; Ivancevic, Nenad; Nenad, Ivancevic; Karamarkovic, Aleksandar; Aleksandar, Karamarkovic; Popovic, Nada; Nada, Popovic; Karadzic, Borivoje; Borivoje, Karadzic; Stijak, Lazar; Stefanovic, Branislav; Branislav, Stefanovic; Milosevic, Zoran; Zoran, Milosević; Bajec, Djordje; Djordje, Bajec

2010-01-01

Early recognition of severe form of acute pancreatitis is important because these patients need more agressive diagnostic and therapeutical approach an can develope systemic complications such as: sepsis, coagulopathy, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), Multiple Organ Dysfunction Syndrome (MODS), Multiple Organ Failure (MOF). To determine role of the combination of Systemic Inflammatory Response Syndrome (SIRS) score and serum Interleukin-6 (IL-6) level on admission as predictor of illness severity and outcome of Severe Acute Pancreatitis (SAP). We evaluated 234 patients with first onset of SAP appears in last twenty four hours. A total of 77 (33%) patients died. SIRS score and serum IL-6 concentration were measured in first hour after admission. In 105 patients with SIRS score 3 and higher, initial measured IL-6 levels were significantly higher than in the group of remaining 129 patients (72 +/- 67 pg/mL, vs 18 +/- 15 pg/mL). All nonsurvivals were in the first group, with SIRS score 3 and 4 and initial IL-6 concentration 113 +/- 27 pg/mL. The values of C-reactive Protein (CRP) measured after 48h, Acute Physiology and Chronic Health Evaluation (APACHE II) score on admission and Ranson score showed the similar correlation, but serum amylase level did not correlate significantly with Ranson score, IL-6 concentration and APACHE II score. The combination of SIRS score on admission and IL-6 serum concentration can be early, predictor of illness severity and outcome in SAP.

/sup 99m/Tc-IDA imaging in the differential diagnosis of acute cholecystitis and acute pancreatitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fonseca, C.; Greenberg, D.; Rosenthall, L.

1979-02-01

Technetium-/sup 99m/-labelled dimethly-acetanilide-iminodiacetic acid (/sup 99m/Tc-IDA) hepato-biliary imaging was evaluated for its efficacy in distinguishing acute cholecystitis from acute pancreatitis. In a retrospective review, gallbladders were demonstrated by /sup 99m/Tc-IDA in 13 of 15 patients (87%) with acute pancreatitis. This is significantly higher than reports on the frequency of gallbladder filling with oral and intravenous cholangiography in the presence of acute cholecystitis.

Safety and Feasibility of the 6-Minute Walk Test in Patients with Acute Stroke.

PubMed

Kubo, Hiroki; Nozoe, Masafumi; Yamamoto, Miho; Kamo, Arisa; Noguchi, Madoka; Kanai, Masashi; Mase, Kyoshi; Shimada, Shinichi

2018-06-01

Our objective was to investigate the safety and feasibility of the 6-minute walk test in patients with acute stroke. Consecutive patients with acute stroke, admitted to the Itami Kosei Neurosurgical Hospital from September 2016 to April 2017 were enrolled. Walking capacity was assessed by a physical therapist using the 6-minute walk test in 94 patients with acute stroke within 14 days of hospital admission. The primary outcomes were safety (i.e., the prevalence of new adverse events during and after the test) and feasibility (i.e., test completion rate) of the 6-minute walk test. The 6-minute walk test was performed for a mean duration of 5.1 days (standard deviation, 2.6 days) after hospital admission. Seventy patients (74.5%) could walk without standby assistance or a walking aid, and 24 patients (25.5%) could walk without standby assistance but with a walking aid. The average distance walked by patients during the 6-minute walk test was 331 m (standard deviation, 107.2 m). Adverse events following the 6-minute walk test occurred in 6 patients (6.4%) and included stroke progression, stroke recurrence, seizures, and neurological deterioration. Heart rate increase (>120 beats/min) occurred in 3 patients (3.2%) during the test. Lastly, 6 patients (6.4%) were unable to complete the 6-minute walk test. Although performance in the 6-minute walk test was decreased in patients with acute stroke, the test itself appears to be safe and feasible in this patient population. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Increased cyclooxygenase-2 and thromboxane synthase expression is implicated in diosgenin-induced megakaryocytic differentiation in human erythroleukemia cells.

PubMed

Cailleteau, C; Liagre, B; Battu, S; Jayat-Vignoles, C; Beneytout, J L

2008-09-01

Differentiation induction as a therapeutic strategy has, so far, the greatest impact in hematopoietic malignancies, most notably leukemia. Diosgenin is a very interesting natural product because, depending on the specific dose used, its biological effect is very different in HEL (human erythroleukemia) cells. For example, at 10 microM, diosgenin induced megakaryocytic differentiation, in contrast to 40 microM diosgenin, which induced apoptosis in HEL cells previously demonstrated using sedimentation field-flow fractionation (SdFFF). The goal of this work focused on the correlation between cyclooxygenase-2 (COX-2) and thromboxane synthase (TxS) and megakaryocytic differentiation induced by diosgenin in HEL cells. Furthermore, the technique of SdFFF, having been validated in our models, was used in this new study as an analytical tool that provided us with more or less enriched differentiated cell fractions that could then be used for further analyses of enzyme protein expression and activity for the first time. In our study, we showed the implication of COX-2 and TxS in diosgenin-induced megakaryocytic differentiation in HEL cells. Furthermore, we showed that the analytical technique of SdFFF may be used as a tool to confirm our results as a function of the degree of cell differentiation.

Leukemic blast cell colony formation in semisolid culture with erythropoietin: a case report of acute poorly differentiated erythroid leukemia.

PubMed

Tomonaga, M; Jinnai, I; Tagawa, M; Amenomori, T; Nishino, K; Yao, E; Nonaka, H; Kuriyama, K; Yoshida, Y; Matsuo, T

1987-02-01

The bone marrow of a patient with acute undifferentiated leukemia developed unique colonies after a 14-day culture in erythropoietin (EPO)-containing methylcellulose. The colonies consisted of 20 to 200 nonhemoglobinized large blast cells. Cytogenetic analysis of single colonies revealed hypotetraploid karyotypes with several marker chromosomes that were identical to those found in directly sampled bone marrow. The concurrently formed erythroid bursts showed only normal karyotypes. No leukemic colony formation was observed in other culture systems with either colony-stimulating activity (CSA) or phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM). The leukemic colonies exhibited a complete EPO-dose dependency similar to that of the patient's normal BFU-E. Although cytochemical and immunologic marker studies of the bone marrow cells failed to clarify the cell lineage of the leukemic cells with extraordinarily large cell size, ultrastructural study revealed erythroid differentiation such as siderosome formation in the cytoplasm and ferritin particles in the rhophecytosis invaginations. These findings indicate that the patient had poorly differentiated erythroid leukemia and that some of the clonogenic cells might respond to EPO in vitro. Corresponding to this biological feature, the leukemic cells were markedly decreased in number in response to repeated RBC transfusions, and partial remission was obtained. These observations suggest that erythroid leukemia distinct from erythroleukemia (M6) with a myeloblastic component, can develop as a minor entity of human acute leukemia.

Veliparib and Topotecan With or Without Carboplatin in Treating Patients With Relapsed or Refractory Acute Leukemia, High-Risk Myelodysplasia, or Aggressive Myeloproliferative Disorders

ClinicalTrials.gov

2018-04-20

Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Essential Thrombocythemia; Hematopoietic and Lymphoid Cell Neoplasm; Myelodysplastic Syndrome; Philadelphia Chromosome Negative, BCR-ABL1 Positive Chronic Myelogenous Leukemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Disease; Secondary Myelodysplastic Syndrome

Kinetics of ultraweak light emission from human erythroleukemia K562 cells upon electroporation.

PubMed

Maccarrone, M; Fantini, C; Agrò, A F; Rosato, N

1998-11-11

Electroporation involves the application of an electric pulse that creates transient aqueous channels (electropores) across the lipid bilayer membranes. Here, we describe an instrument set up suitable to record ultraweak light emission from human erythroleukemia K562 cells during and immediately after delivery of electric pulses. Most of light was emitted in the first seconds after each pulse, following a complex decay which can be fitted by a double exponential equation characterized by two different time constants (T1 and T2), both in the order of seconds. T1 was approximately 10-fold shorter than T2 and both time constants were dependent on field strength of the electric pulse. The effect of various antioxidants on the amount of emitted photons and on T1 and T2 values was investigated, in order to shed some light on the chemical species responsible for cellular luminescence.

High seroprevalence of Mycoplasma pneumoniae IgM in acute Q fever by enzyme-linked immunosorbent assay (ELISA).

PubMed

Lai, Chung-Hsu; Chang, Lin-Li; Lin, Jiun-Nong; Chen, Wei-Fang; Kuo, Li-Li; Lin, Hsi-Hsun; Chen, Yen-Hsu

2013-01-01

Q fever is serologically cross-reactive with other intracellular microorganisms. However, studies of the serological status of Mycoplasma pneumoniae and Chlamydophila pneumoniae during Q fever are rare. We conducted a retrospective serological study of M. pneumoniae and C. pneumoniae by enzyme-linked immunosorbent assay (ELISA), a method widely used in clinical practice, in 102 cases of acute Q fever, 39 cases of scrub typhus, and 14 cases of murine typhus. The seropositive (57.8%, 7.7%, and 0%, p<0.001) and seroconversion rates (50.6%, 8.8%, and 0%, p<0.001) of M. pneumoniae IgM, but not M. pneumoniae IgG and C. pneumoniae IgG/IgM, in acute Q fever were significantly higher than in scrub typhus and murine typhus. Another ELISA kit also revealed a high seropositivity (49.5%) and seroconversion rate (33.3%) of M. pneumoniae IgM in acute Q fever. The temporal and age distributions of patients with positive M. pneumoniae IgM were not typical of M. pneumoniae pneumonia. Comparing acute Q fever patients who were positive for M. pneumoniae IgM (59 cases) with those who were negative (43 cases), the demographic characteristics and underlying diseases were not different. In addition, the clinical manifestations associated with atypical pneumonia, including headache (71.2% vs. 81.4%, p=0.255), sore throat (8.5% vs. 16.3%, p=0.351), cough (35.6% vs. 23.3%, p=0.199), and chest x-ray suggesting pneumonia (19.3% vs. 9.5%, p=0.258), were unchanged between the two groups. Clinicians should be aware of the high seroprevalence of M. pneumoniae IgM in acute Q fever, particularly with ELISA kits, which can lead to misdiagnosis, overestimations of the prevalence of M. pneumoniae pneumonia, and underestimations of the true prevalence of Q fever pneumonia.

High Seroprevalence of Mycoplasma pneumoniae IgM in Acute Q Fever by Enzyme-Linked Immunosorbent Assay (ELISA)

PubMed Central

Lai, Chung-Hsu; Chang, Lin-Li; Lin, Jiun-Nong; Chen, Wei-Fang; Kuo, Li-Li; Lin, Hsi-Hsun; Chen, Yen-Hsu

2013-01-01

Q fever is serologically cross-reactive with other intracellular microorganisms. However, studies of the serological status of Mycoplasma pneumoniae and Chlamydophila pneumoniae during Q fever are rare. We conducted a retrospective serological study of M. pneumoniae and C. pneumoniae by enzyme-linked immunosorbent assay (ELISA), a method widely used in clinical practice, in 102 cases of acute Q fever, 39 cases of scrub typhus, and 14 cases of murine typhus. The seropositive (57.8%, 7.7%, and 0%, p<0.001) and seroconversion rates (50.6%, 8.8%, and 0%, p<0.001) of M. pneumoniae IgM, but not M. pneumoniae IgG and C. pneumoniae IgG/IgM, in acute Q fever were significantly higher than in scrub typhus and murine typhus. Another ELISA kit also revealed a high seropositivity (49.5%) and seroconversion rate (33.3%) of M. pneumoniae IgM in acute Q fever. The temporal and age distributions of patients with positive M. pneumoniae IgM were not typical of M. pneumoniae pneumonia. Comparing acute Q fever patients who were positive for M. pneumoniae IgM (59 cases) with those who were negative (43 cases), the demographic characteristics and underlying diseases were not different. In addition, the clinical manifestations associated with atypical pneumonia, including headache (71.2% vs. 81.4%, p=0.255), sore throat (8.5% vs. 16.3%, p=0.351), cough (35.6% vs. 23.3%, p=0.199), and chest x-ray suggesting pneumonia (19.3% vs. 9.5%, p=0.258), were unchanged between the two groups. Clinicians should be aware of the high seroprevalence of M. pneumoniae IgM in acute Q fever, particularly with ELISA kits, which can lead to misdiagnosis, overestimations of the prevalence of M. pneumoniae pneumonia, and underestimations of the true prevalence of Q fever pneumonia. PMID:24147043

m6A-Driver: Identifying Context-Specific mRNA m6A Methylation-Driven Gene Interaction Networks

PubMed Central

Zhang, Song-Yao; Zhang, Shao-Wu; Liu, Lian; Huang, Yufei

2016-01-01

As the most prevalent mammalian mRNA epigenetic modification, N6-methyladenosine (m6A) has been shown to possess important post-transcriptional regulatory functions. However, the regulatory mechanisms and functional circuits of m6A are still largely elusive. To help unveil the regulatory circuitry mediated by mRNA m6A methylation, we develop here m6A-Driver, an algorithm for predicting m6A-driven genes and associated networks, whose functional interactions are likely to be actively modulated by m6A methylation under a specific condition. Specifically, m6A-Driver integrates the PPI network and the predicted differential m6A methylation sites from methylated RNA immunoprecipitation sequencing (MeRIP-Seq) data using a Random Walk with Restart (RWR) algorithm and then builds a consensus m6A-driven network of m6A-driven genes. To evaluate the performance, we applied m6A-Driver to build the context-specific m6A-driven networks for 4 known m6A (de)methylases, i.e., FTO, METTL3, METTL14 and WTAP. Our results suggest that m6A-Driver can robustly and efficiently identify m6A-driven genes that are functionally more enriched and associated with higher degree of differential expression than differential m6A methylated genes. Pathway analysis of the constructed context-specific m6A-driven gene networks further revealed the regulatory circuitry underlying the dynamic interplays between the methyltransferases and demethylase at the epitranscriptomic layer of gene regulation. PMID:28027310

Busulfan, Fludarabine Phosphate, and Anti-Thymocyte Globulin Followed By Donor Stem Cell Transplant and Azacitidine in Treating Patients With High-Risk Myelodysplastic Syndrome and Older Patients With Acute Myeloid Leukemia

ClinicalTrials.gov

2018-03-05

Acute Myeloid Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; de Novo Myelodysplastic Syndrome; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome; Untreated Adult Acute Myeloid Leukemia

The PPARdelta agonist GW501516 suppresses interleukin-6-mediated hepatocyte acute phase reaction via STAT3 inhibition.

PubMed

Kino, T; Rice, K C; Chrousos, G P

2007-05-01

Interleukin-6 and downstream liver effectors acute phase reactants are implicated in the systemic inflammatory reaction. Peroxisome proliferator-activated receptor delta (PPARdelta), which binds to and is activated by a variety of fatty acids, was recently shown to have anti-inflammatory actions. We examined the ability of the synthetic PPARdelta agonist GW501516 to suppress interleukin-6-induced expression of acute phase proteins in human hepatoma HepG2 cells and rat primary hepatocytes. Results GW501516 dose-dependently suppressed interleukin-6-induced mRNA expression of the acute phase protein alpha1-antichymotrypsin in HepG2 cells. The compound also suppressed interleukin-6-induced mRNA expression of alpha2-acid glycoprotein, beta-fibrinogen and alpha2-macroglobulin in and the secretion of C-reactive protein by rat primary hepatocytes. Depletion of the PPARdelta receptor, but not of PPARalpha or gamma, attenuated the suppressive effect of GW501516 on interleukin-6-induced alpha1-antichymotrypsin mRNA expression, indicating that PPARdelta specifically mediated this effect. Since interleukin-6 stimulates the transcriptional activity of the alpha1-antichymotrypsin promoter by activating the signal transducer and activator of transcription (STAT) 3, we examined functional interaction of this transcription factor and PPARdelta on this promoter. Overexpression of PPARdelta enhanced the suppressive effect of GW501516 on STAT3-activated transcriptional activity of the alpha1-antichymotrypsin promoter, while GW501516 suppressed interleukin-6-induced binding of this transcription factor to this promoter. These findings indicate that agonist-activated PPARdelta interferes with interleukin-6-induced acute phase reaction in the liver by inhibiting the transcriptional activity of STAT3. PPARdelta agonists might be useful for the suppression of systemic inflammatory reactions in which IL-6 plays a central role.

Structural conservation, variability, and immunogenicity of the T6 backbone pilin of serotype M6 Streptococcus pyogenes.

PubMed

Young, Paul G; Moreland, Nicole J; Loh, Jacelyn M; Bell, Anita; Atatoa Carr, Polly; Proft, Thomas; Baker, Edward N

2014-07-01

Group A streptococcus (GAS; Streptococcus pyogenes) is a Gram-positive human pathogen that causes a broad range of diseases ranging from acute pharyngitis to the poststreptococcal sequelae of acute rheumatic fever. GAS pili are highly diverse, long protein polymers that extend from the cell surface. They have multiple roles in infection and are promising candidates for vaccine development. This study describes the structure of the T6 backbone pilin (BP; Lancefield T-antigen) from the important M6 serotype. The structure reveals a modular arrangement of three tandem immunoglobulin-like domains, two with internal isopeptide bonds. The T6 pilin lysine, essential for polymerization, is located in a novel VAKS motif that is structurally homologous to the canonical YPKN pilin lysine in other three- and four-domain Gram-positive pilins. The T6 structure also highlights a conserved pilin core whose surface is decorated with highly variable loops and extensions. Comparison to other Gram-positive BPs shows that many of the largest variable extensions are found in conserved locations. Studies with sera from patients diagnosed with GAS-associated acute rheumatic fever showed that each of the three T6 domains, and the largest of the variable extensions (V8), are targeted by IgG during infection in vivo. Although the GAS BP show large variations in size and sequence, the modular nature of the pilus proteins revealed by the T6 structure may aid the future design of a pilus-based vaccine. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Human Herpesvirus 6 Infection Presenting as an Acute Febrile Illness Associated with Thrombocytopenia and Leukopenia

PubMed Central

Avšič-Županc, Tatjana; Uršič, Tina; Petrovec, Miroslav

2016-01-01

We present an infant with acute fever, thrombocytopenia, and leukopenia, coming from an endemic region for tick-borne encephalitis, human granulocytic anaplasmosis, and hantavirus infection. The primary human herpesvirus 6 infection was diagnosed by seroconversion of specific IgM and IgG and by identification of viral DNA in the acute patient's serum. The patient did not show skin rash suggestive of exanthema subitum during the course of illness. PMID:27980872

Correlation of Acute M1 Middle Cerebral Artery Thrombus Location with Endovascular Treatment Success and Clinical Outcome.

PubMed

Pavabvash, Seyedmehdi; Taleb, Shayandokht; Majidi, Shahram; Qureshi, Adnan I

2017-01-01

The location of the arterial occlusion can help with prognostication and treatment triage of acute stroke patients. We aimed to determine the effects of M1 distance-to-thrombus on angiographic recanalization success rate and clinical outcome following endovascular treatment of acute M1 occlusion. All acute ischemic stroke patients with M1 segment middle cerebral artery (MCA) occlusion on admission CT angiography (CTA) who underwent endovascular treatment were analyzed. The distance between thrombus origin and internal carotid artery (ICA) bifurcation was measured on admission CTA. The modified thrombolysis in cerebral infarction (mTICI) grades 2 b (>50% of distal branch filling) and 3 (complete) were considered as successful recanalization. Favorable outcome was defined by 3-month follow-up modified Rankin scale (mRs) score ≤2. Successful recanalization was achieved in 24 (71%) of 34 consecutive patients included in this study. The M1 distance-to-thrombus was shorter among patients with successful recanalization (5.4 ± 5.4 mm) versus those without (11.3 ± 7.6 mm, p = 0.015). The successful recanalization rate was higher among patients with M1 distance-to-thrombus ≤6 mm (odds ratio: 8, 95% confidence interval: 1.37-46.81, p = 0.023) compared with those with distance-to-thrombus >6 mm. There was no significant correlation between M1 distance-to-thrombus and 3-month mRs (rho: 0.131, p = 0.461); however, the distance-to-thrombus negatively correlated with admission National Institutes of Health Stroke Scale (NIHSS) scores (rho: -0.350, p=0.043). On the other hand, successful recanalization and admission NIHSS score were the only independent predictors of favorable outcome. Shorter distance of M1 thrombus from ICA bifurcation is associated with higher rate of successful recanalization following endovascular treatment.

Correlation of Acute M1 Middle Cerebral Artery Thrombus Location with Endovascular Treatment Success and Clinical Outcome

PubMed Central

Pavabvash, Seyedmehdi; Taleb, Shayandokht; Majidi, Shahram; Qureshi, Adnan I.

2017-01-01

Purpose The location of the arterial occlusion can help with prognostication and treatment triage of acute stroke patients. We aimed to determine the effects of M1 distance-to-thrombus on angiographic recanalization success rate and clinical outcome following endovascular treatment of acute M1 occlusion. Methods All acute ischemic stroke patients with M1 segment middle cerebral artery (MCA) occlusion on admission CT angiography (CTA) who underwent endovascular treatment were analyzed. The distance between thrombus origin and internal carotid artery (ICA) bifurcation was measured on admission CTA. The modified thrombolysis in cerebral infarction (mTICI) grades 2b (>50% of distal branch filling) and 3 (complete) were considered as successful recanalization. Favorable outcome was defined by 3-month follow-up modified Rankin scale (mRs) score ≤2. Results Successful recanalization was achieved in 24 (71%) of 34 consecutive patients included in this study. The M1 distance-to-thrombus was shorter among patients with successful recanalization (5.4 ± 5.4 mm) versus those without (11.3 ± 7.6 mm, p = 0.015). The successful recanalization rate was higher among patients with M1 distance-to-thrombus ≤6 mm (odds ratio: 8, 95% confidence interval: 1.37–46.81, p = 0.023) compared with those with distance-to-thrombus >6 mm. There was no significant correlation between M1 distance-to-thrombus and 3-month mRs (rho: 0.131, p = 0.461); however, the distance-to-thrombus negatively correlated with admission National Institutes of Health Stroke Scale (NIHSS) scores (rho: −0.350, p=0.043). On the other hand, successful recanalization and admission NIHSS score were the only independent predictors of favorable outcome. Conclusion Shorter distance of M1 thrombus from ICA bifurcation is associated with higher rate of successful recanalization following endovascular treatment. PMID:28243346

Decursin and PDBu: two PKC activators distinctively acting in the megakaryocytic differentiation of K562 human erythroleukemia cells.

PubMed

Kim, Hyeon Ho; Ahn, Kyung Seop; Han, Hogyu; Choung, Se Young; Choi, Sang-Yun; Kim, Ik-Hwan

2005-12-01

Protein kinase C (PKC) plays an important role in the proliferation and differentiation of various cell types including normal and leukemic hematopoietic cells. Phorbol 12,13-dibutyrate (PDBu) induces the megakaryocytic differentiation of K562 human erythroleukemia cells through PKC activation. Decursin, a pyranocoumarin from Angelica gigas, exhibits the cytotoxic effects on various human cancer cell lines and in vitro PKC activation. We report here the differences between two PKC activators, tumor-suppressing decursin and tumor-promoting PDBu, in their actions on the megakaryocytic differentiation of K562 cells. First of all, decursin inhibited PDBu-induced bleb formation in K562 cells. Decursin also inhibited the PDBu-induced megakaryocytic differentiation of K562 cells that is characterized by an increase in substrate adhesion, the secretion of granulocyte/macrophage colony stimulating factor (GM-CSF) and interleukin-6 (IL-6), and the surface expression of integrin beta3. The binding of PDBu to PKC was competitively inhibited by decursin. Decursin induced the more rapid down-regulation of PKC alpha and betaII isozymes than that induced by PDBu in K562 cells. Unlike PDBu, decursin promoted the translocation of PKC alpha and betaII to the nuclear membrane. Decursin-induced faster down-regulation and nuclear translocation of PKC alpha and betaII were not affected by the presence of PDBu. All these results indicate that decursin and phorbol ester are PKC activators distinctively acting in megakaryocytic differentiation and PKC modulation in K562 leukemia cells.

Krypton-81m ventilation scanning: acute respiratory disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lavender, J.P.; Irving, H.; Armstrong, J.D. II

1981-02-01

From experience with 700 patients undergoing ventilation and perfusion lung scanning with krypton-81m/technetium-99m technique, 34 patients suffering from nonembolic acute respiratory disease were selected for review. In 16 patients with pneumonia, all had defects of ventilation corresponding to, or larger than, the radiologic consolidation. In 13 patients there was some preservation of perfusion in the consolidated region. In two of the three patients with matched defects, the pneumonia was of long standing. In seven patients with collapse or atelectasis and in 11 patients with acute reversible bronchial obstruction and normal volume lungs, a similar pattern or ventillation and perfusion wasmore » observed.« less

Relation between pretransplant serum levels of soluble CD30 and acute rejection during the first 6 months after a kidney transplant.

PubMed

Shooshtarizadeh, Tina; Mohammadali, Ali; Ossareh, Shahrzad; Ataipour, Yousef

2013-06-01

The immunologic status of kidney allograft recipients affects transplant outcome. High levels of pretransplant serum soluble CD30 correlate with an increased risk of acute rejection. Studies show conflicting results. We evaluated the relation between pretransplant serum sCD30 levels with the risk of posttransplant acute kidney rejection in renal transplant recipients. This prospective cohort study was performed between March 2010 and March 2011 on 77 kidney transplant recipients (53 men [68.8%], 24 women [31.2%]; mean age, 41 ± 14 y). Serum samples were collected 24 hours before transplant and analyzed for soluble CD30 levels by enzyme-linked immunosorbent assay. Patients were followed for 6 months after transplant. Acute biopsy-proven rejection episodes were recorded, serum creatinine levels were measured, and glomerular filtration rates were calculated at the first and sixth months after transplant. Preoperative serum soluble CD30 levels were compared in patients with and without rejection. The mean pretransplant serum soluble CD30 level was 92.1 ± 47.3 ng/mL. At 6 months' follow-up, 10 patients experienced acute rejection. Mean pretransplant soluble CD30 levels were 128.5 ± 84 ng/mL versus 86.7 ± 37 ng/mL in patients with and without acute rejection episodes (P = .008). At 100 ng/mL, the sensitivity, specificity, and positive and negative predictive values of pretransplant serum soluble CD30 level to predict acute rejection were 70%, 73.6%, 29.1%, and 94.3%. We showed a significant relation between pretransplant serum soluble CD30 levels and acute allograft rejection. High pretransplant levels of serum soluble CD30 can be a risk factor for kidney transplant rejection, and its high negative predictive value at various cutoffs make it useful to find candidates with a low risk of acute rejection after transplant.

m6A level and isoform characterization sequencing (m6A-LAIC-seq) reveals the census and complexity of the m6A epitranscriptome

PubMed Central

Molinie, Benoit; Wang, Jinkai; Lim, Kok-Seong; Hillebrand, Roman; Lu, Zhi-xiang; Van Wittenberghe, Nicholas; Howard, Benjamin D.; Daneshvar, Kaveh; Mullen, Alan C.; Dedon, Peter

2017-01-01

N6-Methyladenosine (m6A) is a widespread, reversible chemical modification of RNA molecules, implicated in many aspects of RNA metabolism. Little quantitative information exists as to either how many transcript copies of particular genes are m6A modified (‘m6A levels’) or the relationship of m6A modification(s) to alternative RNA isoforms. To deconvolute the m6A epitranscriptome, we developed m6A-level and isoform-characterization sequencing (m6A-LAIC-seq). We found that cells exhibit a broad range of nonstoichiometric m6A levels with cell-type specificity. At the level of isoform characterization, we discovered widespread differences in the use of tandem alternative polyadenylation (APA) sites by methylated and nonmethylated transcript isoforms of individual genes. Strikingly, there is a strong bias for methylated transcripts to be coupled with proximal APA sites, resulting in shortened 3′ untranslated regions, while nonmethylated transcript isoforms tend to use distal APA sites. m6A-LAIC-seq yields a new perspective on transcriptome complexity and links APA usage to m6A modifications. PMID:27376769

Acute psychosis associated with recreational use of benzofuran 6-(2-aminopropyl)benzofuran (6-APB) and cannabis.

PubMed

Chan, Wui Ling; Wood, David M; Hudson, Simon; Dargan, Paul I

2013-09-01

There is evidence from around Europe of the availability and use of 6-(2-aminopropyl)benzofuran (6-APB) as a recreational drug. However, there is currently limited information on the acute toxicity of this compound. We describe here a case of acute toxicity associated with recreational use of legal high (6-APB) and cannabis, in which the comprehensive toxicological analysis confirmed the presence of a significant amount of 6-APB together with metabolites of both tetrahydrocannabinol and the synthetic cannabinoid receptor agonist (JWH-122). A 21-year-old gentleman with no previous medical and psychiatric history was brought to the emergency department (ED) after he had developed agitation and paranoid behaviour following the use of 6-APB purchased over the Internet. There was no obvious medical cause for his acute psychosis. He required diazepam to control his agitation and was subsequently transferred to a psychiatric hospital for ongoing management of his psychosis. Toxicological screening of a urine sample collected after presentation to the ED detected 6-APB, with an estimated urinary concentration of 2,000 ng/ml; other drugs were also detected, but at lower concentrations including metabolites of the synthetic cannabinoid receptor agonist JWH-122 and tetrahydrocannabinol. This is the first case of analytically confirmed acute toxicity associated with the detection of 6-APB which will provide some information on acute toxicity of this drug to help clinicians with the management of such patients and legislative authorities in their consideration for the need of its control.

Transgenic Mice with Increased Astrocyte Expression of IL-6 Show Altered Effects of Acute Ethanol on Synaptic Function

PubMed Central

Hernandez, Ruben V.; Puro, Alana C.; Manos, Jessica C.; Huitron-Resendiz, Salvador; Reyes, Kenneth C.; Liu, Kevin; Vo, Khanh; Roberts, Amanda J.; Gruol, Donna L.

2015-01-01

A growing body of evidence has revealed that resident cells of the central nervous system (CNS), and particularly the glial cells, comprise a neuroimmune system that serves a number of functions in the normal CNS and during adverse conditions. Cells of the neuroimmune system regulate CNS functions through the production of signaling factors, referred to as neuroimmune factors. Recent studies show that ethanol can activate cells of the neuroimmune system, resulting in the elevated production of neuroimmune factors, including the cytokine interleukin-6 (IL-6). Here we analyzed the consequences of this CNS action of ethanol using transgenic mice that express elevated levels of IL-6 through increased astrocyte expression (IL-6-tg) to model the increased IL-6 expression that occurs with ethanol use. Results show that increased IL-6 expression induces neuroadaptive changes that alter the effects of ethanol. In hippocampal slices from non-transgenic (non-tg) littermate control mice, synaptically evoked dendritic field excitatory postsynaptic potential (fEPSP) and somatic population spike (PS) at the Schaffer collateral to CA1 pyramidal neuron synapse were reduced by acute ethanol (20 or 60 mM). In contrast, acute ethanol enhanced the fEPSP and PS in hippocampal slices from IL-6 tg mice. Long-term synaptic plasticity of the fEPSP (i.e., LTP) showed the expected dose-dependent reduction by acute ethanol in non-tg hippocampal slices, whereas LTP in the IL-6 tg hippocampal slices was resistant to this depressive effect of acute ethanol. Consistent with altered effects of acute ethanol on synaptic function in the IL-6 tg mice, EEG recordings showed a higher level of CNS activity in the IL-6 tg mice than in the non-tg mice during the period of withdrawal from an acute high dose of ethanol. These results suggest a potential role for neuroadaptive effects of ethanol-induced astrocyte production of IL-6 as a mediator or modulator of the actions of ethanol on the CNS, including

m6ASNP: a tool for annotating genetic variants by m6A function.

PubMed

Jiang, Shuai; Xie, Yubin; He, Zhihao; Zhang, Ya; Zhao, Yuli; Chen, Li; Zheng, Yueyuan; Miao, Yanyan; Zuo, Zhixiang; Ren, Jian

2018-05-01

Large-scale genome sequencing projects have identified many genetic variants for diverse diseases. A major goal of these projects is to characterize these genetic variants to provide insight into their function and roles in diseases. N6-methyladenosine (m6A) is one of the most abundant RNA modifications in eukaryotes. Recent studies have revealed that aberrant m6A modifications are involved in many diseases. In this study, we present a user-friendly web server called "m6ASNP" that is dedicated to the identification of genetic variants that target m6A modification sites. A random forest model was implemented in m6ASNP to predict whether the methylation status of an m6A site is altered by the variants that surround the site. In m6ASNP, genetic variants in a standard variant call format (VCF) are accepted as the input data, and the output includes an interactive table that contains the genetic variants annotated by m6A function. In addition, statistical diagrams and a genome browser are provided to visualize the characteristics and to annotate the genetic variants. We believe that m6ASNP is a very convenient tool that can be used to boost further functional studies investigating genetic variants. The web server "m6ASNP" is implemented in JAVA and PHP and is freely available at [60].

Human herpesvirus-6 infection-associated acute encephalopathy without skin rash.

PubMed

Yamamoto, Shiho; Takahashi, Satoru; Tanaka, Ryosuke; Okayama, Akie; Araki, Akiko; Katano, Harutaka; Tanaka-Taya, Keiko; Azuma, Hiroshi

2015-09-01

Human herpesvirus-6 (HHV-6) is the etiological agent of exanthema subitum-associated encephalopathy, which usually occurs in children younger than 3 years. Brain imaging shows various abnormalities. A previously healthy 4-year-old girl developed acute encephalopathy with clinical features consisting of fever, repetitive seizures, and a disturbance of consciousness. The patient did not show skin rash suggestive of exanthema subitum during the course of her illness. The primary HHV-6 infection was diagnosed based on the absence of IgG against HHV-6 and identification of the virus DNA in the acute phase serum and a significant increase of the anti-HHV-6 IgG titers in the convalescent phase sera. Diffusion-weighted images showed transient high signal intensity in the bilateral periventricular white matter and splenium of the corpus callosum and in the gray matter structures such as the bilateral basal ganglia and thalami. Upon therapy with steroid and γ-globulin, the patient recovered without any neurological deficits. Primary HHV-6 infection can cause acute encephalopathy without exanthema subitum. The etiological diagnosis is possible only by examining the blood and cerebrospinal fluid, when the patient shows no skin rash. This condition should be included in the differential diagnosis of acute encephalopathy even in patients older than 3 years. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Mechanism of action for the cytotoxic effects of the nitric oxide prodrug JS-K in murine erythroleukemia cells.

PubMed

Kaczmarek, Monika Z; Holland, Ryan J; Lavanier, Stephen A; Troxler, Jami A; Fesenkova, Valentyna I; Hanson, Charlotte A; Cmarik, Joan L; Saavedra, Joseph E; Keefer, Larry K; Ruscetti, Sandra K

2014-03-01

The nitric oxide (NO) prodrug JS-K, a promising anti-cancer agent, consists of a diazeniumdiolate group necessary for the release of NO as well as an arylating ring. In this study, we research the mechanism by which JS-K kills a murine erythroleukemia cell line and determine the roles of NO and arylation in the process. Our studies indicate that JS-K inhibits the PI 3-kinase/Akt and MAP kinase pathways. This correlates with the activation of the tumor suppressor FoxO3a and increased expression of various caspases, leading to apoptosis. The arylating capability of JS-K appears to be sufficient for inducing these biological effects. Overall, these data suggest that JS-K kills tumor cells by arylating and inactivating signaling molecules that block the activation of a tumor suppressor. Published by Elsevier Ltd.

Co-culture of stromal and erythroleukemia cells in a perfused hollow fiber bioreactor system as an in vitro bone marrow model for myeloid leukemia.

PubMed

Usuludin, Suaidah Binte Mohamed; Cao, Xue; Lim, Mayasari

2012-05-01

We have developed a hematopoietic co-culture system using the hollow fiber bioreactor (HFBR) as a potential in vitro bone marrow model for evaluating leukemia. Supporting stroma using HS-5 cells was established in HFBR system and the current bioprocess configuration yielded an average glucose consumption of 640 mg/day and an average protein concentration of 6.40 mg/mL in the extracapillary space over 28 days. Co-culture with erythroleukemia K562 cells was used as a model for myelo-leukemic cell proliferation and differentiation. Two distinct localizations of K562 cells (loosely adhered and adherent cells) were identified and characterized after 2 weeks. The HFBR co-culture resulted in greater leukemic cell expansion (3,130 fold vs. 43 fold) compared to a standard tissue culture polystyrene (TCP) culture. Majority of expanded cells (68%) in HFBR culture were the adherent population, highlighting the importance of cell-cell contact for myelo-leukemic proliferation. Differentiation tendencies in TCP favored maturation toward monocyte and erythrocyte lineages but maintained a pool of myeloid progenitors. In contrast, HFBR co-culture exhibited greater lineage diversity, stimulating monocytic and megakaryocytic differentiation while inhibiting erythroid maturation. With the extensive stromal expansion capacity on hollow fiber surfaces, the HFBR system is able to achieve high cell densities and 3D cell-cell contacts mimicking the bone marrow microenvironment. The proposed in vitro system represents a dynamic and highly scalable 3D co-culture platform for the study of cell-stroma dependent hematopoietic/leukemic cell functions and ex vivo expansion. Copyright © 2011 Wiley Periodicals, Inc.

Coexpression of the genes for interleukin 6 and its receptor without apparent involvement in the proliferation of acute myeloid leukemia cells.

PubMed

Lopez, M; Maroc, N; Kerangueven, F; Bardin, F; Courcoul, M; Lavezzi, C; Birg, F; Mannoni, P

1991-09-01

Leukemic cells isolated from patients with either acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL) were screened for their capacity to express the interleukin 6 (IL-6) and IL-6 receptor genes, both at the RNA and protein levels. Variable levels (10 to greater than 600 U/ml) of an IL-6 activity, inhibited by neutralizing anti-IL-6 antibodies, were detected in AML cell supernatants using the B9 cell bioassay. High levels (greater than 100 U/ml) were observed in differentiated (M4 and M5 stages) AML, as well as in less mature (M1 and M2 stages) AML. Detection of the IL-6 transcript correlated with the biological activity. In addition, both IL-6 activity and IL-6 mRNA were detected in "fresh" leukemic cells, indicating that the glycoprotein was actually synthesized in vivo. In contrast, the IL-6 gene was less frequently expressed in ALL. The IL-6 receptor gene was transcribed in both AML and ALL; binding experiments showed that the protein was present at the cell surface. The spontaneous in vitro proliferation of leukemic cells coexpressing the transcripts for IL-6 and its receptor was not significantly inhibited by a neutralizing anti-IL-6 antibody, suggesting that IL-6 is not primarily implicated in the proliferation of the leukemic clone via an autocrine loop. Synthesis of IL-6 could, however, confer on leukemic cells a selective growth advantage through activation of the cytokine cascade.

Two 6-minute Walk Tests Are Required During Hospitalisation for Acute Exacerbation of COPD.

PubMed

Osadnik, Christian R; Borges, Rodrigo C; McDonald, Christine F; Carvalho, Celso R F; Holland, Anne E

2016-06-01

The 6-minute walk test (6MWT) is recommended to be performed twice to accurately assess exercise performance in stable chronic obstructive pulmonary disease (COPD) due to the presence of a learning effect. It is unknown whether a learning effect exists when the 6MWT is performed during hospitalisation for acute exacerbation of COPD (AECOPD). This study investigated whether repeat 6MWTs are necessary when conducted in inpatients with AECOPD. Pooled analysis was undertaken of data from two studies (Australia and Brazil) involving 46 participants (25 males, mean age 67.2 years, FEV1 43% predicted) admitted with AECOPD. Two 6MWTs, separated by ≥20 minutes, were performed on the day of discharge. Six-minute walk distance (6MWD; primary outcome), perceived dyspnoea (Borg scale), heart rate and oxyhaemoglobin saturation were recorded. 6MWD data from tests one (T1) and two (T2) were analysed via visual inspection of Bland-Altman plots. Factors associated with test improvement or decline were explored. Mean 6MWD difference between T1 and T2 was 6.2 m, however limits of agreement were wide (-92.2 m to 104.5 m). 32 (70%) participants improved (by any distance) from T1 to T2 by a mean (± standard deviation) of 32 m ± 28 m. Of these, 14 (30%) improved by a distance > 30 m. Fourteen (30%) participants recorded poorer 6MWD at T2 by a mean of 52 m ± 36 m. No factors were able to identify participants who improved or declined upon repeat testing. When performed in patients admitted to hospital with AECOPD, the 6MWT needs to be conducted twice in order to better estimate 6MWD.

The potential role of ribosomal protein S5 on cell cycle arrest and initiation of murine erythroleukemia cell differentiation.

PubMed

Matragkou, Christina N; Papachristou, Eleni T; Tezias, Sotirios S; Tsiftsoglou, Asterios S; Choli-Papadopoulou, Theodora; Vizirianakis, Ioannis S

2008-07-01

Evidence now exists to indicate that some ribosomal proteins besides being structural components of the ribosomal subunits are involved in the regulation of cell differentiation and apoptosis. As we have shown earlier, initiation of erythroid differentiation of murine erythroleukemia (MEL) cells is associated with transcriptional inactivation of genes encoding ribosomal RNAs and ribosomal proteins S5 (RPS5) and L35a. In this study, we extended these observations and investigated whether transfection of MEL cells with RPS5 cDNA affects the onset of initiation of erythroid maturation and their entrance in cell cycle arrest. Stably transfected MEL cloned cells (MEL-C14 and MEL-C56) were established and assessed for their capacity to produce RPS5 RNA transcript and its translated product. The impact of RPS5 cDNA transfection on the RPS5 gene expression patterns and the accumulation of RPS5 protein in inducible transfected MEL cells were correlated with their ability to: (a) initiate differentiation, (b) enter cell cycle arrest at G(1)/G(0) phase, and (c) modulate the level of cyclin-dependent kinases CDK2, CDK4, and CDK6. The data presented indicate that deregulation of RPS5 gene expression (constitutive expression) affects RPS5 protein level and delays both the onset of initiation of erythroid maturation and entrance in cell cycle arrest in inducer-treated MEL cells. 2008 Wiley-Liss, Inc.

Doxorubicin and ifosfamide combination chemotherapy in previously treated acute leukemia in adults: a Southwest Oncology Group pilot study.

PubMed

Ryan, D H; Bickers, J N; Vial, R H; Hussein, K; Bottomley, R; Hewlett, J S; Wilson, H E; Stuckey, W J

1980-01-01

The Southwest Oncology Group did a limited institutional pilot study of the combination of doxorubicin and ifosfamide in the treatment of previously treated adult patients with acute leukemia. Thirty-four patients received one or two courses of the combination. All patients had received prior chemotherapy and 32 had received prior anthracycline chemotherapy. Three patients died before their responses could be fully evaluated. Fourteen patients achieved complete remission (41%) and one patient achieved partial remission. The complete remission rate was 27% for patients with acute myeloblastic leukemia (myelomonoblastic leukemia, monoblastic leukemia, and erythroleukemia) and 89% for patients with acute lymphocytic and undifferentiated leukemia (ALL). Toxic effects included severe hematologic reactions in 33 of 34 patients, hematuria in six patients, altered sensorium in one patient, and congestive heart failure in one patient. The safety of the combination was established and toxic side effects of this therapy were tolerable. The 89% complete remission rate for previously treated patients with ALL suggests that the combination of doxorubicin and ifosfamide may be particularly effective in ALL.

Acute meningitis prognosis using cerebrospinal fluid interleukin-6 levels.

PubMed

Vázquez, Jorge Alejandro; Adducci, Maria del Carmen; Coll, Carlos; Godoy Monzón, Daniel; Iserson, Kenneth V

2012-08-01

Improved diagnostic tests would aid in diagnosing and treating community-acquired meningitis. To analyze the diagnostic value of interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) of patients presenting with symptoms of acute meningitis. In a 6-month prospective, observational, cross-sectional emergency department (ED) study, serum and CSF samples were obtained from all patients with a headache and fever in whom the physician suspected meningitis. Patients were excluded if computed tomography findings contraindicated a lumbar puncture, if they had bleeding disorders, or if their serum indicated bleeding. IL-6 levels were measured and compared in patients with (Group A) and without (Group B) bacterial meningitis. Samples were obtained from 53 patients, of whom 40 were ultimately found to have meningitis. These 40 patients averaged 49.6 ± 21.9 years, with number of men 18 (45%), hospitalizations 21 (52%), mortality 3 (.07%), and IL-6 average rating 491 (median: 14.5; range 0000-6000). Findings in the two groups were: Group A (with meningitis): n = 13, average IL-6 level: 1495 (median: 604; 25/75 percentiles: 232.5-2030; 95% confidence interval [CI] 371.7-2618.6; range 64-6000). Group B (with aseptic meningitis): n = 27, average IL-6 level: 7.34 (median: 5; 25/75 percentiles: 0.0/15.1; 95% CI 3.94-10.73; range 0-23.6). Mann-Whitney rank sum test: p < 0.0001. In patients with acute bacterial meningitis, CSF cytokine concentrations are elevated. Measuring CSF inflammatory cytokine levels in patients with acute meningitis could be a valuable ED diagnostic tool. Using this tool could improve the prognosis of patients with bacterial meningitis by allowing more rapid initiation of antibiotic treatment. Copyright © 2012 Elsevier Inc. All rights reserved.

Emerging trends in Lassa fever: redefining the role of immunoglobulin M and inflammation in diagnosing acute infection.

PubMed

Branco, Luis M; Grove, Jessica N; Boisen, Matt L; Shaffer, Jeffrey G; Goba, Augustine; Fullah, Mohammed; Momoh, Mambu; Grant, Donald S; Garry, Robert F

2011-10-24

Lassa fever (LF) is a devastating hemorrhagic viral disease that is endemic to West Africa and responsible for thousands of human deaths each year. Analysis of humoral immune responses (IgM and IgG) by antibody-capture ELISA (Ab-capture ELISA) and Lassa virus (LASV) viremia by antigen-capture ELISA (Ag-capture ELISA) in suspected patients admitted to the Kenema Government Hospital (KGH) Lassa Fever Ward (LFW) in Sierra Leone over the past five years is reshaping our understanding of acute LF. Analyses in LF survivors indicated that LASV-specific IgM persists for months to years after initial infection. Furthermore, exposure to LASV appeared to be more prevalent in historically non-endemic areas of West Africa with significant percentages of reportedly healthy donors IgM and IgG positive in LASV-specific Ab-capture ELISA. We found that LF patients who were Ag positive were more likely to die than suspected cases who were only IgM positive. Analysis of metabolic and immunological parameters in Ag positive LF patients revealed a strong correlation between survival and low levels of IL-6, -8, -10, CD40L, BUN, ALP, ALT, and AST. Despite presenting to the hospital with fever and in some instances other symptoms consistent with LF, the profiles of Ag negative IgM positive individuals were similar to those of normal donors and nonfatal (NF) LF cases, suggesting that IgM status cannot necessarily be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa. Only LASV viremia assessed by Ag-capture immunoassay, nucleic acid detection or virus isolation should be used to diagnose acute LASV infection in West Africans. LASV-specific IgM serostatus cannot be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa. By applying these criteria, we identified a dysregulated metabolic and pro-inflammatory response profile conferring a poor prognosis in acute LF. In addition to suggesting that the

Emerging trends in Lassa fever: redefining the role of immunoglobulin M and inflammation in diagnosing acute infection

PubMed Central

2011-01-01

Background Lassa fever (LF) is a devastating hemorrhagic viral disease that is endemic to West Africa and responsible for thousands of human deaths each year. Analysis of humoral immune responses (IgM and IgG) by antibody-capture ELISA (Ab-capture ELISA) and Lassa virus (LASV) viremia by antigen-capture ELISA (Ag-capture ELISA) in suspected patients admitted to the Kenema Government Hospital (KGH) Lassa Fever Ward (LFW) in Sierra Leone over the past five years is reshaping our understanding of acute LF. Results Analyses in LF survivors indicated that LASV-specific IgM persists for months to years after initial infection. Furthermore, exposure to LASV appeared to be more prevalent in historically non-endemic areas of West Africa with significant percentages of reportedly healthy donors IgM and IgG positive in LASV-specific Ab-capture ELISA. We found that LF patients who were Ag positive were more likely to die than suspected cases who were only IgM positive. Analysis of metabolic and immunological parameters in Ag positive LF patients revealed a strong correlation between survival and low levels of IL-6, -8, -10, CD40L, BUN, ALP, ALT, and AST. Despite presenting to the hospital with fever and in some instances other symptoms consistent with LF, the profiles of Ag negative IgM positive individuals were similar to those of normal donors and nonfatal (NF) LF cases, suggesting that IgM status cannot necessarily be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa. Conclusion Only LASV viremia assessed by Ag-capture immunoassay, nucleic acid detection or virus isolation should be used to diagnose acute LASV infection in West Africans. LASV-specific IgM serostatus cannot be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa. By applying these criteria, we identified a dysregulated metabolic and pro-inflammatory response profile conferring a poor prognosis in acute LF. In

Circulating miRNAs in acute new-onset atrial fibrillation and their target mRNA network.

PubMed

da Silva, Ananília Medeiros Gomes; de Araújo, Jéssica Nayara Góes; de Oliveira, Katiene Macêdo; Novaes, Ana Eloísa Melo; Lopes, Mariana Borges; de Sousa, Júlio César Vieira; Filho, Antônio Amorim de Araújo; Luchessi, André Ducati; de Rezende, Adriana Augusto; Hirata, Mário Hiroyuki; Silbiger, Vivian Nogueira

2018-04-20

MicroRNAs (miRNAs) are involved in the pathogenesis of atrial fibrillation (AF), acting on development and progression. Our pilot study investigated the expression of six miRNAs and their miRNA-mRNA interactions in patients with acute new-onset AF, well-controlled AF, and normal sinus rhythm (controls). Plasma of acute new-onset AF patients (n = 5) was collected in the emergency room when patients presented with irregular and fast-atrial fibrillation rhythm. Samples from well-controlled AF (n = 16) and control (n =  15) patients were collected during medical appointments following an ECG. Expression of miR-21, miR-133a, miR-133b, miR-150, miR-328, and miR-499 was analyzed by real-time PCR. Ingenuity Pathway Analysis and the TargetScan database identified the top 30 mRNA targets of these miRNA, seeking the miRNA-mRNA interactions in cardiovascular process. Increased expression of miR-133b (1.4-fold), miR-328 (2.0-fold), and miR-499 (2.3-fold) was observed in patients with acute new-onset AF, compared with well-controlled AF and control patients. Decreased expression of miR-21 was seen in patients with well-controlled AF compared to those with acute new-onset AF and controls (0.6-fold). The miRNA-mRNA interaction demonstrated that SMAD7 and FASLG genes were the targets of miR-21, miR-133b, and miR-499 and were directly related to AF, being involved in apoptosis and fibrosis. The miRNAs had different expression profiles dependent on the AF condition, with higher expression in the acute new-onset AF than well-controlled AF. Clinically, this may contribute to an effective assessment for patients, leading to early detection of AF and monitoring to reduce the risk of other serious cardiovascular events. © 2018 Wiley Periodicals, Inc.

Inhibitory effects of physalin B and physalin F on various human leukemia cells in vitro.

PubMed

Chiang, H C; Jaw, S M; Chen, P M

1992-01-01

Physalins B and F were isolated and characterized from the ethanolic extract of the whole plant of Physalis angulata L. (Solanaceae). Both physalin B and physalin F inhibited the growth of several human leukemia cells: K562 (erythroleukemia), APM1840 (acute T lymphoid leukemia), HL-60 (acute promyelocytic leukemia), KG-1 (acute myeloid leukemia), CTV1 (acute monocytic leukemia) and B cell (acute B lymphoid leukemia). Physalin F showed a stronger activity against these leukemia cells than physalin B, especially against acute myeloid leukemia (KG-1) and acute B lymphoid leukemia (B cell). From the structural features, the active site seems to be the functional epoxy group for physalin F and the double bond for physalin B located at carbon 5 and 6; the former is much more active than the latter as regards anti-leukemic effects.

Acute viral hepatitis E presenting with haemolytic anaemia and acute renal failure in a patient with glucose-6-phosphate dehydrogenase deficiency.

PubMed

Tomar, Laxmikant Ramkumarsingh; Aggarwal, Amitesh; Jain, Piyush; Rajpal, Surender; Agarwal, Mukul P

2015-10-01

The association of acute hepatitis E viral (HEV) infection with glucose-6-phosphate dehydrogenase (G6PD) deficiency leading to extensive intravascular haemolysis is a very rare clinical entity. Here we discuss such a patient, who presented with acute HEV illness, developed severe intravascular haemolysis and unusually high levels of bilirubin, complicated by acute renal failure (ARF), and was later on found to have a deficiency of G6PD. The patient recovered completely with haemodialysis and supportive management. © The Author(s) 2014.

Dual specificity phosphatase 5 and 6 are oppositely regulated in human skeletal muscle by acute exercise.

PubMed

Pourteymour, Shirin; Hjorth, Marit; Lee, Sindre; Holen, Torgeir; Langleite, Torgrim M; Jensen, Jørgen; Birkeland, Kåre I; Drevon, Christian A; Eckardt, Kristin

2017-10-01

Physical activity promotes specific adaptations in most tissues including skeletal muscle. Acute exercise activates numerous signaling cascades including pathways involving mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK)1/2, which returns to pre-exercise level after exercise. The expression of MAPK phosphatases (MKPs) in human skeletal muscle and their regulation by exercise have not been investigated before. In this study, we used mRNA sequencing to monitor regulation of MKPs in human skeletal muscle after acute cycling. In addition, primary human myotubes were used to gain more insights into the regulation of MKPs. The two ERK1/2-specific MKPs, dual specificity phosphatase 5 (DUSP5) and DUSP6, were the most regulated MKPs in skeletal muscle after acute exercise. DUSP5 expression was ninefold higher immediately after exercise and returned to pre-exercise level within 2 h, whereas DUSP6 expression was reduced by 43% just after exercise and remained below pre-exercise level after 2 h recovery. Cultured myotubes express both MKPs, and incubation with dexamethasone (Dex) mimicked the in vivo expression pattern of DUSP5 and DUSP6 caused by exercise. Using a MAPK kinase inhibitor, we showed that stimulation of ERK1/2 activity by Dex was required for induction of DUSP5 However, maintaining basal ERK1/2 activity was required for basal DUSP6 expression suggesting that the effect of Dex on DUSP6 might involve an ERK1/2-independent mechanism. We conclude that the altered expression of DUSP5 and DUSP6 in skeletal muscle after acute endurance exercise might affect ERK1/2 signaling of importance for adaptations in skeletal muscle during exercise. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Purtscher's retinopathy that occurred 6 months before acute pancreatitis.

PubMed

Sharma, Ashish G; Kazim, Nadia A; Eliott, Dean; Houghton, Odette; Abrams, Gary W

2006-01-01

To report Purtscher's retinopathy in a patient with chronic pancreatitis 6 months before the development of fulminant acute pancreatitis. Observational case report. Review of clinical chart, photographs, fluorescein angiography, and optical coherence tomography. A 45-year-old man with a history of alcohol abuse with a 3-day history of decreased vision in both eyes was examined. Diffuse retinal whitening and intraretinal hemorrhages that were consistent with Purtscher's retinopathy were present in both eyes. Serum amylase and lipase levels were normal. Six months later, he experienced intractable abdominal pain. Serum amylase and lipase levels were elevated markedly. Abdominal computed tomography and endoscopic retrograde cholangiopancreatography confirmed acute pancreatitis, with evidence of coexisting chronic pancreatitis. His funduscopic examination after the development of acute pancreatitis was improved, with almost complete resolution of retinal whitening and hemorrhages. Visual acuity remained poor because of retinal ischemia. Purtscher's retinopathy can be associated with chronic pancreatitis and can precede the development of fulminant acute pancreatitis.

BIRC6/Apollon gene expression in childhood acute leukemia: impact on therapeutic response and prognosis.

PubMed

Ismail, Eman Abdel Rahman; Mahmoud, Hanan Mohamed; Tawfik, Lamis Mohamed; Habashy, Deena Mohamed; Adly, Amira Abdel Moneam; El-Sherif, Nayera Hazaa; Abdelwahab, Mahmoud Ahmed

2012-02-01

Although BIRC6/Apollon seems to play a critical role as an antiapoptotic regulator, its clinical relevance in acute leukemia remains largely elusive. Therefore, we aimed to investigate BIRC6 gene expression in childhood acute leukemia in relation to clinicopathological characteristics at presentation, therapeutic response, and prognosis. BIRC6 expression level was assessed in 75 children with acute leukemia; 30 patients with acute myeloblastic leukemia (AML) and 45 patients with acute lymphoblastic leukemia (ALL) using real-time quantitative reverse transcriptase-polymerase chain reaction. The median level of BIRC6 expression did not differ significantly between AML and ALL patients. BIRC6 expression level was higher in patients with AML and ALL with extramedullary involvement, white blood cell (WBC) count ≥ 10 × 10(9) /L, and unfavorable cytogenetics at diagnosis. BIRC6 gene expression was higher in patients with unfavorable response to therapy at day 14, those who developed relapse or died in both leukemic groups. The best cutoff value of BIRC6 to predict therapeutic response and disease outcome was determined. AML and ALL patients with BIRC6 overexpression had significantly shorter overall and disease free survivals. This is the first report to study BIRC6 gene in pediatric ALL. Our results suggested that BIRC6 gene expression could be considered as an adverse risk factor in childhood acute leukemia and, hence, could be used to guide therapeutic regimens. © 2012 John Wiley & Sons A/S.

mRNA Traffic Control Reviewed: N6-Methyladenosine (m6 A) Takes the Driver's Seat.

PubMed

Visvanathan, Abhirami; Somasundaram, Kumaravel

2018-01-01

Messenger RNA is a flexible tool box that plays a key role in the dynamic regulation of gene expression. RNA modifications variegate the message conveyed by the mRNA. Similar to DNA and histone modifications, mRNA modifications are reversible and play a key role in the regulation of molecular events. Our understanding about the landscape of RNA modifications is still rudimentary in contrast to DNA and histone modifications. The major obstacle has been the lack of sensitive detection methods since they are non-editing events. However, with the advent of next-generation sequencing techniques, RNA modifications are being identified precisely at single nucleotide resolution. In recent years, methylation at the N6 position of adenine (m 6 A) has gained the attention of RNA biologists. The m 6 A modification has a set of writers (methylases), erasers (demethylases), and readers. Here, we provide a summary of interesting facts, conflicting findings, and recent advances in the technical and functional aspects of the m 6 A epitranscriptome. © 2017 WILEY Periodicals, Inc.

Coexistence of IgM antihepatitis A virus and IgM antihepatitis E virus in acute viral hepatitis: a prospective, multicentre study in Korea.

PubMed

Jang, J-H; Jung, Y M; Kim, J S; Lee, S H; Kim, J-W; Hwang, S G; Rim, K S; Park, S J; Park, Y M; Kang, S-K; Lee, H S; Yun, H; Kim, J-H; Jeong, S-H

2011-10-01

This study investigated the clinical, serological and molecular characteristics of coexistence of both immunoglobulin M (IgM) antihepatitis A virus (HAV) and IgM antihepatitis E virus (HEV) in acute viral hepatitis using a prospective, multicentre design. Among a total of 771 symptomatic cases with acute viral hepatitis enrolled in a Korean city from September 2006 to August 2008, coexistence of IgM anti-HAV and IgM anti-HEV was found in 43 patients (A+E group; 6%), while the existence of IgM anti-HAV alone was found in 595 patients (A group; 77%) and that of IgM anti-HEV alone in 14 patients (E group; 2%). Clinical data analysis and measurement of IgM and IgG anti-HEV were performed using two different commercial kits, and HAV RNA and HEV RNA were detected in available serum or stool samples. The clinical features of the A+E group were similar to those of the A group. HAV RNA detection rates in the A+E and A group were similar, while HEV RNA was detected only in the stool samples of the E group, not in the A+E group. Comparative testing of anti-HEV using two different ELISA kits showed markedly discordant results for IgM anti-HEV positivity and consistently low positivity for IgG anti-HEV in the A+E group. Coexistence of IgM anti-HEV measured by the Genelabs ELISA kit in the setting of hepatitis A appears to yield false-positive results in nonendemic areas of HEV infection. Diagnosis of hepatitis E using IgM anti-HEV should be made with caution. © 2011 Blackwell Publishing Ltd.

Interleukin-6 in cerebrospinal fluid as a biomarker of acute meningitis.

PubMed

García-Hernández, Pablo; Prieto, Belén; Martínez-Morillo, Eduardo; Rodríguez, Verónica; Álvarez, Francisco V

2016-01-01

Microbiological culture of cerebrospinal fluid is the gold standard to differentiate between aseptic and bacterial meningitis, but this method has low sensitivity. A fast and reliable new marker would be of interest in clinical practice. Interleukin-6, secreted by T cells in response to meningeal pathogens and quickly delivered into cerebrospinal fluid, was evaluated as a marker of acute meningitis. A total of 150 cerebrospinal fluid samples were analysed by an electrochemiluminescence method, selected according to patient diagnosis: (a) bacterial meningitis confirmed by positive culture (n = 26); (b) bacterial meningitis with negative culture or not performed (n = 15); (c) viral meningitis confirmed by polymerase chain reaction or immunoglobulin G determination (n = 23); (d) viral meningitis with polymerase chain reaction negative or not performed (n = 42); and (e) controls (n = 44). Cerebrospinal fluid interleukin-6 concentration showed significant differences between all pathologic groups and the control group (P < 0.001). As a diagnostic tool for bacterial meningitis, interleukin-6 showed an area under the curve of 0.937 (95% confidence intervals: 0.895-0.978), significantly higher than those of classical biomarkers. An interleukin-6 cutoff of 1418 pg/mL showed 95.5% sensitivity and 77.5% specificity, whereas a value of 15,060 pg/mL showed 63.6% sensitivity and 96.7% specificity, for diagnosis of bacterial meningitis. Interleukin-6 measured by electrochemiluminescence method is a promising marker for early differentiation between aseptic and bacterial meningitis. More studies are needed to validate clinical implications for future practice in an emergency laboratory. © The Author(s) 2015.

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury

PubMed Central

Shi, Yingfeng; Xu, Liuqing; Tang, Jinhua; Fang, Lu; Ma, Shuchen; Ma, Xiaoyan; Nie, Jing; Pi, Xiaoling; Qiu, Andong; Zhuang, Shougang

2017-01-01

Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction; expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules; and an increase of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. These changes were companied by increased HDAC6 expression in the cytoplasm of renal tubular cells. Administration of TA significantly reduced serum creatinine and blood urea nitrogen levels as well as attenuated renal tubular damage in injured kidneys. HDAC6 inhibition also resulted in decreased expression of NGAL, reduced apoptotic cell, and inactivated caspase-3 in the kidney after acute injury. Moreover, injury to the kidney increased phosphorylation of nuclear factor (NF)-κB and expression of multiple cytokines/chemokines including tumor necrotic factor-α and interleukin-6 and monocyte chemoattractant protein-1, as well as macrophage infiltration. Treatment with TA attenuated all those responses. Finally, HDAC6 inhibition reduced the level of oxidative stress by suppressing malondialdehyde (MDA) and preserving expression of superoxide dismutase (SOD) in the injured kidney. Collectively, these data indicate that HDAC6 contributes to the pathogenesis of rhabdomyolysis-induced AKI and suggest that HDAC6 inhibitors have therapeutic potential for AKI treatment. PMID:28052874

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury.

PubMed

Shi, Yingfeng; Xu, Liuqing; Tang, Jinhua; Fang, Lu; Ma, Shuchen; Ma, Xiaoyan; Nie, Jing; Pi, Xiaoling; Qiu, Andong; Zhuang, Shougang; Liu, Na

2017-03-01

Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction; expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules; and an increase of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. These changes were companied by increased HDAC6 expression in the cytoplasm of renal tubular cells. Administration of TA significantly reduced serum creatinine and blood urea nitrogen levels as well as attenuated renal tubular damage in injured kidneys. HDAC6 inhibition also resulted in decreased expression of NGAL, reduced apoptotic cell, and inactivated caspase-3 in the kidney after acute injury. Moreover, injury to the kidney increased phosphorylation of nuclear factor (NF)-κB and expression of multiple cytokines/chemokines including tumor necrotic factor-α and interleukin-6 and monocyte chemoattractant protein-1, as well as macrophage infiltration. Treatment with TA attenuated all those responses. Finally, HDAC6 inhibition reduced the level of oxidative stress by suppressing malondialdehyde (MDA) and preserving expression of superoxide dismutase (SOD) in the injured kidney. Collectively, these data indicate that HDAC6 contributes to the pathogenesis of rhabdomyolysis-induced AKI and suggest that HDAC6 inhibitors have therapeutic potential for AKI treatment. Copyright © 2017 the American Physiological Society.

Preventive effects of interleukin-6 in lipopolysaccharide/d-galactosamine induced acute liver injury via regulating inflammatory response in hepatic macrophages.

PubMed

Li, Long; Duan, Chaoli; Zhao, Yan; Zhang, Xiaofang; Yin, Hongyan; Wang, Tianxi; Huang, Caoxin; Liu, Suhuan; Yang, Shuyu; Li, Xuejun

2017-10-01

Lipopolysaccharide/d-Galactosamine (LPS/d-Gal)-induced acute liver injury is characterized by significant inflammatory responses including TNF-α and interleukin-6 (IL-6) and is a widely applied experimental model for inflammation research. TNF-α is critical in the progression of LPS/d-Gal-induced liver injury. However, the role of IL-6 in this model is still unknown. In the present study, we aim to elucidate the involvement of IL-6 in the pathogenesis of acute liver injury induced by LPS/d-Gal in mice and its underlying mechanism. To induce acute liver injury, LPS (50μg/kg body weight) and d-Gal (400mg/kg body weight) were injected intraperitoneally in the C57BL/6 mice. The vehicle (saline) or a single dose of recombinant IL-6 (200μg/kg body weight) was administered 2h prior to LPS/d-Gal injection. Mice were sacrificed 2h and 6h after LPS/d-Gal injection. The results indicated that IL-6 treatment could protect mice from LPS/d-Gal-induced tissue damage, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, as well as hepatocyte apoptosis and inflammation. Furthermore, in vitro study showed that IL-6 treatment could significantly suppress LPS-triggered expression of proinflammatory cytokines and chemokines, TNF-α, RANTES and MCP-1 in macrophages while promoting the expression of M2 markers, such as Arg-1 and Mrc-1 in macrophages. Taken together, these findings revealed a novel and unexpected role of IL-6 in ameliorating LPS/d-Gal-induced acute liver injury via regulating inflammatory responses in hepatic macrophages. Copyright © 2017. Published by Elsevier B.V.

FTO, m6 Am , and the hypothesis of reversible epitranscriptomic mRNA modifications.

PubMed

Mauer, Jan; Jaffrey, Samie R

2018-05-12

The fate of mRNA is regulated by epitranscriptomic nucleotide modifications, the most abundant of which is N 6 -methyladenosine (m 6 A). Although the pattern and distribution of m 6 A in mRNA is mediated by specific methyltransferases, a recent hypothesis is that specific demethylases or 'erasers' allow m 6 A to be dynamically reversed by signaling pathways. In this Review, we discuss the data in support and against this model. New insights into the function of fat mass and obesity-associated protein (FTO), the original enzyme thought to be an m 6 A eraser, reveal that its physiologic target is not m 6 A, but instead is N 6 ,2'-O-dimethyladenosine (m 6 A m ). Another m 6 A demethylase, ALKBH5, appears to have functions limited to sperm development in normal mice. Overall, the majority of the data suggest that m 6 A is generally not reversible, although m 6 A may be susceptible to demethylation in pathophysiological states such as cancer. © 2018 Federation of European Biochemical Societies.

m6aViewer: software for the detection, analysis, and visualization of N6-methyladenosine peaks from m6A-seq/ME-RIP sequencing data.

PubMed

Antanaviciute, Agne; Baquero-Perez, Belinda; Watson, Christopher M; Harrison, Sally M; Lascelles, Carolina; Crinnion, Laura; Markham, Alexander F; Bonthron, David T; Whitehouse, Adrian; Carr, Ian M

2017-10-01

Recent methods for transcriptome-wide N 6 -methyladenosine (m 6 A) profiling have facilitated investigations into the RNA methylome and established m 6 A as a dynamic modification that has critical regulatory roles in gene expression and may play a role in human disease. However, bioinformatics resources available for the analysis of m 6 A sequencing data are still limited. Here, we describe m6aViewer-a cross-platform application for analysis and visualization of m 6 A peaks from sequencing data. m6aViewer implements a novel m 6 A peak-calling algorithm that identifies high-confidence methylated residues with more precision than previously described approaches. The application enables data analysis through a graphical user interface, and thus, in contrast to other currently available tools, does not require the user to be skilled in computer programming. m6aViewer and test data can be downloaded here: http://dna2.leeds.ac.uk/m6a. © 2017 Antanaviciute et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice.

PubMed

Pomozi, Viola; Brampton, Christopher; van de Wetering, Koen; Zoll, Janna; Calio, Bianca; Pham, Kevin; Owens, Jesse B; Marh, Joel; Moisyadi, Stefan; Váradi, András; Martin, Ludovic; Bauer, Carolin; Erdmann, Jeanette; Aherrahrou, Zouhair; Le Saux, Olivier

2017-06-01

Soft tissue calcification occurs in several common acquired pathologies, such as diabetes and hypercholesterolemia, or can result from genetic disorders. ABCC6, a transmembrane transporter primarily expressed in liver and kidneys, initiates a molecular pathway inhibiting ectopic calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into pyrophosphate (PPi), a major calcification inhibitor. Heritable mutations in ABCC6 underlie the incurable calcification disorder pseudoxanthoma elasticum and some cases of generalized arterial calcification of infancy. Herein, we determined that the administration of PPi and the bisphosphonate etidronate to Abcc6 -/- mice fully inhibited the acute dystrophic cardiac calcification phenotype, whereas alendronate had no significant effect. We also found that daily injection of PPi to Abcc6 -/- mice over several months prevented the development of pseudoxanthoma elasticum-like spontaneous calcification, but failed to reverse already established lesions. Furthermore, we found that the expression of low amounts of the human ABCC6 in liver of transgenic Abcc6 -/- mice, resulting in only a 27% increase in plasma PPi levels, led to a major reduction in acute and chronic calcification phenotypes. This proof-of-concept study shows that the development of both acute and chronic calcification associated with ABCC6 deficiency can be prevented by compensating PPi deficits, even partially. Our work indicates that PPi substitution represents a promising strategy to treat ABCC6-dependent calcification disorders. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

IL-6, a central acute-phase mediator, as an early biomarker for exposure to zinc-based metal fumes.

PubMed

Baumann, R; Joraslafsky, S; Markert, A; Rack, I; Davatgarbenam, S; Kossack, V; Gerhards, B; Kraus, T; Brand, P; Gube, M

2016-12-12

Systemic C-reactive protein (CRP) increases 1day after short-term inhalation of welding fumes containing zinc and/or copper. The aim of the current study was to find further, possibly earlier systemic biomarkers after inhalation of different welding fumes containing zinc and traces of aluminum, with or without copper, as these metal combinations become more common in modern joining technology. The study group consisted of 15 non-smoking male volunteers with healthy lung function data and without any occupational metal fume exposure. On 4 different exposure days, the members of the study group were exposed under controlled conditions to ambient air or 3 different welding fumes for 6h. Spirometric and impulse oscillometric measurements and differential blood counts were performed and serum samples were collected before exposure and 6, 10 and 29h after start of exposure. The biomarker concentrations in serum were measured by electrochemiluminescent assays. Systemic increases of IL-6 peaked significantly at 10h compared to baseline ("ZincZinc": P=0.0005 (median increase (m. incr.)=1.36pg/mL); "ZincAlu": P=0.0012 (m. incr.=1.48pg/mL); "AluBronze": P=0.0005 (m. incr.=2.66pg/mL)). At 29h, CRP and serum amyloid A (SAA) increased distinctively ("ZincZinc": P=0.032 (m. incr.=0.65μg/mL) [CRP], 0.077 (m. incr.=0.61μg/mL) [SAA]; "ZincAlu": P=0.001 (m. incr.=1.15μg/mL) [CRP], 0.0024 (m. incr.=0.94μg/mL) [SAA]; "AluBronze": P=0.002 (m. incr.=2.5μg/mL) [CRP], 0.002 (m. incr.=0.97μg/mL) [SAA]). The median increases of CRP and IL-6 were most pronounced for the welding fume which contained besides zinc also copper (AluBronze). For differentiating AluBronze from control exposure, receiver operating characteristic (ROC) curve analysis was performed and the area under the ROC curve (AUC) for the IL-6 increases (10h versus 0h) was 0.931. The additional inflammatory mediators [vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interferon-γ (IFN

Design Considerations for Post-Acute Care mHealth: Patient Perspectives.

PubMed

Sanger, Patrick; Hartzler, Andrea; Lober, William B; Evans, Heather L; Pratt, Wanda

2014-01-01

Many current mobile health applications ("apps") and most previous research have been directed at management of chronic illnesses. However, little is known about patient preferences and design considerations for apps intended to help in a post-acute setting. Our team is developing an mHealth platform to engage patients in wound tracking to identify and manage surgical site infections (SSI) after hospital discharge. Post-discharge SSIs are a major source of morbidity and expense, and occur at a critical care transition when patients are physically and emotionally stressed. Through interviews with surgical patients who experienced SSI, we derived design considerations for such a post-acute care app. Key design qualities include: meeting basic accessibility, usability and security needs; encouraging patient-centeredness; facilitating better, more predictable communication; and supporting personalized management by providers. We illustrate our application of these guiding design considerations and propose a new framework for mHealth design based on illness duration and intensity.

Changes in Oxygen Consumption and Heart Rate After Acute Myocardial Infarction During 6-Month Follow-up.

PubMed

Choe, Yuri; Han, Jae-Young; Choi, In-Sung; Park, Hyeng-Kyu

2018-06-01

Exercise intensity is a particularly important determinant of physiological responses to exercise training in patients with acute myocardial infarction. Heart rate (HR) is commonly used as a practical way of prescribing and monitoring exercise as specific intensities based on a linear relationship between the percentage of maximum HR (%HR max ) and the percentage of maximum oxygen consumption (%VO 2max ) regardless of age, gender, or exercise mode. To examine the change in variability in the correlation between %HR max and %VO 2max after acute myocardial infarction. Retrospective study. Regional cardio-cerebrovascular center at a tertiary hospital. A total of 66 patients were enrolled who were referred for cardiac rehabilitation (CR) after percutaneous intervention, and who had reached stage 3 of the modified Bruce Protocol (mBP) on an exercise tolerance test (ETT). There were 54 men and 12 women with an average age of 56.7 ± 9.48 years, ejection fraction (EF) of 56.4% ± 8.89%, and body mass index (BMI) of 24.73 ± 2.86 kg/m 2 . All patients participated in a 4-week outpatient CR program and underwent ETT with a gas analyzer to determine maximal heart rate and maximal oxygen consumption before CR and 1 month, 3 months, and 6 months after CR. VO 2max and HR max were defined as the highest values attained during the ETT. The HR and VO 2 values at each stage of the mBP were expressed as percentages of their maximum. %HR max and %VO 2max were calculated at each stage of the mBP. The maximum METs and VO 2max significantly improved at 1 month after CR, but not significantly at 3 and 6 months after CR. The correlation between VO 2max and HR max progressively changed in a favorable manner during CR. The relationship between %HR max and %VO 2max indicated a coefficient of variation before and 1, 3, and 6 months after of 0.800, 0.826, 0.832, and 0.880, respectively. This study showed that the %HR max correlates better with the %VO 2max in the late-stage post-AMI than in

Acute SSRI-induced anxiogenic and brain metabolic effects are attenuated 6 months after initial MDMA-induced depletion.

PubMed

Andó, Rómeó D; Adori, Csaba; Kirilly, Eszter; Molnár, Eszter; Kovács, Gábor G; Ferrington, Linda; Kelly, Paul A T; Bagdy, György

2010-03-05

To assess the functional state of the serotonergic system, the acute behavioural and brain metabolic effect of SSRI antidepressants were studied during the recovery period after MDMA-induced neuronal damage. The effects of the SSRI fluoxetine and the serotonin receptor agonist meta-chloro-phenylpiperazine (m-CPP) were investigated in the social interaction test in Dark Agouti rats, 6 months after treatment with a single dose of MDMA (15 or 30 mg kg(-1), i.p.). At earlier time points these doses of MDMA have been shown to cause 30-60% loss in axonal densities in several brain regions. Densities of the serotonergic axons were assessed using serotonin-transporter and tryptophan-hydroxylase immunohistochemistry. In a parallel group of animals, brain function was examined following an acute challenge with either fluoxetine or citalopram, using 2-deoxyglucose autoradiographic imaging. Six months after MDMA treatment the densities of serotonergic axons were decreased in only a few brain areas including hippocampus and thalamus. Basal anxiety was unaltered in MDMA-treated animals. However, the acute anxiogenic effects of fluoxetine, but not m-CPP, were attenuated in animals pretreated with MDMA. The metabolic response to both citalopram and fluoxetine was normal in most of the brain areas examined with the exception of ventromedial thalamus and hippocampal sub-fields where the response was attenuated. These data provide evidence that 6 months after MDMA-induced damage serotonergic axons show recovery in most brain areas, but serotonergic functions to challenges with SSRIs including anxiety and aggression remain altered. Copyright 2009 Elsevier B.V. All rights reserved.

Metformin alleviated endotoxemia-induced acute lung injury via restoring AMPK-dependent suppression of mTOR.

PubMed

Wu, Kejia; Tian, Rui; Huang, Jing; Yang, Yongqiang; Dai, Jie; Jiang, Rong; Zhang, Li

2018-05-31

Inflammation requires intensive metabolic support and modulation of the metabolic pathways might become a novel strategy to limit inflammatory injury. Recent studies have revealed the anti-inflammatory effects of the anti-diabetic reagent metformin, but the underlying mechanisms remain unclear. In the present study, the potential effects of metformin on endotoxemia-induced acute lung injury (ALI) and their relationship with the representative metabolic regulator, including AMPK, sirtuin 1 and mTOR, were investigated. The results indicated that treatment with metformin suppressed LPS-induced upregulation of IL-6 and TNF-α, alleviated pulmonary histological abnormalities, improved the survival rate of LPS-challenged mice. Treatment with metformin reversed LPS-induced decline of AMPK phosphorylation. Co-administration of the AMPK inhibitor compound C abolished the stimulatory effects of metformin on AMPK phosphorylation, the suppressive effects of metformin on IL-6 induction and pulmonary lesions. In addition, co-administration of the mTOR activator 3BDO but not the sirtuin 1 inhibitor EX-527 abolished the effects of metformin on IL-6 induction and pulmonary lesions. Finally, treatment with metformin suppressed LPS-induced p70S6K1 phosphorylation, which was abolished by the AMPK inhibitor. These data suggest that metformin might provide anti-inflammatory benefits in endotoxemia-induced inflammatory lung injury via restoring AMPK-dependent suppression of mTOR. Copyright © 2018. Published by Elsevier B.V.

Rethinking m6A Readers, Writers, and Erasers

PubMed Central

Meyer, Kate D.; Jaffrey, Samie R.

2018-01-01

In recent years, m6A has emerged as an abundant and dynamically regulated modification throughout the transcriptome. Recent technological advances have enabled the transcriptome-wide identification of m6A residues, which in turn has provided important insights into the biology and regulation of this pervasive regulatory mark. Also central to our current understanding of m6A are the discovery and characterization of m6A readers, writers, and erasers. Over the last few years, studies into the function of these proteins have led to important discoveries about the regulation and function of m6A. However, during this time our understanding of these proteins has also evolved considerably, sometimes leading to the reversal of early conceptions regarding the reading, writing and erasing of m6A. In this review, we summarize recent advances in m6A research, and we highlight how these new findings have reshaped our understanding of how m6A is regulated in the transcriptome. PMID:28759256

Possible involvement of AMPK in acute exercise-induced expression of monocarboxylate transporters MCT1 and MCT4 mRNA in fast-twitch skeletal muscle.

PubMed

Takimoto, Masaki; Takeyama, Mirei; Hamada, Taku

2013-11-01

The regulatory mechanisms responsible for acute exercise-induced expression of monocarboxylate transporters MCT1 and MCT4 mRNA in skeletal muscle remain unclear. 5'-adenosine-activated protein kinase (AMPK) is a key signaling molecule that regulates gene expression at the mRNA level. We examined whether AMPK activation is involved in acute exercise-induced expression of MCT1 and MCT4 mRNA in fast-twitch muscle. Male Sprague-Dawley rats were subjected to an acute bout of either 5min high-intensity intermittent swimming (HIS) or 6-h low-intensity prolonged swimming (LIS). The effects of acute exercise on the phosphorylation of AMPK (p-AMPK), calcium/calmodulin pendent kinase II (p-CaMKII), p38 mitogen-activated protein kinase (p-p38MAPK), and MCTs mRNA were analyzed in vivo. To observe the direct effects of AMPK activation on MCTs mRNA, the effects of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), caffeine, and dantrolene were analyzed in vitro using an isolated muscle incubation model. The p-AMPK increased in response to both HIS and LIS, although the p-CaMKII and p-p38MAPK were increased only following HIS. Irrespective of exercise intensity, MCT1 and MCT4 mRNA was also transiently upregulated by both HIS and LIS. Direct exposure of the epitrochlearis muscle to 0.5mmol/L AICAR or 1mmol/L caffeine, which activated p-AMPK increased both MCT1 and MCT4 mRNA levels. When pAMPK was inhibited by dantrolene, neither MCT1 nor MCT4 mRNA was increased. These results suggest that acute exercise-induced increases in MCT1 and MCT4 mRNA expression may be possibly mediated by AMPK activation, at least in part in fast-twitch muscle. © 2013.

Synthesis and biological activity of M6-P and M6-P analogs on fibroblast and keratinocyte proliferation.

PubMed

Clavel, Caroline; Barragan-Montero, Véronique; Garric, Xavier; Molès, Jean-Pierre; Montero, Jean-Louis

2005-09-01

A new synthetic route to obtain the carboxylate analog of mannose 6-phosphate (M6-P) is presented. The effects of the M6-P, the carboxylate and two other analogs (the phosphonate and the alpha,beta ethylenic carboxylate) on the proliferation of human keratinocytes and dermal fibroblasts as well as on the proliferation of a murine fibroblast cell line, 3T3-J2 are tested. We observed that M6-P is a potent inhibitor of proliferation of both fibroblasts and keratinocytes. Among its analogs, the phosphonate showed a similar effect on human dermal fibroblasts but not on keratinocytes.

Xuebijing injection improves the respiratory function in rabbits with oleic acid-induced acute lung injury by inhibiting IL-6 expression and promoting IL-10 expression at the protein and mRNA levels

PubMed Central

WANG, YUXIA; JI, MINGLI; WANG, LEI; CHEN, LIPING; LI, JING

2014-01-01

Xuebijing injection is a complex herbal medicine, and clinical and experimental studies have shown that it has a significant effect on acute respiratory distress syndrome and multiple organ dysfunction syndrome. However, the majority of studies regarding Xuebijing injection have focused on serum inflammatory factors, and few studies have been carried out from the perspective of the protein and mRNA expression of inflammatory cytokines. In this study, 60 healthy rabbits of mixed gender were randomly assigned to a normal control group (CG), oleic acid group (model group; MG) and oleic acid + Xuebijing injection group (treatment group; TG). Rabbits of the CG were treated with normal saline through the ear vein, rabbits of the MG were injected with oleic acid (0.4 ml/kg) and rabbits of the TG received 0.4 ml/kg oleic acid + 10 ml/kg Xuebijing injection. Blood samples were collected from the common carotid artery of all rabbits of all groups 1 h after the ear vein was injected with the corresponding reagent, and was used to measure the arterial partial pressure of oxygen (PaO2) and of carbon dioxide (PaCO2). The activity of myeloperoxidase (MPO) was tested, and the protein and mRNA expression levels of interleukin (IL)-6 and IL-10 were determined. Rabbits of the MG exhibited evident respiratory dysfunction (PaO2 and PaCO2 were low), histopathological lung damage and overactive inflammatory responses (the expression of the proinflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10 was increased at the protein and mRNA levels). Following the administration of the Xuebijing injection, the inflammatory response of the rabbits was significantly reduced. Xuebijing injection raised PaO2 and PaCO2, weakened the activity of MPO in the lung tissue, downregulated the expression of the proinflammatory cytokine IL-6 and further increased the expression of the anti-inflammatory cytokine IL-10. These results demonstrated that Xuebijing injection improved the respiratory

Predicting Acute and Persistent Neuropathy Associated with Oxaliplatin

PubMed Central

Alejandro, Linh; Behrendt, Carolyn E.; Chen, Kim; Openshaw, Harry; Shibata, Stephen

2014-01-01

Objectives We sought to predict oxaliplatin-associated peripheral neuropathy during modified FOLFOX6 (mFOLFOX6) therapy. Methods In a 50% female sample, patients with previously untreated, primary or recurrent colorectal cancer were followed through a first course of mFOLFOX6 with oxaliplatin 85 mg/m2 every 2 weeks. Accounting for correlation among a subject's cycles, logistic regression estimated per-cycle risk of acute (under 14 days) and persistent (14 days or more) neuropathy. Proportional hazards regression predicted time to persistent neuropathy. Results Among mFOLFOX6 recipients (n=50, age 58.9 +10.1 years), 36% received concomitant bevacizumab. Of total cycles, 94.2% (422/448) were evaluable. Most (84%) subjects reported neuropathy at least once: 74% reported acute and 48% reported persistent symptoms. On multivariate analysis, risk factors shared by acute and persistent neuropathy were body-surface area >2.0, acute neuropathy in a past cycle, and lower body weight. In addition, risk of acute neuropathy decreased with age (adjusted for renal function and winter season), while risk of persistent neuropathy increased with cumulative dose of oxaliplatin and persistent neuropathy in a past cycle. Concomitant bevacizumab was not a risk factor when administered in Stage IV disease but was associated with persistent neuropathy when administered experimentally in Stage III. Females had no increased risk of either form of neuropathy. After 3 cycles, weight, body-surface area, and prior acute neuropathy predicted time to persistent neuropathy. Conclusions Routinely available clinical factors predict acute and persistent neuropathy associated with oxaliplatin. When validated, the proposed prognostic score for persistent neuropathy can help clinicians counsel patients about chemotherapy. PMID:22547012

Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Okunieff, Paul; Xu Jianhua; Hu Dongping

2006-07-01

Purpose: To determine whether curcumin ameliorates acute and chronic radiation skin toxicity and to examine the expression of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-18, IL-1Ra, tumor necrosis factor [TNF]-{alpha}, and lymphotoxin-{beta}) or fibrogenic cytokines (transforming growth factor [TGF]-{beta}) during the same acute and chronic phases. Methods and Materials: Curcumin was given intragastrically or intraperitoneally to C3H/HeN mice either: 5 days before radiation; 5 days after radiation; or both 5 days before and 5 days after radiation. The cutaneous damage was assessed at 15-21 days (acute) and 90 days (chronic) after a single 50 Gy radiation dose was given to themore » hind leg. Skin and muscle tissues were collected for measurement of cytokine mRNA. Results: Curcumin, administered before or after radiation, markedly reduced acute and chronic skin toxicity in mice (p < 0.05). Additionally, curcumin significantly decreased mRNA expression of early responding cytokines (IL-1 IL-6, IL-18, TNF-{alpha}, and lymphotoxin-{beta}) and the fibrogenic cytokine, TGF-{beta}, in cutaneous tissues at 21 days postradiation. Conclusion: Curcumin has a protective effect on radiation-induced cutaneous damage in mice, which is characterized by a downregulation of both inflammatory and fibrogenic cytokines in irradiated skin and muscle, particularly in the early phase after radiation. These results may provide the molecular basis for the application of curcumin in clinical radiation therapy.« less

Specific receptors for phorbol diesters on freshly isolated human myeloid and lymphoid leukemia cells: comparable binding characteristics despite different cellular responses.

PubMed

Goodwin, B J; Moore, J O; Weinberg, J B

1984-02-01

Freshly isolated human leukemia cells have been shown in the past to display varying in vitro responses to phorbol diesters, depending on their cell type. Specific receptors for the phorbol diesters have been demonstrated on numerous different cells. This study was designed to characterize the receptors for phorbol diesters on leukemia cells freshly isolated from patients with different kinds of leukemia and to determine if differences in binding characteristics for tritium-labeled phorbol 12,13-dibutyrate (3H-PDBu) accounted for the different cellular responses elicited in vitro by phorbol diesters. Cells from 26 patients with different kinds of leukemia were studied. PDBu or phorbol 12-myristate 13-acetate (PMA) caused cells from patients with acute myeloblastic leukemia (AML), acute promyelocytic (APML), acute myelomonocytic (AMML), acute monocytic (AMoL), acute erythroleukemia (AEL), chronic myelocytic leukemia (CML) in blast crisis (myeloid), acute undifferentiated leukemia (AUL), and hairy cell leukemia (HCL) (n = 15) to adhere to plastic and spread. However, they caused no adherence or spreading and only slight aggregation of cells from patients with acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), or CML-blast crisis (lymphoid) (n = 11). All leukemia cells studied, irrespective of cellular type, displayed specific receptors for 3H-PDBu. The time courses for binding by all leukemia types were similar, with peak binding at 5-10 min at 37 degrees C and 120 min at 4 degrees C. The binding affinities were similar for patients with ALL (96 +/- 32 nM, n = 4), CLL (126 +/- 32 nM, n = 6), and acute nonlymphoid leukemia (73 +/- 14 nM, n = 11). Likewise, the numbers of specific binding sites/cell were comparable for the patients with ALL (6.2 +/- 1.3 X 10(5) sites/cell, n = 4), CLL (5.0 +/- 2.0 X 10(5) sites/cell, n = 6), and acute nonlymphoid leukemia (4.4 +/- 1.9 X 10(5) sites/cell, n = 11). Thus, the differing responses to phorbol diesters of

Chromosomal mapping of the human M6 genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olinsky, S.; Loop, B.T.; DeKosky, A.

1996-05-01

M6 is a neuronal membrane glycoprotein that may have an important role in neural development. This molecule was initially defined by a monoclonal antibody that affected the survival of cultured cerebellar neurons and the outgrowth of neurites. The nature of the antigen was discovered by expression cDNA cloning using this monoclonal antibody. Two distinct murine M6 cDNAs (designated M6a and M6b) whose deduced amino acid sequences were remarkably similar to that of the myelin proteolipid protein human cDNA and genomic clones encoding M6a and M6b and have characterized them by restriction mapping, Southern hybridization with cDNA probes, and sequence analysis.more » We have localized these genes within the human genome by FISH (fluorescence in situ hybridization). The human M6a gene is located at 4q34, and the M6b gene is located at Xp22.2 A number of human neurological disorders have been mapped to the Xp22 region, including Aicardi syndrome (MIM 304050), Rett syndrome (MIM 312750), X-linked Charcot-Marie-Tooth neuropathy (MIM 302801), and X-linked mental retardation syndromes (MRX1, MIM 309530). This raises the possibility that a defect in the M6b gene is responsible for one of these neurological disorders. 8 refs., 3 figs.« less

Reversible methylation of m6Am in the 5′ cap controls mRNA stability

PubMed Central

Mauer, Jan; Luo, Xiaobing; Blanjoie, Alexandre; Jiao, Xinfu; Grozhik, Anya V.; Patil, Deepak P.; Linder, Bastian; Pickering, Brian F.; Vasseur, Jean-Jacques; Chen, Qiuying; Gross, Steven S.; Elemento, Olivier; Debart, Françoise; Kiledjian, Megerditch; Jaffrey, Samie R.

2017-01-01

Internal bases in mRNA can be subjected to modifications that influence the fate of mRNA in cells. One of the most prevalent modified bases is found at the 5′ end of mRNA, at the first encoded nucleotide adjacent to the 7-methylguanosine cap. Here we show that this nucleotide, N6,2′-O-dimethyladenosine (m6Am), is a reversible modification that influences cellular mRNA fate. Using a transcriptome-wide map of m6Am we find that m6Am-initiated transcripts are markedly more stable than mRNAs that begin with other nucleotides. We show that the enhanced stability of m6Am-initiated transcripts is due to resistance to the mRNA-decapping enzyme DCP2. Moreover, we find that m6Am is selectively demethylated by fat mass and obesity-associated protein (FTO). FTO preferentially demethylates m6Am rather than N6-methyladenosine (m6A), and reduces the stability of m6Am mRNAs. Together, these findings show that the methylation status of m6Am in the 5′ cap is a dynamic and reversible epitranscriptomic modification that determines mRNA stability. PMID:28002401

High-throughput m6A-seq reveals RNA m6A methylation patterns in the chloroplast and mitochondria transcriptomes of Arabidopsis thaliana.

PubMed

Wang, Zegang; Tang, Kai; Zhang, Dayong; Wan, Yizhen; Wen, Yan; Lu, Quanyou; Wang, Lei

2017-01-01

This study is the first to comprehensively characterize m6A patterns in the Arabidopsis chloroplast and mitochondria transcriptomes based on our open accessible data deposited in NCBI's Gene Expression Omnibus with GEO Series accession number of GSE72706. Over 86% of the transcripts were methylated by m6A in the two organelles. Over 550 and 350 m6A sites were mapped, with ~5.6 to ~5.8 and ~4.6 to ~4.9 m6A sites per transcript, to the chloroplast and mitochondria genome, respectively. The overall m6A methylation extent in the two organelles was greatly higher than that in the nucleus. The m6A motif sequences in the transcriptome of two organelles were similar to the nuclear motifs, suggesting that selection of the m6A motifs for RNA methylation was conserved between the nucleus and organelle transcriptomes. The m6A patterns of rRNAs and tRNAs in the organelle were similar to those in the nucleus. However, the m6A patterns in coding RNAs were distinct between the nucleus and the organelle, suggesting that that regulation of the m6A methylation patterns may be different between the nuclei and the organelles. The extensively methylated transcripts in the two organelles were mainly associated with rRNA, ribosomal proteins, photosystem reaction proteins, tRNA, NADH dehydrogenase and redox. On average, 64% and 79% of the transcripts in the two organelles showed differential m6A methylation across three organs of the leaves, flowers and roots. The m6A methylation extent in the chloroplast was higher than that in the mitochondria. This study provides deep insights into the m6A methylation topology and differentiation in the plant organelle transcriptomes.

CPX-351 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

ClinicalTrials.gov

2017-06-12

Adult Acute Erythroid Leukemia (M6); Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

M6-C artificial disc placement.

PubMed

Coric, Domagoj; Parish, John; Boltes, Margaret O

2017-01-01

There has been a steady evolution of cervical total disc replacement (TDR) devices over the last decade resulting in surgical technique that closely mimics anterior cervical discectomy and fusion as well as disc design that emphasizes quality of motion. The M6-C TDR device is a modern-generation artificial disc composed of titanium endplates with tri-keel fixation as well as a polyethylene weave with a polyurethane core. Although not yet approved by the FDA, M6-C has finished a pilot and pivotal US Investigational Device Exemption (IDE) study. The authors present the surgical technique for implantation of a 2-level M6-C cervical TDR device. The video can be found here: https://youtu.be/rFEAqINLRCo .

Blood antioxidant and oxidative stress biomarkers acute responses to a 1000-m kayak sprint in elite male kayakers.

PubMed

Teixeira, V H; Valente, H F; Casal, S I; Marques, F P; Moreira, P A

2013-02-01

This study aimed to investigate the response of blood antioxidants and biomarkers of lipid peroxidation, muscle damage and inflammation to a 1000m kayak trial in elite male kayakers. Enzymatic (superoxide dismutase [SOD], glutathione reductase [Gr] and glutathione peroxidase [GPx] activities) and non-enzymatic (total antioxidant status [TAS], uric acid, α-tocopherol, α-carotene, β-carotene, lycopene and lutein and zeaxanthin) antioxidants, thiobarbituric acid reactive substances (TBARS), creatine kinase (CK), interleukin-6 (IL-6) and cortisol were determined in 15 elite male kayakers before and 15 min after a 1000-m kayak simulated race. Both enzymatic and non-enzymatic antioxidants were unaffected by exercise, with the exception of α-carotene which decreased (P=0.013). Uric acid levels were incremented following exercise (P=0.016). The acute exercise resulted in a significant decrease in TAS (P=0.001) and in an increase in CK (P=0.023), TBARS (P<0.001) and IL-6 (P=0.028). Our study suggests that a 1000-m kayak simulated race induces oxidative stress and damage in highly-trained kayakers.

Massive splenomegaly in acute erythroid leukaemia (FAB Class-M6): an unusual presentation.

PubMed

Sherazi, Syed Furqan Haider; Butt, Zeeshan

2012-09-01

AML-M6 has a peak incidence in the seventh decade with slight male preponderance, and can also present at a younger age. The usual features are anaemia, thrombocytopenia, malaise, fatigue, easy bruising, epistaxis and petechiae. Splenomegaly may occur in 20-40 % of the cases but massive splenomegaly is rare presentation and have been only reported once in humans and once in animals. A 22 year Asian female, presented with fatigue, pallor, mild jaundice, exertional dyspnoea, epigastric pain, tender right hypochondrium and massive splenomegaly. Investigations revealed anaemia and thrombocytopenia, tear drop cells, basophilic stippling, piokilocytosis and anisochromia; increased uric acid and LDH. Abdominal ultrasound showed enlarged liver (22cm) and spleen (20cm). Bone marrow aspiration revealed 51% erythroid and 24% non-erythroid precursors, depressed leukopoeisis and megakarypoeisis. Erythroblasts were PAS and CD71 positive and also reacted to Antihaemoglobin-Antibody. This report highlights characteristic features and diagnostic criteria of erythroleukaemia, differential diagnosis of massive splenomegaly and their rare association.

HLA-DR-, CD33+, CD56+, CD16- myeloid/natural killer cell acute leukemia: a previously unrecognized form of acute leukemia potentially misdiagnosed as French-American-British acute myeloid leukemia-M3.

PubMed

Scott, A A; Head, D R; Kopecky, K J; Appelbaum, F R; Theil, K S; Grever, M R; Chen, I M; Whittaker, M H; Griffith, B B; Licht, J D

1994-07-01

We have identified and characterized a previously unrecognized form of acute leukemia that shares features of both myeloid and natural killer (NK) cells. From a consecutive series of 350 cases of adult de novo acute myeloid leukemia (AML), we identified 20 cases (6%) with a unique immunophenotype: CD33+, CD56+, CD11a+, CD13lo, CD15lo, CD34+/-, HLA-DR-, CD16-. Multicolor flow cytometric assays confirmed the coexpression of myeloid (CD33, CD13, CD15) and NK cell-associated (CD56) antigens in each case, whereas reverse transcription polymerase chain reaction (RT-PCR) assays confirmed the identity of CD56 (neural cell adhesion molecule) in leukemic blasts. Although two cases expressed CD4, no case expressed CD2, CD3, or CD8 and no case showed clonal rearrangement of genes encoding the T-cell receptor (TCR beta, gamma, delta). Leukemic blasts in the majority of cases shared unique morphologic features (deeply invaginated nuclear membranes, scant cytoplasm with fine azurophilic granularity, and finely granular Sudan black B and myeloperoxidase cytochemical reactivity) that were remarkably similar to those of acute promyelocytic leukemia (APL); particularly the microgranular variant (FAB AML-M3v). However, all 20 cases lacked the t(15;17) and 17 cases tested lacked the promyelocytic/retinoic acid receptor alpha (RAR alpha) fusion transcript in RT-PCR assays; 12 cases had 46,XX or 46,XY karyotypes, whereas 2 cases had abnormalities of chromosome 17q: 1 with del(17)(q25) and the other with t(11;17)(q23;q21) and the promyelocytic leukemia zinc finger/RAR alpha fusion transcript. All cases tested (6/20), including the case with t(11;17), failed to differentiate in vitro in response to all-trans retinoic acid (ATRA), suggesting that these cases may account for some APLs that have not shown a clinical response to ATRA. Four of 6 cases tested showed functional NK cell-mediated cytotoxicity, suggesting a relationship between these unique CD33+, CD56+, CD16- acute leukemias and

Dynamic m(6)A mRNA methylation directs translational control of heat shock response.

PubMed

Zhou, Jun; Wan, Ji; Gao, Xiangwei; Zhang, Xingqian; Jaffrey, Samie R; Qian, Shu-Bing

2015-10-22

The most abundant mRNA post-transcriptional modification is N(6)-methyladenosine (m(6)A), which has broad roles in RNA biology. In mammalian cells, the asymmetric distribution of m(6)A along mRNAs results in relatively less methylation in the 5' untranslated region (5'UTR) compared to other regions. However, whether and how 5'UTR methylation is regulated is poorly understood. Despite the crucial role of the 5'UTR in translation initiation, very little is known about whether m(6)A modification influences mRNA translation. Here we show that in response to heat shock stress, certain adenosines within the 5'UTR of newly transcribed mRNAs are preferentially methylated. We find that the dynamic 5'UTR methylation is a result of stress-induced nuclear localization of YTHDF2, a well-characterized m(6)A 'reader'. Upon heat shock stress, the nuclear YTHDF2 preserves 5'UTR methylation of stress-induced transcripts by limiting the m(6)A 'eraser' FTO from demethylation. Remarkably, the increased 5'UTR methylation in the form of m(6)A promotes cap-independent translation initiation, providing a mechanism for selective mRNA translation under heat shock stress. Using Hsp70 mRNA as an example, we demonstrate that a single m(6)A modification site in the 5'UTR enables translation initiation independent of the 5' end N(7)-methylguanosine cap. The elucidation of the dynamic features of 5'UTR methylation and its critical role in cap-independent translation not only expands the breadth of physiological roles of m(6)A, but also uncovers a previously unappreciated translational control mechanism in heat shock response.

Effects of a Dissostichus mawsoni-CaM recombinant proteins feed additive on the juvenile orange-spotted grouper (Epinephelus coioides) under the acute low temperature challenge.

PubMed

Luo, Sheng-Wei; Wang, Wei-Na; Cai, Luo; Qi, Zeng-Hua; Wang, Cong; Liu, Yuan; Peng, Chang-Lian; Chen, Liang-Biao

2015-10-01

The effects of Dissostichus mawsoni-Calmodulin (Dm-CaM) on growth performance, enzyme activities, respiratory burst, MDA level and immune-related gene expressions of the orange-spotted grouper (Epinephelus coioides) exposed to the acute low temperature stress were evaluated. The commercial diet supplemented with Dm-CaM protein was fed to the groupers for 6 weeks. No significant difference was observed in the specific growth rates, weight gains and survivals. After the feeding trial, the groupers were exposed to acute low temperature challenge. The groupers fed with Dm-CaM additive diet showed a significant decrease in the respiratory burst activity, while the blood cell number increased significantly at 25 °C by comparing with the control and additive control group. The enzymatic activity of SOD, ACP and ALP increased significantly in Dm-CaM additive group, while MDA level maintained stable with the lowest value. qRT-PCR analysis indicated that the up-regulated transcript expressions of CaM, C3, SOD2, LysC and HSPA4 were observed in Dm-CaM additive group. These results indicated that Dm-CaM additive diet may regulate the grouper immune response to the acute low temperature challenge.

Fludarabine, cytarabine, and attenuated-dose idarubicin (m-FLAI) combination therapy for elderly acute myeloid leukemia patients.

PubMed

Kim, Inho; Koh, Youngil; Yoon, Sung-Soo; Park, Seonyang; Kim, Byoung Kook; Kim, Dae-Young; Lee, Jung-Hee; Lee, Kyoo-Hyung; Cheong, June-Won; Lee, Hong-Kee; Kim, Sung-Hyun; Kim, Hyuk; Joo, Young Don; Lee, Sang-Min; Won, Jong-Ho; Park, Sung-Kyu; Hong, Dae-Sik; Kim, Se-Hyung; Sohn, Sang Kyun; Kim, Chul-Soo; Park, Eunkyung; Kim, Min Kyoung; Park, Moo Rim; Lee, Je-Hwan; Min, Yoo Hong

2013-01-01

We performed a phase II trial to evaluate the efficacy and safety of the modified fludarabine, cytarabine, and attenuated-dose idarubicin (m-FLAI) regimen in elderly acute myeloid leukemia (AML) patients. Elderly (≥60 years) AML patients who had not previously received chemotherapy were enrolled in the study. Patients received two consecutive cycles of m-FLAI chemotherapy as an induction. The m-FLAI regimen comprised fludarabine (25 mg/m(2) , days 1-4), cytarabine (1,000 mg/m(2) , days 1-4), and attenuated-dose idarubicin (5 mg/m(2) , days 1-3). The primary end point was complete remission (CR) rate. Secondary end points were overall survival (OS), event-free survival (EFS), and treatment-related mortality (TRM). There were 108 patients (median age 68.4 years, M:F = 64:44) enrolled in the study. CR was achieved in 56.5% of patients, and the TRM rate was 21.3%. Median OS and median EFS were 10.2 and 6.6 months, respectively. The mortality at 30 and 60 days was 15 and 21%, respectively. Performance status and comorbidity did not have prognostic value in this patient cohort. Bone marrow expression of CD117 was associated with increased EFS and OS. m-FLAI is an effective induction regimen for previously untreated AML in elderly patients. In addition, bone-marrow CD117 expression is an independent favorable prognostic factor in elderly AML patients. (ClinicalTrials.gov number, NCT01247493). Copyright © 2012 Wiley Periodicals, Inc.

Post-transcriptional m6A editing of HIV-1 mRNAs enhances viral gene expression

PubMed Central

Kennedy, Edward M.; Bogerd, Hal P.; Kornepati, Anand V. R.; Kang, Dong; Ghoshal, Delta; Marshall, Joy B.; Poling, Brigid C.; Tsai, Kevin; Gokhale, Nandan S.; Horner, Stacy M.; Cullen, Bryan R.

2016-01-01

Summary Covalent addition of a methyl group to the adenosine N6 (m6A) is an evolutionarily conserved and common RNA modification that is thought to modulate several aspects of RNA metabolism. While the presence of multiple m6A editing sites on diverse viral RNAs was reported starting almost 40 years ago, how m6A editing affects virus replication has remained unclear. Here, we used photo-crosslinking-assisted m6A sequencing techniques to precisely map several m6A editing sites on the HIV-1 genome and report that they cluster in the HIV-1 3’ untranslated region (3'UTR). Viral 3'UTR m6A sites or analogous cellular m6A sites strongly enhanced mRNA expression in cis by recruiting the cellular YTHDF m6A “reader” proteins. Reducing YTHDF expression inhibited, while YTHDF overexpression enhanced, HIV-1 protein and RNA expression, and virus replication in CD4+ T cells. These data identify m6A editing, and the resultant recruitment of YTHDF proteins, as major positive regulators of HIV-1 mRNA expression. PMID:27117054

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia.

PubMed

Hawwa, Ahmed F; Collier, Paul S; Millership, Jeff S; McCarthy, Anthony; Dempsey, Sid; Cairns, Carole; McElnay, James C

2008-12-01

To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m(-2) day(-1)). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype.

Biological mechanism analysis of acute renal allograft rejection: integrated of mRNA and microRNA expression profiles.

PubMed

Huang, Shi-Ming; Zhao, Xia; Zhao, Xue-Mei; Wang, Xiao-Ying; Li, Shan-Shan; Zhu, Yu-Hui

2014-01-01

Renal transplantation is the preferred method for most patients with end-stage renal disease, however, acute renal allograft rejection is still a major risk factor for recipients leading to renal injury. To improve the early diagnosis and treatment of acute rejection, study on the molecular mechanism of it is urgent. MicroRNA (miRNA) expression profile and mRNA expression profile of acute renal allograft rejection and well-functioning allograft downloaded from ArrayExpress database were applied to identify differentially expressed (DE) miRNAs and DE mRNAs. DE miRNAs targets were predicted by combining five algorithm. By overlapping the DE mRNAs and DE miRNAs targets, common genes were obtained. Differentially co-expressed genes (DCGs) were identified by differential co-expression profile (DCp) and differential co-expression enrichment (DCe) methods in Differentially Co-expressed Genes and Links (DCGL) package. Then, co-expression network of DCGs and the cluster analysis were performed. Functional enrichment analysis for DCGs was undergone. A total of 1270 miRNA targets were predicted and 698 DE mRNAs were obtained. While overlapping miRNA targets and DE mRNAs, 59 common genes were gained. We obtained 103 DCGs and 5 transcription factors (TFs) based on regulatory impact factors (RIF), then built the regulation network of miRNA targets and DE mRNAs. By clustering the co-expression network, 5 modules were obtained. Thereinto, module 1 had the highest degree and module 2 showed the most number of DCGs and common genes. TF CEBPB and several common genes, such as RXRA, BASP1 and AKAP10, were mapped on the co-expression network. C1R showed the highest degree in the network. These genes might be associated with human acute renal allograft rejection. We conducted biological analysis on integration of DE mRNA and DE miRNA in acute renal allograft rejection, displayed gene expression patterns and screened out genes and TFs that may be related to acute renal allograft

Biological mechanism analysis of acute renal allograft rejection: integrated of mRNA and microRNA expression profiles

PubMed Central

Huang, Shi-Ming; Zhao, Xia; Zhao, Xue-Mei; Wang, Xiao-Ying; Li, Shan-Shan; Zhu, Yu-Hui

2014-01-01

Objectives: Renal transplantation is the preferred method for most patients with end-stage renal disease, however, acute renal allograft rejection is still a major risk factor for recipients leading to renal injury. To improve the early diagnosis and treatment of acute rejection, study on the molecular mechanism of it is urgent. Methods: MicroRNA (miRNA) expression profile and mRNA expression profile of acute renal allograft rejection and well-functioning allograft downloaded from ArrayExpress database were applied to identify differentially expressed (DE) miRNAs and DE mRNAs. DE miRNAs targets were predicted by combining five algorithm. By overlapping the DE mRNAs and DE miRNAs targets, common genes were obtained. Differentially co-expressed genes (DCGs) were identified by differential co-expression profile (DCp) and differential co-expression enrichment (DCe) methods in Differentially Co-expressed Genes and Links (DCGL) package. Then, co-expression network of DCGs and the cluster analysis were performed. Functional enrichment analysis for DCGs was undergone. Results: A total of 1270 miRNA targets were predicted and 698 DE mRNAs were obtained. While overlapping miRNA targets and DE mRNAs, 59 common genes were gained. We obtained 103 DCGs and 5 transcription factors (TFs) based on regulatory impact factors (RIF), then built the regulation network of miRNA targets and DE mRNAs. By clustering the co-expression network, 5 modules were obtained. Thereinto, module 1 had the highest degree and module 2 showed the most number of DCGs and common genes. TF CEBPB and several common genes, such as RXRA, BASP1 and AKAP10, were mapped on the co-expression network. C1R showed the highest degree in the network. These genes might be associated with human acute renal allograft rejection. Conclusions: We conducted biological analysis on integration of DE mRNA and DE miRNA in acute renal allograft rejection, displayed gene expression patterns and screened out genes and TFs that may

The m6A pathway facilitates sex determination in Drosophila

PubMed Central

Kan, Lijuan; Grozhik, Anya V.; Vedanayagam, Jeffrey; Patil, Deepak P.; Pang, Nan; Lim, Kok-Seong; Huang, Yi-Chun; Joseph, Brian; Lin, Ching-Jung; Despic, Vladimir; Guo, Jian; Yan, Dong; Kondo, Shu; Deng, Wu-Min; Dedon, Peter C.; Jaffrey, Samie R.; Lai, Eric C.

2017-01-01

The conserved modification N6-methyladenosine (m6A) modulates mRNA processing and activity. Here, we establish the Drosophila system to study the m6A pathway. We first apply miCLIP to map m6A across embryogenesis, characterize its m6A ‘writer’ complex, validate its YTH ‘readers’ CG6422 and YT521-B, and generate mutants in five m6A factors. While m6A factors with additional roles in splicing are lethal, m6A-specific mutants are viable but present certain developmental and behavioural defects. Notably, m6A facilitates the master female determinant Sxl, since multiple m6A components enhance female lethality in Sxl sensitized backgrounds. The m6A pathway regulates Sxl processing directly, since miCLIP data reveal Sxl as a major intronic m6A target, and female-specific Sxl splicing is compromised in multiple m6A pathway mutants. YT521-B is a dominant m6A effector for Sxl regulation, and YT521-B overexpression can induce female-specific Sxl splicing. Overall, our transcriptomic and genetic toolkit reveals in vivo biologic function for the Drosophila m6A pathway. PMID:28675155

Calcium-binding proteins annexin A2 and S100A6 are sensors of tubular injury and recovery in acute renal failure.

PubMed

Cheng, Chao-Wen; Rifai, Abdalla; Ka, Shuk-Man; Shui, Hao-Ai; Lin, Yuh-Feng; Lee, Wei-Hwa; Chen, Ann

2005-12-01

Rise in cellular calcium is associated with acute tubular necrosis, the most common cause of acute renal failure (ARF). The mechanisms that calcium signaling induce in the quiescent tubular cells to proliferate and differentiate during acute tubular necrosis have not been elucidated. Acute tubular necrosis induced in mice by single intravenous injection of uranyl nitrate and examined after 1, 3, 7, and 14 days. Renal function was monitored and kidneys were evaluated by histology, immunohistochemistry, Western blotting, in situ hybridization, and real-time reverse transcription-polymerase chain reaction (RT-PCR). Models of folic acid induced-ARF and ischemic/reperfusion (I/R) injury were similarly investigated. Analysis of mRNA expression of intracellular calcium and phospholipid-binding proteins demonstrated selective expression of S100A6 and Annexin A2 (Anxa2) in the renal cortex with marked elevation on day 3, and gradually decline on day 7 and further attenuation on day 14. Similarly, the expression of both proteins, as demonstrated by immunohistochemistry and Western blot analysis, was increased and reached the peak level on day 7 and then gradually declined by day 14. Vimentin, a marker of dedifferentiated cells, was highly expressed during the recovery phase. Combined in situ hybridization immunohistochemistry revealed colocalization of both S100A6 and Anxa2 with proliferating cell nuclear antigen (PCNA). The universality of this phenomenon was confirmed in two other mouse acute tubular necrosis models, the ischemic-reperfusion injury and folic acid-induced ARF. Collectively, these findings demonstrate that S100A6 and Anxa2 expression, initiated in response to tubular injury, persist in parallel throughout the recovery process of tubular cells in acute renal failure.

Reduced m6A mRNA methylation is correlated with the progression of human cervical cancer

PubMed Central

Kong, Beihua; Song, Chen; Cong, Jianglin; Hou, Jianqing; Wang, Shaoguang

2017-01-01

The m6A mRNA methylation involves in mRNA splicing, degradation and translation. Recent studies have revealed that reduced m6A mRNA methylation might promote cancer development. However, the role of m6A mRNA methylation in cervical cancer development remains unknown. Therefore, we investigated the role of m6A methylation in cervical cancer in the current study. We first evaluated the m6A mRNA methylation level in 286 pairs of cervical cancer samples and their adjacent normal tissues by dot blot assay. Then the role of m6A on patient survival rates and cervical cancer progression were assessed. The m6A level was significantly reduced in the cervical cancer when comparing with the adjacent normal tissue. The m6A level reduction was significantly correlated with the FIGO stage, tumor size, differentiation, lymph invasion and cancer recurrence. It was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with cervical cancer. Reducing m6A level via manipulating the m6A regulators expression promoted cervical cancer cell proliferation. And increasing m6A level significantly suppressed tumor development both in vitro and in vivo. Our results showed that the reduced m6A level is tightly associated with cervical cancer development and m6A mRNA methylation might be a potential therapeutic target in cervical cancer. PMID:29228737

Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition.

PubMed

Kasner, Margaret T; Mick, Rosemarie; Jeschke, Grace R; Carabasi, Matthew; Filicko-O'Hara, Joanne; Flomenberg, Neal; Frey, Noelle V; Hexner, Elizabeth O; Luger, Selina M; Loren, Alison W; Mangan, James K; Wagner, John L; Weiss, Mark; Carroll, Martin; Perl, Alexander E

2018-04-02

Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.

Structure and stability of M6N8 clusters (M = Si, Ge, Sn, Ti).

PubMed

Davydova, Elena I; Timoshkin, Alexey Y; Frenking, Gernot

2010-06-10

The structures and stabilities of the M(6)N(8) clusters (M = Si, Ge, Sn, Ti) have been theoretically studied at DFT and ab initio levels of theory. Two new isomers have been considered: cage-like molecules and propeller-like molecules. It is shown that only for M = Si are both isomers true minima on the potential energy surface. The thermodynamics of the dissociation process (1/6)M(6)N(8) --> (1/3)M(3)N(4) is discussed. For each M(3)N(4) molecule, four structures with different multiplicity are considered. The thermodynamic analysis shows that independently of the multiplicity of M(3)N(4) nitrides all M(6)N(8) clusters are stable in the gas phase in a wide temperature range and could be potential intermediates in chemical vapor deposition of the nitride materials.

Prevalence and Prognosis of Hyperkalemia in Patients with Acute Myocardial Infarction

PubMed Central

Grodzinsky, Anna; Goyal, Abhinav; Gosch, Kensey; McCullough, Peter A.; Fonarow, Gregg C.; Mebazaa, Alexandre; Masoudi, Frederick A.; Spertus, John A.; Palmer, Biff F.; Kosiborod, Mikhail

2016-01-01

Background Hyperkalemia is common and potentially dangerous in hospitalized patients; its contemporary prevalence and prognostic importance following acute myocardial infarction are not well described. Methods In 38,689 consecutive acute myocardial infarction patients from the Cerner Health Facts database, we evaluated the association between maximum in-hospital potassium levels (max K) and in-hospital mortality. Patients were stratified by dialysis status, and grouped by max K as follows: <5 mEq/L, 5–<5.5 mEq/L, 5.5–<6.0 mEq/L, 6.0–<6.5 mEq/L, and ≥ 6.5 mEq/L. Multivariable logistic regression was used to adjust for multiple patient and site characteristics. The relationship between number of hyperkalemic values and in-hospital mortality was also evaluated. Results Of 38,689 acute myocardial infarction patients, 886 were on dialysis. The rate of hyperkalemia (max K ≥ 5.0 mEq/L) was 22.6% in non-dialysis and 66.8% in dialysis patients. Moderate-severe hyperkalemia (max K ≥ 5.5 mEq/L) occurred in 9.8% of patients. There was a steep increase in mortality with higher max K levels. In-hospital mortality exceeded 15% once max K ≥5.5 mEq/L regardless of dialysis status. The relationship between higher max K and increased mortality risk persisted after multivariable adjustment. In addition, patients with greater number of hyperkalemic values (vs. a single value) experienced higher in-hospital mortality. Conclusions Hyperkalemia is common in patients hospitalized with acute myocardial infarction. Higher max K levels and number of hyperkalemic events are associated with a steep mortality increase; with higher risks for adverse outcomes observed even at mild levels of hyperkalemia. Whether more intensive management of hyperkalemia may improve outcomes in acute myocardial infarction patients merits further study. PMID:27060233

Arabidopsis m6A demethylase activity modulates viral infection of a plant virus and the m6A abundance in its genomic RNAs

PubMed Central

Martínez-Pérez, Mireya; Aparicio, Frederic; López-Gresa, Maria Pilar; Bellés, Jose María; Sánchez-Navarro, Jesus A.

2017-01-01

N6-methyladenosine (m6A) is an internal, reversible nucleotide modification that constitutes an important regulatory mechanism in RNA biology. Unlike mammals and yeast, no component of the m6A cellular machinery has been described in plants at present. m6A has been identified in the genomic RNAs of diverse mammalian viruses and, additionally, viral infection was found to be modulated by the abundance of m6A in viral RNAs. Here we show that the Arabidopsis thaliana protein atALKBH9B (At2g17970) is a demethylase that removes m6A from single-stranded RNA molecules in vitro. atALKBH9B accumulates in cytoplasmic granules, which colocalize with siRNA bodies and associate with P bodies, suggesting that atALKBH9B m6A demethylase activity could be linked to mRNA silencing and/or mRNA decay processes. Moreover, we identified the presence of m6A in the genomes of two members of the Bromoviridae family, alfalfa mosaic virus (AMV) and cucumber mosaic virus (CMV). The demethylation activity of atALKBH9B affected the infectivity of AMV but not of CMV, correlating with the ability of atALKBH9B to interact (or not) with their coat proteins. Suppression of atALKBH9B increased the relative abundance of m6A in the AMV genome, impairing the systemic invasion of the plant, while not having any effect on CMV infection. Our findings suggest that, as recently found in animal viruses, m6A modification may represent a plant regulatory strategy to control cytoplasmic-replicating RNA viruses. PMID:28923956

Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study.

PubMed

Schmiegelow, Kjeld; Al-Modhwahi, Ibrahim; Andersen, Mette Klarskov; Behrendtz, Mikael; Forestier, Erik; Hasle, Henrik; Heyman, Mats; Kristinsson, Jon; Nersting, Jacob; Nygaard, Randi; Svendsen, Anne Louise; Vettenranta, Kim; Weinshilboum, Richard

2009-06-11

Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL.

Vitamin B6 versus mianserin and placebo in acute neuroleptic-induced akathisia: a randomized, double-blind, controlled study.

PubMed

Miodownik, Chanoch; Lerner, Vladimir; Statsenko, Nikolay; Dwolatzky, Tzvi; Nemets, Boris; Berzak, Elina; Bergman, Joseph

2006-01-01

Treatment strategies against acute neuroleptic-induced akathisia (NIA) include anticholinergic (antimuscarinic) agents, dopamine agonists, GABAergic agents, beta-blockers, benzodiazepines, and serotonin antagonists. However, many patients who have acute akathisia fail to respond. In previous studies, mianserin and vitamin B6 were found to be effective in the treatment of acute akathisia. The purpose of this study was to compare the efficacy of B(6), mianserin and placebo in the treatment of acute NIA. Sixty schizophrenia and schizoaffective inpatients who have NIA were randomly divided to receive vitamin B(6) 1,200 mg/d, mianserin 15 mg/d, or placebo for 5 days, in a double-blind design. The Barnes Akathisia Rating Scale, Brief Psychiatric Rating Scale, and Clinical Global Impression were used to assess the severity of NIA and psychotic symptoms. The assessment was made at baseline and daily for the duration of the study. Compared with the placebo group, the vitamin B(6)-treated and mianserin-treated patients showed a significant improvement in the subjective (P < 0.0001), subjective distress (P < 0.0001), and global (P < 0.0001) subscales. The objective subscale did not show significant positive results (P = 0.056), but there was a trend toward symptom amelioration in both groups. A reduction of at least 2 points on the Barnes Akathisia Rating Scale global subscale was noted in the vitamin B(6) group (13/23, 56%) as well as in the mianserin groups (13/20, 65%), and in only one patient in the placebo group (1/17, 6%; P < 0.0005). Our results indicate that high doses of B(6) and a low dose of mianserin may be a useful addition to current treatments of NIA. The efficacy of vitamin B(6) and mianserin suggests that the pathophysiology of acute NIA is heterogeneous with the various subtypes of acute NIA responding differently to the various pharmacological approaches.

The effect of n-3/n-6 polyunsaturated fatty acids on acute reflux esophagitis in rats.

PubMed

Zhuang, Ze-Hao; Xie, Jing-Jing; Wei, Jing-Jing; Tang, Du-Peng; Yang, Li-Yong

2016-10-04

Polyunsaturated fatty acids (PUFAs) play various roles in inflammation. However, the effect of PUFAs in the development of reflux esophagitis (RE) is unclear. This study is to investigate the potential effect of n-3/n-6 PUFAs on acute RE in rats along with the underlying protective mechanisms. Forty Sprague Dawley rats were randomly divided into four groups (n = 10 in each group). RE model was established by pyloric clip and section ligation. Fish oil- and soybean oil-based fatty emulsion (n-3 and n-6 groups), or normal saline (control and sham operation groups) was injected intraperitoneally 2 h prior to surgery and 24 h postoperatively (2 mL/kg, respectively). The expressions of interleukin (IL)-1β, IL-8, IL-6 and myeloid differentiation primary response gene 88 (MyD88) in esophageal tissues were evaluated by Western blot and immunohistochemistry after 72 h. The malondialdehyde (MDA) and superoxide dismutase (SOD) expression in the esophageal tissues were determined to assess the oxidative stress. The mildest macroscopic/microscopic esophagitis was found in the n-3 group (P < 0.05). The expression of IL-1β, IL-8, IL-6 and MyD88 were increased in all RE groups, while the lowest and highest expression were found in n-3 and n-6 group, respectively (P < 0.05). The MDA levels were increased in all groups (P < 0.05), in an ascending trend from n-3, n-6 groups to control group. The lowest and highest SOD levels were found in the control and n-3 group, respectively (P < 0.05). n-3 PUFAs may reduce acute RE in rats, which may be due to inhibition of the MyD88-NF-kB pathway and limit oxidative damage.

Structure and expression of MHC class Ib genes of the central M region in rat and mouse: M4, M5, and M6.

PubMed

Lambracht-Washington, Doris; Moore, Yuki F; Wonigeit, Kurt; Lindahl, Kirsten Fischer

2008-04-01

The M region at the telomeric end of the murine major histocompatibility complex (MHC) contains class I genes that are highly conserved in rat and mouse. We have sequenced a cosmid clone of the LEW rat strain (RT1 haplotype) containing three class I genes, RT1.M6-1, RT1.M4, and RT1.M5. The sequences of allelic genes of the BN strain (RT1n haplotype) were obtained either from cDNAs or genomic clones. For the coding parts of the genes few differences were found between the two RT1 haplotypes. In LEW, however, only RT1.M5 and RT1.M6 have open reading frames; whereas in BN all three genes were intact. In line with the findings in BN, transcription was found for all three rat genes in several tissues from strain Sprague Dawley. Protein expression in transfectants could be demonstrated for RT1.M6-1 using the monoclonal antibody OX18. By sequencing of transcripts obtained by RT-PCR, a second, transcribed M6 gene, RT1.M6-2, was discovered, which maps next to RT1.M6-1 outside of the region covered by the cosmid. In addition, alternatively spliced forms for RT1.M5 and RT1.M6 were detected. Of the orthologous mouse genes, H2-M4, H2-M5, and H2-M6, only H2-M5 has an open reading frame. Other important differences between the corresponding parts of the M region of the two species are insertion of long LINE repeats, duplication of RT1.M6, and the inversion of RT1.M5 in the rat. This demonstrates substantial evolutionary dynamics in this region despite conservation of the class I gene sequences themselves.

Regulatory Role of N6 -methyladenosine (m6 A) Methylation in RNA Processing and Human Diseases.

PubMed

Wei, Wenqiang; Ji, Xinying; Guo, Xiangqian; Ji, Shaoping

2017-09-01

N 6 -methyladenosine (m 6 A) modification is an abundant and conservative RNA modification in bacterial and eukaryotic cells. m 6 A modification mainly occurs in the 3' untranslated regions (UTRs) and near the stop codons of mRNA. Diverse strategies have been developed for identifying m 6 A sites in single nucleotide resolution. Dynamic regulation of m 6 A is found in metabolism, embryogenesis, and developmental processes, indicating a possible epigenetic regulation role along RNA processing and exerting biological functions. It has been known that m 6 A editing involves in nuclear RNA export, mRNA degradation, protein translation, and RNA splicing. Deficiency of m 6 A modification will lead to kinds of diseases, such as obesity, cancer, type 2 diabetes mellitus (T2DM), infertility, and developmental arrest. Some specific inhibitors against methyltransferase and demethylase have been developed to selectively regulate m 6 A modification, which may be advantageous for treatment of m 6 A related diseases. J. Cell. Biochem. 118: 2534-2543, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Evaluation of a rapid IgM detection test for diagnosis of acute leptospirosis in dogs.

PubMed

Lizer, J; Grahlmann, M; Hapke, H; Velineni, S; Lin, D; Kohn, B

2017-05-27

Recently, a lateral flow assay (LFA) for detection of Leptospira -specific IgM in canine sera became commercially available in Europe. The present study aims to evaluate the diagnostic performance of this assay using canine sera from a collection of diagnostic accessions. Diagnostic sensitivity was assessed by testing 37 acute-phase and 9 corresponding convalescent-phase sera from dogs with a confirmed diagnosis of leptospirosis. Specificity was determined by testing sera from sick dogs with non-leptospiral infections (n=15) and healthy dogs with incomplete history of vaccination (n=45). During acute phase of illness, LFA scored positive for 28/37 sera with a sensitivity of 75.7 per cent while only 9/37 (24.3 per cent) samples were positive on microscopic agglutination test. The specificity of the LFA was 98.3 per cent (59/60). This test showed 89.7 and 100 per cent overall agreements with clinical diagnosis for acute-phase and convalescent-phase sera, respectively. The impact of vaccination on the LFA was also determined and vaccine-stimulated IgM responses were negative in 19/25 (76 per cent) dogs at 12 weeks post vaccination. In conclusion, the LFA is a rapid and reliable test for early detection of Leptospira -specific IgM during acute phase of canine leptospirosis. However, interpretation of a positive result must be made in the context of clinical signs and vaccination history. British Veterinary Association.

Influence of interleukin-1β and interleukin-6 gene polymorphisms on the development of acute pancreatitis.

PubMed

Chi, D Z; Chen, J; Huang, D P

2015-02-03

We investigated the association between 3 main proinflammatory cytokines [interleukin (IL)-1β and IL-6] and the risk of acute pancreatitis. Polymerase chain reaction-restriction fragment length polymorphism was used to genotype IL-1β+3954 C/T (rs1143634) and IL-1β-511 C/T (rs16944) and IL-6 -174 G/C (rs1800795) and IL-6 -634 C/G (rs1800796). The genotype distributions of IL-1β+3954 C/T (rs1143634) and IL-1β-511 C/T (rs16944) and IL-6 -174 G/C (rs1800795) and IL-6 -634 C/G (rs1800796) were in Hardy-Weinberg equilibrium for the control group. Multivariate regression analyses showed that subjects carrying the rs1143634 TT genotype had a significantly increased risk of acute pancreatitis, with an adjusted odds ratio (95% confidence interval) of 2.11 (1.03-4.51). Subjects carrying the IL-1β rs1143634 TT genotype had a significantly increased risk of acute pancreatitis in our Chinese population.

[Role of 6% hydroxyethylstarch 130/0.4 and furosemide in the treatment of acute pancreatitis].

PubMed

Wang, Jiandong; Chen, Youdai; Dong, Yun; Hu, Weijian; Zhou, Ping; Chang, Li; Feng, Shiyan; Lin, Jian; Zhao, Yu

2010-10-01

This study was conducted to observe the effects of intravenously administered 6% hydroxyethylstarch 130/ 0.4 solution and furosemide on the outcome of acute pancreatitis patients. Patients admitted to our center from October 16, 2007 through August 31, 2009 were given intravenous infusions of 6% hydroxyethylstarch 130/0. 4 solution (1 000-2 000 ml administered for an adult) soon after admission. At the same time, furosemide was administered as intravenous bolus, trying to maintain a fluid balance. The dose level of hydroxyethylstarch was gradually lowered from the second day after admission. A total of 135 patients (54% of patients with a Ranson's score > or = 3 and 61% with a Balthazar CT score > or = D) were treated with our protocol. Only 4% and 7% patients developed pancreatic and systemic complications respectively; only 1 patient underwent necrosectomy. The in-hospital mortality rate was 4%. It was estimated that, on the average, 18. 3% of blood volume was lost on admission. Our study suggest that intravenously administered 6% hydroxyethylstarch 130/0. 4 solution and furosemide might be beneficial for patients with acute pancreatitis. Plasma extravasation is a central event of acute pancreatitis. The reversal of hypovolemia is crucial for the success in treatment of acute pancreatitis.

Striatal output markers do not alter in response to circling behaviour in 6-OHDA lesioned rats produced by acute or chronic administration of the monoamine uptake inhibitor BTS 74 398.

PubMed

Lane, E L; Cheetham, S; Jenner, P

2008-01-01

The monoamine uptake inhibitor BTS 74 398 induces ipsilateral circling in 6-hydroxydopamine (6-OHDA) lesioned rats without induction of abnormal motor behaviours associated with L-dopa administration. We examined whether this was reflected in the expression of peptide mRNA in the direct and indirect striatal output pathways.6-OHDA lesioning of the nigrostriatal pathway increased striatal expression of PPE-A mRNA and decreased levels of PPT mRNA with PPE-B mRNA expression remaining unchanged. Acute L-dopa administration normalised PPE-A mRNA and elevated PPT mRNA while PPE-B mRNA expression remained unchanged. Acute administration of BTS 74 398 did not alter striatal peptide mRNA levels. Following chronic treatment with L-dopa, PPE-A mRNA expression in the lesioned striatum continued to be normalised and PPT mRNA was increased compared to the intact side. PPE-B mRNA expression was also markedly increased relative to the non-lesioned striatum. Chronic BTS 74 398 administration did not alter mRNA expression in the 6-OHDA lesioned striatum although small increases in PPT mRNA expression in the intact and sham lesioned striatum were observed. The failure of BTS 74 398 to induce changes in striatal neuropeptide mRNA correlated with its failure to induce abnormal motor behaviours or behavioural sensitisation but does not explain how it produces a reversal of motor deficits. An action in another area of the brain appears likely and may explain the subsequent failure of BTS 74 398 and related compounds to exert anti-parkinsonian actions in man.

Emergency therapeutic leukapheresis in a case of acute myeloid leukemia M5

PubMed Central

Ranganathan, Sudha; Sesikeran, Shyamala; Gupta, Vineet; Vanajakshi

2008-01-01

Cell separators in India are routinely used for plateletpheresis, peripheral blood stem cell collections and therapeutic plasma exchange. Therapeutic leukapheresis, particularly as an emergency procedure, has been uncommonly performed and reported. Here, a case of a 53-year-old male, diagnosed with acute myeloid leukemia subtype M5 (AML M5) with hyperleukocytosis, who underwent emergency leukaphereis, is reported. After two procedures, there was a decrease of WBC count by 85%, which enabled cytotoxic therapy to be initiated. PMID:20041073

IL-4/IL-13-mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury.

PubMed

Zhang, Ming-Zhi; Wang, Xin; Wang, Yinqiu; Niu, Aolei; Wang, Suwan; Zou, Chenhang; Harris, Raymond C

2017-02-01

Cytokines IL-4 and IL-13 play important roles in polarization of macrophages/dendritic cells to an M2 phenotype, which is important for recovery from acute kidney injury. Both IL-4 and IL-13 activate JAK3/STAT6 signaling. In mice with diphtheria toxin receptor expression in proximal tubules (selective injury model), a relatively selective JAK3 inhibitor, tofacitinib, led to more severe kidney injury, delayed recovery from acute kidney injury, increased inflammatory M1 phenotype markers and decreased reparative M2 phenotype markers of macrophages/dendritic cells, and development of more severe renal fibrosis after diphtheria toxin administration. Similarly, there was delayed recovery and increased tubulointerstitial fibrosis in these diphtheria toxin-treated mice following tamoxifen-induced deletion of both IL-4 and IL-13, with increased levels of M1 and decreased levels of M2 markers in the macrophages/dendritic cells. Furthermore, deletion of IL-4 and IL-13 led to a decrease of tissue reparative M2a phenotype markers but had no effect on anti-inflammatory M2c phenotype markers. Deletion of IL-4 and IL-13 also inhibited recovery from ischemia-reperfusion injury in association with increased M1 and decreased M2 markers and promoted subsequent tubulointerstitial fibrosis. Thus, IL-4 and IL-13 are required to effectively polarize macrophages/dendritic cells to an M2a phenotype and to promote recovery from acute kidney injury. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Transradial primary angioplasty and stenting in Indian patients with acute myocardial infarction: acute results and 6-month follow-up.

PubMed

Ranjan, Alok; Patel, Tejas M; Shah, Sanjay C; Malhotra, Hemant; Patel, Rajni; Vayada, Nishith; Pothiwala, Rasesh; Fonseca, Keith; Tanwar, Narendra S

2005-01-01

Coronary angioplasty and stent implantation is effective as primary intervention in acute myocardial infarction. Because of fewer puncture site complications and improved patient comfort, transradial access has been increasingly used as an alternative to transfemoral access for percutaneous coronary interventions. We studied 103 patients (94 men, 9 women: mean age 52.5 +/- 11.96 years) with a diagnosis of acute myocardial infarction (<12 hours after onset), who underwent primary percutaneous coronary intervention. Transradial access was used in all patients with a normal Allen's test and transfemoral access was used additionally only if intra-aortic balloon counterpulsation was required. Follow-up duration was 6 months. Transradial access was successfully achieved in all patients. Radial artery cannulation took <2 min in more than 85% patients. During percutaneous coronary intervention, cannulation to balloon inflation times and total procedure times were 11.3 +/- 5.2 min and 19.9 +/- 10.8 min, respectively. Stents were implanted in 99 (96.1%) patients andplain balloon angioplastywas performed in 3.9%. The primary success rate was 98.1%, with no major bleeding complications. Total length of hospitalization averaged 2.4 +/- 0.8 days. In-hospital major adverse clinical events rate was 5.9%. Six-month clinical follow-up was achieved for 84 (86.6%) patients. Six (7.1%) patients died during follow-up. Follow-up coronary angiography was performed in 22 (26.2%) patients. After 6 months, 7 patients required revascularizationof the target lesion. The rate of survival without myocardial infarction, bypass surgery or repeat coronary angioplasty was 88.5% at 6 months. Transradial access may represent a safe and feasible technique for performing primary percutaneous coronary intervention with good acute results and without major bleeding complications.

Interleukin-6 is associated with chronic hyperglycemia and insulin resistance in patients after acute pancreatitis.

PubMed

Gillies, Nicola; Pendharkar, Sayali A; Asrani, Varsha M; Mathew, Juby; Windsor, John A; Petrov, Maxim S

2016-01-01

Diabetes is a pervasive disease, with a mounting prevalence and burden on health care systems. Under this collective term of diabetes falls diabetes after diseases of the exocrine pancreas, a condition which was previously under-recognised and often mislabeled as type 2 diabetes mellitus and is now increasingly acknowledged as a stand-alone entity. However, there is a paucity of clinical studies investigating the underlying pathophysiology of diabetes after acute pancreatitis, the most frequent disease of the pancreas. This study aimed to investigate the role of adipocytokines in glucose metabolism after acute pancreatitis. This was a cross-sectional follow-up study of a patient cohort diagnosed with acute pancreatitis. Fasting venous blood samples were collected to analyse markers of glucose metabolism (fasting blood glucose, haemoglobin A1c, homeostasis model assessment (HOMA-IR) as a measure of insulin resistance) and adypocytokines (adiponectin, interleukin-6, leptin, monocyte chemoattractant protein-1, retinol binding protein-4, resistin, and tumor necrosis factor-α). Participants were categorized into two groups: normoglycemia after acute pancreatitis and chronic hyperglycemia after acute pancreatitis (CHAP). Binary logistic regression and linear regression analyses were used to investigate the association between each of the adipocytokines and markers of glucose metabolism. Potential confounders were adjusted for in multivariate analyses. A total of 83 patients with acute pancreatitis were included, of whom 19 developed CHAP. Interleukin-6 was significantly associated with CHAP in both unadjusted and adjusted models (p = 0.030 and p = 0.018, respectively). Further, it was also significantly associated with HOMA-IR in both unadjusted and adjusted models (p = 0.029 and p = 0.037, respectively). Other adipocytokines were not significantly associated with markers of glucose metabolism. Interleukin-6 appears to be implicated in the development of chronic

Evaluation of a commercial IgE ELISA in comparison with IgA and IgM ELISAs, IgG avidity assay and complement fixation for the diagnosis of acute toxoplasmosis.

PubMed

Kodym, P; Machala, L; Rohácová, H; Sirocká, B; Malý, M

2007-01-01

A panel of sera from patients with known case histories representative of acute toxoplasmosis (primarily lymphadenopathy, n = 106), latent toxoplasmosis (asymptomatic, n = 368) and negative samples (n = 54) was used to evaluate the capacity of five serological tests to differentiate among patients with acute or latent toxoplasmosis and non-infected individuals. Positive IgA, IgE and IgM ELISA results and low IgG avidity and complement fixation test (CFT) titres of >or=256 were considered to be indicative of acute toxoplasmosis. The most sensitive methods were IgM ELISA (98.1%) and CFT (97.1%), albeit with low specificity (65.0% and 64.5%, respectively) and positive predictive values (43.3% and 42.7%, respectively). IgG avidity assay and IgE ELISA had the highest specificity (97.7% and 91.7%, respectively) and the highest positive predictive values (89.4% and 75.6%, respectively). The best association between serological results and clinical findings was obtained with IgE ELISA (86%, as expressed via Youden's index). In a subset of 259 samples categorised by the period between the onset of clinical symptoms and sampling, >50% of patients had enlarged lymph nodes for <4 months, despite a broad range of differences. However, IgM remained positive for 12-18 months, IgA for 6-9 months and IgE for 4-6 months. IgG avidity remained low for a maximum of 4 months, after which avidity increased despite the persistence of enlarged lymph nodes and a positive IgE assay. Detection of IgE appears to be a highly specific test for confirming the acute nature of Toxoplasma infections that have been detected by other sensitive methods.

ETV6-RUNX1 + Acute Lymphoblastic Leukaemia in Identical Twins.

PubMed

Ford, Anthony M; Greaves, Mel

2017-01-01

Acute leukaemia is the major subtype of paediatric cancer with a cumulative risk of 1 in 2000 for children up to the age of 15 years. Childhood acute lymphoblastic leukaemia (ALL) is a biologically and clinically diverse disease with distinctive subtypes; multiple chromosomal translocations exist within the subtypes and each carries its own prognostic relevance. The most common chromosome translocation observed is the t(12;21) that results in an in-frame fusion between the first five exons of ETV6 (TEL) and almost the entire coding region of RUNX1 (AML1).The natural history of childhood ALL is almost entirely clinically silent and is well advanced at the point of diagnosis. It has, however, been possible to backtrack this process through molecular analysis of appropriate clinical samples: (i) leukaemic clones in monozygotic twins that are either concordant or discordant for ALL; (ii) archived neonatal blood spots or Guthrie cards from individuals who later developed leukaemia; and (iii) stored, viable cord blood cells.Here, we outline our studies on the aetiology and pathology of childhood ALL that provide molecular evidence for a monoclonal, prenatal origin of ETV6-RUNX1+ leukaemia in monozygotic identical twins. We provide mechanistic support for the concept that altered patterns of infection during early childhood can deliver the necessary promotional drive for the progression of ETV6-RUNX1+ pre-leukaemic cells into a postnatal overt leukaemia.

[Clinical features and prognosis of acute myeloid leukemia-M(4).].

PubMed

Li, Wei; Mi, Ying-Chang; Wang, Ying; Lin, Dong; Wei, Hui; Liu, Xu-Ping; Bian, Shou-Geng; Wang, Jian-Xiang

2010-01-01

To investigate factors that affect survival and prognosis of acute myeloid leukemia (AML)-M(4). Seventy AML-M(4) patients were divided into three groups, neither eosinophilia nor inv(16)\\[Eos(-)\\], eosinophilia with inv (16)\\[Eos(+) inv(16)(+)\\], and eosinophilia with no inv(16)\\[Eos(+) inv(16)(-)\\]. Clinical features, immunophenotype, chromosome karyotype, overall survival (OS) and relapse-free survival (RFS) were analyzed. The total complete remssion (CR) rate was 85.7%, CR rate after the first course of induction therapy was 71.4%. The median OS was 20 (1.2 - 162.4) months, and median RFS 78.0 (1.2 - 129.5) months. The 3 and 5 year OS rates were 42% and 42%, and 3 and 5 year RFS rates were 59% and 54%, respectively. The CR rate, CR after the first course of induction therapy and the median OS for the Eos(-) group were 76.9%, 61.5% and 11.2 (1.2 - 162.4) months; for the Eos(+) group were 96.8%, 89.6% and did not reach; for the Eos(+)inv16(+) group were 100%, 94.4% and did not reach; and for the Eos(+) inv(16)(-) group were 91.7%,69.2% and 14.3 months respectively. The statistical assay showed significant difference between Eos(+)inv(16)(-) and Eos(+)inv(16)(+) groups in OS. The Eos(+) patients present with early onset and low count of platelets. Eosinophilia emerged as a favorable prognostic factor, and the concomitant presence of both eosinophilia and inv(16) is associated with a significantly favorlable prognosis.

Do Acute Myocardial Infarction and Heart Failure Readmissions Flagged as Potentially Preventable by the 3M Potentially Preventable Readmissions Software Have More Process-of-Care Problems?

PubMed

Borzecki, Ann M; Chen, Qi; Mull, Hillary J; Shwartz, Michael; Bhatt, Deepak L; Hanchate, Amresh; Rosen, Amy K

2016-09-01

The 3M Potentially Preventable Readmissions (3M-PPR) software matches clinically related index admission and readmission diagnoses that may signify in-hospital or postdischarge quality problems. To assess whether the PPR algorithm identifies preventable readmissions, we compared processes of care between PPR software-flagged and nonflagged cases. Using 2006 to 2010 national VA administrative data, we identified acute myocardial infarction and heart failure discharges associated with 30-day all-cause readmissions, then flagged cases (PPR-Yes/PPR-No) using the 3M-PPR software. To assess care quality, we abstracted medical records of 100 readmissions per condition using tools containing explicit processes organized into admission work-up, in-hospital evaluation/treatment, discharge readiness, postdischarge period. We derived quality scores, scaled to a maximum of 25 per section (maximum total score=100) and compared cases on total and section-specific mean scores. For acute myocardial infarction, 77 of 100 cases were flagged as PPR-Yes. Section quality scores were highest for in-hospital evaluation/treatment (20.5±2.8) and lowest for postdischarge care (6.8±9.1). Total and section-related mean scores did not differ by PPR status; respective PPR-Yes versus PPR-No total scores were 61.6±11.1 and 60.4±9.4; P=0.98. For heart failure, 86 of 100 cases were flagged as PPR-Yes. Section scores were highest for discharge readiness (18.8±2.4) and lowest for postdischarge care (7.3±8.1). Like acute myocardial infarction, total and section-related mean scores did not differ by PPR status; PPR-Yes versus PPR-No total scores were 61.2±10.8 and 63.4±7.0, respectively; P=0.47. Among VA acute myocardial infarction and heart failure readmissions, the 3M-PPR software does not distinguish differences in case-level quality of care. Whether 3M-PPR software better identifies preventable readmissions by using other methods to capture poorly documented processes or performing different

M6 membrane protein plays an essential role in Drosophila oogenesis.

PubMed

Zappia, María Paula; Brocco, Marcela Adriana; Billi, Silvia C; Frasch, Alberto C; Ceriani, María Fernanda

2011-01-01

We had previously shown that the transmembrane glycoprotein M6a, a member of the proteolipid protein (PLP) family, regulates neurite/filopodium outgrowth, hence, M6a might be involved in neuronal remodeling and differentiation. In this work we focused on M6, the only PLP family member present in Drosophila, and ortholog to M6a. Unexpectedly, we found that decreased expression of M6 leads to female sterility. M6 is expressed in the membrane of the follicular epithelium in ovarioles throughout oogenesis. Phenotypes triggered by M6 downregulation in hypomorphic mutants included egg collapse and egg permeability, thus suggesting M6 involvement in eggshell biosynthesis. In addition, RNAi-mediated M6 knockdown targeted specifically to follicle cells induced an arrest of egg chamber development, revealing that M6 is essential in oogenesis. Interestingly, M6-associated phenotypes evidenced abnormal changes of the follicle cell shape and disrupted follicular epithelium in mid- and late-stage egg chambers. Therefore, we propose that M6 plays a role in follicular epithelium maintenance involving membrane cell remodeling during oogenesis in Drosophila.

M6 Membrane Protein Plays an Essential Role in Drosophila Oogenesis

PubMed Central

Zappia, María Paula; Brocco, Marcela Adriana; Billi, Silvia C.; Frasch, Alberto C.; Ceriani, María Fernanda

2011-01-01

We had previously shown that the transmembrane glycoprotein M6a, a member of the proteolipid protein (PLP) family, regulates neurite/filopodium outgrowth, hence, M6a might be involved in neuronal remodeling and differentiation. In this work we focused on M6, the only PLP family member present in Drosophila, and ortholog to M6a. Unexpectedly, we found that decreased expression of M6 leads to female sterility. M6 is expressed in the membrane of the follicular epithelium in ovarioles throughout oogenesis. Phenotypes triggered by M6 downregulation in hypomorphic mutants included egg collapse and egg permeability, thus suggesting M6 involvement in eggshell biosynthesis. In addition, RNAi-mediated M6 knockdown targeted specifically to follicle cells induced an arrest of egg chamber development, revealing that M6 is essential in oogenesis. Interestingly, M6-associated phenotypes evidenced abnormal changes of the follicle cell shape and disrupted follicular epithelium in mid- and late-stage egg chambers. Therefore, we propose that M6 plays a role in follicular epithelium maintenance involving membrane cell remodeling during oogenesis in Drosophila. PMID:21603606

[C1q/tumor necrosis factor related protein 6 (CTRP6) is involved in gentamicin-induced acute kidney injury in rats].

PubMed

Li, Rong; Yang, Xiaoxia; Yu, Yan; Zhou, Meilan; Tian, Xiujuan; Feng, Shidong; Wang, Hanmin

2016-11-01

Objective To explore the role of the anti-inflammatory cytokine C1q/tumor necrosis factor related protein 6 (CTRP6) in gentamicin-induced acute kidney injury in rats. Methods SD rats were divided into 5 groups including control group, model group and the other 3 experimental groups. The rats in model group and experimental groups were subcutaneously injected with gentamicin at the dose of 400 mg/(kg.d) for consecutive 2 days to induce acute renal injury. Two days before gentamicin injection, the rats in the 3 experimental groups were given pAd-CTRP6 at the doses of 0.5, 5 and 50 mg/kg, respectively. The serum levels of blood urea nitrogen (BUN) and creatinine (Cr) were respectively assayed with picric acid colorimetry and ultraviolet spectrophotometry; ELISA was used to detect serum CTRP6 content and the production of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) in the kidney homogenate; Western blotting was performed to detect the expressions of CTRP6, caspase-1 and pyrin domain containing 3 (NLRP3) proteins in the renal tissues of rats. Results Compared with control group, serum BUN and Cr contents increased in the model rats; the secretion of inflammatory factors IL-1β and TNF-α, as well as the expressions of caspase-1 and NLRP3 were also enhanced in the model group. Compared with the model group, serum BUN and Cr contents decreased in the experimental groups; the secretion of IL-1β and TNF-α, as well as the expressions of caspase-1 and NLRP3 were also attenuated in the experimental groups. Moreover, with the increase of the injection dosage of pAd-CTRP6, the suppressive effect was gradually strengthened. Conclusion CTRP6 can attenuate gentamicin-induced acute renal injury in rats in a dose-dependent manner.

Leukotriene-mediated neuroinflammation, toxic brain damage, and neurodegeneration in acute methanol poisoning.

PubMed

Zakharov, Sergey; Kotikova, Katerina; Nurieva, Olga; Hlusicka, Jiri; Kacer, Petr; Urban, Pavel; Vaneckova, Manuela; Seidl, Zdenek; Diblik, Pavel; Kuthan, Pavel; Navratil, Tomas; Pelclova, Daniela

2017-04-01

The role of neuroinflammation in methanol-induced toxic brain damage has not been studied. We studied acute concentrations and the dynamics of leukotrienes (LT) in serum in hospitalized patients with acute methanol poisoning and in survivors. Series of acute cysteinyl-LT and LTB4 concentration measurements were performed in 28/101 hospitalized patients (mean observation time: 88 ± 20 h). In 36 survivors, control LT measurements were performed 2 years after discharge. The acute maximum (C max ) LT concentrations were higher than concentrations in survivors: C max for LTC4 was 80.7 ± 5.6 versus 47.9 ± 4.5 pg/mL; for LTD4, 51.0 ± 6.6 versus 23.1 ± 2.1 pg/mL; for LTE4, 64.2 ± 6.0 versus 26.2 ± 3.9 pg/mL; for LTB4, 59.8 ± 6.2 versus 27.2 ± 1.4 pg/mL (all p < 0.001). The patients who survived had higher LT concentrations than those who died (all p < 0.01). Among survivors, patients with CNS sequelae had lower LTE4 and LTB4 than did those without sequelae (both p < 0.05). The LT concentrations increased at a rate of 0.4-0.5 pg/mL/h and peaked 4-5 days after admission. The patients with better outcomes had higher cys-LTs (all p < 0.01) and LTB4 (p < 0.05). More severely poisoned patients had lower acute LT concentrations than those with minor acidemia. The follow-up LT concentrations in survivors with and without CNS sequelae did not differ (all p > 0.05). The mean decrease in LT concentration was 30.9 ± 9.0 pg/mL for LTC4, 26.3 ± 8.6 pg/mL for LTD4, 37.3 ± 6.4 pg/mL for LTE4, and 32.0 ± 8.8 pg/mL for LTB4. Our findings suggest that leukotriene-mediated neuroinflammation may play an important role in the mechanisms of toxic brain damage in acute methanol poisoning in humans. Acute elevation of LT concentrations was moderate, transitory, and was not followed by chronic neuroinflammation in survivors.

RNA epitranscriptomics: Regulation of infection of RNA and DNA viruses by N6 -methyladenosine (m6 A).

PubMed

Tan, Brandon; Gao, Shou-Jiang

2018-04-26

N 6 -methyladenosine (m 6 A) was discovered 4 decades ago. However, the functions of m 6 A and the cellular machinery that regulates its changes have just been revealed in the last few years. m 6 A is an abundant internal mRNA modification on cellular RNA and is implicated in diverse cellular functions. Recent works have demonstrated the presence of m 6 A in the genomes of RNA viruses and transcripts of a DNA virus with either a proviral or antiviral role. Here, we first summarize what is known about the m 6 A "writers," "erasers," "readers," and "antireaders" as well as the role of m 6 A in mRNA metabolism. We then review how the replications of numerous viruses are enhanced and restricted by m 6 A with emphasis on the oncogenic DNA virus, Kaposi sarcoma-associated herpesvirus (KSHV), whose m 6 A epitranscriptome was recently mapped. In the context of KSHV, m 6 A and the reader protein YTHDF2 acts as an antiviral mechanism during viral lytic replication. During viral latency, KSHV alters m 6 A on genes that are implicated in cellular transformation and viral latency. Lastly, we discuss future studies that are important to further delineate the functions of m 6 A in KSHV latent and lytic replication and KSHV-induced oncogenesis. Copyright © 2018 John Wiley & Sons, Ltd.

Prevalence and Prognosis of Hyperkalemia in Patients with Acute Myocardial Infarction.

PubMed

Grodzinsky, Anna; Goyal, Abhinav; Gosch, Kensey; McCullough, Peter A; Fonarow, Gregg C; Mebazaa, Alexandre; Masoudi, Frederick A; Spertus, John A; Palmer, Biff F; Kosiborod, Mikhail

2016-08-01

Hyperkalemia is common and potentially dangerous in hospitalized patients; its contemporary prevalence and prognostic importance after acute myocardial infarction are not well described. In 38,689 consecutive patients with acute myocardial infarction from the Cerner Health Facts database, we evaluated the association between maximum in-hospital potassium levels and in-hospital mortality. Patients were stratified by dialysis status and grouped by maximum potassium as follows: <5 mEq/L, 5 to <5.5 mEq/L, 5.5 to <6.0 mEq/L, 6.0 to <6.5 mEq/L, and ≥6.5 mEq/L. Multivariable logistic regression was used to adjust for multiple patient and site characteristics. The relationship between the number of hyperkalemic values and the in-hospital mortality was evaluated. Of 38,689 patients with acute myocardial infarction, 886 were on dialysis. The rate of hyperkalemia (maximum potassium ≥5.0 mEq/L) was 22.6% in patients on dialysis and 66.8% in patients not on dialysis. Moderate to severe hyperkalemia (maximum potassium ≥5.5 mEq/L) occurred in 9.8% of patients. There was a steep increase in mortality with higher maximum potassium levels. In-hospital mortality exceeded 15% once maximum potassium was ≥5.5 mEq/L regardless of dialysis status. The relationship between higher maximum potassium and increased mortality risk persisted after multivariable adjustment. In addition, patients with a greater number of hyperkalemic values (vs a single value) experienced higher in-hospital mortality. Hyperkalemia is common in patients who are hospitalized with acute myocardial infarction. Higher maximum potassium levels and number of hyperkalemic events are associated with a steep mortality increase, with higher risks for adverse outcomes observed even at mild levels of hyperkalemia. Whether more intensive management of hyperkalemia may improve outcomes in patients with acute myocardial infarction merits further study. Copyright © 2016 Elsevier Inc. All rights reserved.

Mesenchymal stem cells ameliorate rhabdomyolysis-induced acute kidney injury via the activation of M2 macrophages

PubMed Central

2014-01-01

Introduction The mortality of rhabdomyolysis-induced acute kidney injury (AKI) is still high, as there is no effective therapy. It has been shown that bone marrow-derived mesenchymal stem cells (MSCs) can induce M2 macrophages, which mediate MSC protection in other experimental inflammation-related organ injury. This study was designed to investigate the protective effects of macrophage activation in MSC therapy of rhabdomyolysis-induced AKI. Methods MSCs were injected into glycerol-induced rhabdomyolysis mice. Renal injury was evaluated using the serum creatinine, urea nitrogen, renal pathology and acute tubular necrosis score. The distribution of MSCs was detected using two-photon fluorescence confocal imaging. Immunofluorescence of anti-F4/80 and anti-CD206 was performed to determine macrophages and M2 macrophages in the tissues of the kidney, and M2 macrophage infiltration was also evaluated using western blotting analyses. After depletion of macrophages using clodronate liposomes at the phase of kidney repair, renal injury was re-evaluated. RAW 264.7 macrophages were incubated with lipopolysaccharide and co-cultured with MSCs and subsequently visualised using immunofluorescence staining and flow cytometry analysis. Finally, disparate phenotype macrophages, including normal macrophages (M0), lipopolysaccharide-stimulated macrophages (M1), and MSC-co-cultured macrophages (M2), were infused into mice with AKI, which were pre-treated with liposomal clodronate. Results In vivo infusion of MSCs protected AKI mice from renal function impairment and severe tubular injury, which was accompanied by a time-dependent increase in CD206-positive M2 macrophage infiltration. In addition, depleting macrophages with clodronate delayed restoration of AKI. In vitro, macrophages co-cultured with MSCs acquired an anti-inflammatory M2 phenotype, which was characterised by an increased expression of CD206 and the secretory cytokine interleukin (IL)-10. The concentrations of IL-10, IL

Research on M23C6 precipitation of 690 alloy

NASA Astrophysics Data System (ADS)

Zhigang, Song; han, Feng; Wenjie, Zheng; Lihong, Zhang; Mingjuan, Ma; Weijun, Sang

Precipitation M23C6 of 690 alloy was studied in this paper. Firstly, M23C6 precipitation and evolution of chromium-depleted zone of 690 alloy during TT were studied. Evolution of chromium-depleted zone of 690 alloy was affected markedly by TT.The test results showed that the lowest chromium concentration in chromium-depleted zone raised dramatically after TT for 10 20h because of chromium backfill.The morphology of M23C6 in 690 alloy specimens changed obviously during different TT temperatures of 650 850°C. 690 alloy could get good M23C6 morphology though TT at 700 725°C and there appeared coarse M23C6 presenting multiple layer morphology when TT temperature reached 750 850°C. When treated for TT different time at 715°C, the M23C6 amount increased with extension of TT time and M23C6 could precipitate adequately while the TT time reached 15h.

Technetium-99m(Sn2+)pyrophosphate in ischemic and infarcted dog myocardium in early stages of acute coronary occlusion: histochemical and tissue-counting comparisons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bianco, J.A.; Kemper, A.J.; Taylor, A.

1983-06-01

We have investigated the pattern of accumulation of Tc-99m(Sn2+)pyrophosphate (Tc-99m PPi) in myocardial tissue of dogs during the early stages of acute occlusion of the left anterior descending coronary artery. Three groups were studied after: (a) 40 min occlusion followed by 6 hr reperfusion (n . 6); (b) 6 hr occlusion followed by one hour reperfusion (n . 5); and (c) 7 hr occlusion with no reperfusion (n . 4). Areas of myocardial infarction were defined with triphenyl-tetrazolium chloride (TTC) staining, and blood flow was determined with 9-mu radioactive microspheres. In Group C uptake in infarcted and peri-infarct areas wasmore » not enhanced, most likely owing to low flow. In Group B, with late reperfusion, Tc-99m PPi sequestration was increased in both infarcted and peri-infarcted tissues. In Group A, areas ischemic during occlusion but with normal flow and viability by TTC after 6 hr of reperfusion showed significant uptake of Tc-99m PPi (twice the uptake of nonischemic regions).« less

Long-term remission in BCR/ABL-positive AML-M6 patient treated with Imatinib Mesylate.

PubMed

Pompetti, Franca; Spadano, Antonio; Sau, Antonella; Mennucci, Antonio; Russo, Rosa; Catinella, Virginia; Franchi, Paolo Guanciali; Calabrese, Giuseppe; Palka, Giandomenico; Fioritoni, Giuseppe; Iacone, Antonio

2007-04-01

BCR/ABL-positive acute myeloid leukemia (AML) is a rare disease, characterized by a poor prognosis, with resistance to induction chemotherapy and frequent relapses in responsive patients. Here we report a case of BCR/ABL-positive AML-M6 who, after relapse, was treated with Imatinib Mesylate (600 mg/die) and within 4 months achieved a cytogenetic and molecular complete response. After more than 4 years of continuous Imatinib therapy, nested RT-PCR for BCR/ABL is persistently negative. The case reported shows that the response obtained with Imatinib Mesylate in BCR/ABL-positive AML may be long lasting, offering a chance of successful treatment for this poor prognosis group of patients.

[Monoclonal antibodies in diagnosis of acute leukemias].

PubMed

Krawczyńska, A; Robak, T

1996-01-01

Immunophenotyping has become an essential component for the study of acute myeloblastic (AML) and lymphoblastic (ALL) leukaemias. The recent development of highly specific monoclonal antibodies (Mc Ab) to differentiation antigens (CD) of haematopoetic cells have made it readily available to clinical laboratories in most major hospitals. Immunophenotyping complements standard morphology by providing information on lineage, stage of differentiation and clonality. In addition some of the flow cytometry findings have independent prognostic significance. Monoclonal antibodies useful in defining lineage (B-cell versus T-cell) and stages of differentiation of ALL. It can be also used in identifying characteristic feature of AML and aiding in lineage determination in acute leukaemias that are morphologically undifferentiated. Surface immunophenotyping is especially helpful for recognizing mixed lineage acute leukaemia and diagnosing certain rare entities such as erythroleukaemia (M6), acute megakaryocytic leukaemia (M7) and minimally differentiation acute myeloid leukaemia.

[((H)L)2Fe6(NCMe)m]n+ (m = 0, 2, 4, 6; n = -1, 0, 1, 2, 3, 4, 6): an electron-transfer series featuring octahedral Fe6 clusters supported by a hexaamide ligand platform.

PubMed

Zhao, Qinliang; Harris, T David; Betley, Theodore A

2011-06-01

Using a trinucleating hexaamide ligand platform, the all-ferrous hexanuclear cluster ((H)L)(2)Fe(6) (1) is obtained from reaction of 3 equiv of Fe(2)(Mes)(4) (Mes = 2,4,6-Me(3)C(6)H(2)) with 2 equiv of the ligand ((H)L)H(6). Compound 1 was characterized by X-ray diffraction analysis, (57)Fe Mössbauer, SQUID magnetometry, mass spectrometry, and combustion analysis, providing evidence for an S=6 ground state and delocalized electronic structure. The cyclic voltammogram of [((H)L)(2)Fe(6)](n+) in acetonitrile reveals a rich redox chemistry, featuring five fully reversible redox events that span six oxidation states ([((H)L)(2)Fe(6)](n+), where n=-1→4) within a 1.3 V potential range. Accordingly, each of these species is readily accessed chemically to provide the electron-transfer series [((H)L)(2)Fe(6)(NCMe)(m)][PF(6)](n) (m=0, n=-1 (2); m=2, n=1 (3); m=4, n=2 (4); m=6, n=3 (5); m=6, n=4 (6)). Compounds 2-6 were isolated and characterized by X-ray diffraction, (57)Fe Mössbauer and multinuclear NMR spectroscopy, and combustion analysis. Two-electron oxidation of the tetracationic cluster in 6 by 2 equiv of [NO](+) generates the thermally unstable hexacationic cluster [((H)L)(2)Fe(6)(NCMe)(m)](6+), which is characterized by NMR and (57)Fe Mössbauer spectroscopy. Importantly, several stepwise systematic metrical changes accompany oxidation state changes to the [Fe(6)] core, namely trans ligation of solvent molecules and variation in Mössbauer spectra, spin ground state, and intracluster Fe-Fe separation. The observed metrical changes are rationalized by considering a qualitative, delocalized molecular orbital description, which provides a set of frontier orbitals populated by Fe 3d electrons. © 2011 American Chemical Society

The impact of high-dose methotrexate on intracellular 6-mercaptopurine disposition during interval therapy of childhood acute lymphoblastic leukemia.

PubMed

Adam de Beaumais, T; Dervieux, T; Fakhoury, M; Medard, Y; Azougagh, S; Zhang, D; Yakouben, K; Jacqz-Aigrain, E

2010-09-01

Low-dose methotrexate (MTX) therapy is the cornerstone treatment of acute lymphoblastic leukemia (ALL) and may enhance the activation of 6-mercaptopurine (6-MP) to 6-thioguanine nucleotides (6-TGN). Yet, data have established that high-dose MTX (HDMTX) hampers the accumulation of 6-TGN in red blood cells (RBC) and lymphoblasts. To clarify the pharmacokinetic interactions between these two antimetabolites, we serially measured RBC 6-TGN and MTX polyglutamates (MTXPG) levels following repeated courses of HDMTX (5 g/m(2) over 24 h) with daily oral 6-MP (25 mg/m(2)) during interval therapy in 20 children with ALL. HDMTX produced a rapid reduction in RBC 6-TGN 24 h after the start of MTX, and this effect was sustained at least by the third day (median decrease -21%; P < 0.001). However, a return to pre-infusion of 6-TGN levels was observed by the time of the following HDMTX course 14 days later (P < 0.001). RBC MTX polyglutamates accumulation followed Michaelis-Menten kinetics but was not associated with the change in pre-infusion 6-TGN levels which remained stable during the interval period. HDMTX does not appear to enhance 6-MP activation to 6-TGN. Moreover, given that the deleterious effect of HDMTX on intracellular 6-MP disposition has been shown to be several folds greater in lymphoblasts than in RBC. Our data warrant additional studies elucidating the optimal MTX dose synergizing with 6-MP.

ACUTE EFFECT OF ETHANOL ON HEPATIC RETICULAR G6Pase AND Ca2+ POOL

PubMed Central

Jacobs-Harper, Amy; Crumbly, Ashlee; Romani, Andrea

2012-01-01

Background Hydrolysis of glucose 6-phosphate via glucose 6-phosphatase enlarges the reticular Ca2+ pool of the hepatocyte. Exposure of liver cells to ethanol impairs reticular Ca2+ homeostasis. The present study investigated the effect of acute ethanol administration on glucose 6-phosphate supported Ca2+ accumulation in liver cells. Methods Total microsomes were isolated from rat livers acutely perfused with varying doses of ethanol (0.01%, 0.1%, or 1% v/v) for 8 minutes. Calcium uptake was assessed by 45Ca redistribution. Inorganic phosphate (Pi) formation was measured as an indicator of glucose 6-phosphatase hydrolytic activity. Results Glucose 6-phosphate-supported Ca2+ uptake decreased in a manner directly proportional to the dose of ethanol infused in the liver whereas Ca2+ uptake via SERCA pumps was decreased by ~25% only at the highest dose of alcohol administered. The reduced accumulation of Ca2+ within the microsomes resulted in a smaller IP3-induced Ca2+ release. Kinetic assessment of IP3 and passive Ca2+ release indicated a faster mobilization in microsomes from ethanol-treated livers, suggesting alcohol-induced alteration of Ca2+ releasing mechanisms. Pre-treatment of livers with chloromethiazole or dithio-threitol, but not 4-methyl-pyrazole prevented the inhibitory effect of ethanol on glucose 6-phosphatase activity and Ca2+ homeostasis. Conclusions Liver glucose 6-phosphatase activity and IP3-mediated Ca2+ release are rapidly inhibited following acute (8 min) exposure to ethanol, thus compromising the ability of the endoplasmic reticulum to dynamically modulate Ca2+ homeostasis in the hepatocyte. The protective effect of chloromethiazole and di-thio-threitol suggests that the inhibitory effect of ethanol is mediated through its metabolism via reticular cyP4502E1 and consequent free radicals formation. PMID:22958133

Rapid Acute Dose Assessment Using MCNP6

NASA Astrophysics Data System (ADS)

Owens, Andrew Steven

Acute radiation doses due to physical contact with a high-activity radioactive source have proven to be an occupational hazard. Multiple radiation injuries have been reported due to manipulating a radioactive source with bare hands or by placing a radioactive source inside a shirt or pants pocket. An effort to reconstruct the radiation dose must be performed to properly assess and medically manage the potential biological effects from such doses. Using the reference computational phantoms defined by the International Commission on Radiological Protection (ICRP) and the Monte Carlo N-Particle transport code (MCNP6), dose rate coefficients are calculated to assess doses for common acute doses due to beta and photon radiation sources. The research investigates doses due to having a radioactive source in either a breast pocket or pants back pocket. The dose rate coefficients are calculated for discrete energies and can be used to interpolate for any given energy of photon or beta emission. The dose rate coefficients allow for quick calculation of whole-body dose, organ dose, and/or skin dose if the source, activity, and time of exposure are known. Doses are calculated with the dose rate coefficients and compared to results from the International Atomic Energy Agency (IAEA) reports from accidents that occurred in Gilan, Iran and Yanango, Peru. Skin and organ doses calculated with the dose rate coefficients appear to agree, but there is a large discrepancy when comparing whole-body doses assessed using biodosimetry and whole-body doses assessed using the dose rate coefficients.

Immunoglobulin M indirect-fluorescent antibody test for the diagnosis of acute toxoplasmosis during pregnancy in the avidity era: A 14-year experience at the Tuscany Reference Center for Infectious Diseases in Pregnancy, Florence, Italy.

PubMed

Trotta, Michele; Borchi, Beatrice; Zammarchi, Lorenzo; Sterrantino, Gaetana; Brogi, Michela; Kiros, Seble Tekle; Lorini, Chiara; Bonaccorsi, Guglielmo; Colao, Maria Grazia; Bartoloni, Alessandro

2016-12-01

The aim of this study was to evaluate immunoglobulin M indirect-fluorescent antibody test (IgM IFAT) for the diagnosis of acute or chronic Toxoplasma infection in pregnancy. Pregnant women with suspected acute toxoplasmosis referred to the Tuscany Reference Center for Infectious Diseases in Pregnancy during the period 1998-2012 were retrospectively enrolled. All women were tested with a panel of serological tests, including enzyme-linked immunosorbent assay for IgG avidity and IgM IFAT. On the basis of anamnestic, clinical, and serological criteria, pregnant women were classified into three groups: recently infected (RI), latently infected (LI), and doubtful latently infected (DLI). Patients classified as DLI were excluded from the analysis. The association between IgM IFAT (positive or negative) and the diagnosis of infection (acute or chronic) was assessed. Positive predictive value and negative predictive value of the IgM IFAT were calculated. A total of 810 pregnant women were enrolled in the study: 302 in the RI group and 508 in the LI group. Fifty-two women classified as DLI were excluded. IgM IFAT was positive in 172 out of 302 (56.9%) pregnant women in the RI group and in 29 out of 508 (5.7%) in the LI group. The positive predictive value and negative predictive value of IgM IFAT in predicting RI was 85.6% and 78.6%, respectively. IgM IFAT has reasonable sensitivity and specificity in diagnosing recent infection and, mostly in case of borderline avidity test, could be considered as a further aid for an accurate diagnosis of acute toxoplasmosis in pregnancy. © 2016 Japan Society of Obstetrics and Gynecology.

Induction of Erythroid Differentiation in Human Erythroleukemia Cells by Depletion of Malic Enzyme 2

PubMed Central

Everett, Peter; Clish, Clary B.; Sukhatme, Vikas P.

2010-01-01

Malic enzyme 2 (ME2) is a mitochondrial enzyme that catalyzes the conversion of malate to pyruvate and CO2 and uses NAD as a cofactor. Higher expression of this enzyme correlates with the degree of cell de-differentiation. We found that ME2 is expressed in K562 erythroleukemia cells, in which a number of agents have been found to induce differentiation either along the erythroid or the myeloid lineage. We found that knockdown of ME2 led to diminished proliferation of tumor cells and increased apoptosis in vitro. These findings were accompanied by differentiation of K562 cells along the erythroid lineage, as confirmed by staining for glycophorin A and hemoglobin production. ME2 knockdown also totally abolished growth of K562 cells in nude mice. Increased ROS levels, likely reflecting increased mitochondrial production, and a decreased NADPH/NADP+ ratio were noted but use of a free radical scavenger to decrease inhibition of ROS levels did not reverse the differentiation or apoptotic phenotype, suggesting that ROS production is not causally involved in the resultant phenotype. As might be expected, depletion of ME2 induced an increase in the NAD+/NADH ratio and ATP levels fell significantly. Inhibition of the malate-aspartate shuttle was insufficient to induce K562 differentiation. We also examined several intracellular signaling pathways and expression of transcription factors and intermediate filament proteins whose expression is known to be modulated during erythroid differentiation in K562 cells. We found that silencing of ME2 leads to phospho-ERK1/2 inhibition, phospho-AKT activation, increased GATA-1 expression and diminished vimentin expression. Metabolomic analysis, conducted to gain insight into intermediary metabolic pathways that ME2 knockdown might affect, showed that ME2 depletion resulted in high orotate levels, suggesting potential impairment of pyrimidine metabolism. Collectively our data point to ME2 as a potentially novel metabolic target for

Reliability and effect of sodium bicarbonate: buffering and 2000-m rowing performance.

PubMed

Carr, Amelia J; Slater, Gary J; Gore, Christopher J; Dawson, Brian; Burke, Louise M

2012-06-01

The aim of this study was to determine the effect and reliability of acute and chronic sodium bicarbonate ingestion for 2000-m rowing ergometer performance (watts) and blood bicarbonate concentration [HCO3-]. In a crossover study, 7 well-trained rowers performed paired 2000-m rowing ergometer trials under 3 double-blinded conditions: (1) 0.3 grams per kilogram of body mass (g/kg BM) acute bicarbonate; (2) 0.5 g/kg BM daily chronic bicarbonate for 3 d; and (3) calcium carbonate placebo, in semi-counterbalanced order. For 2000-m performance and [HCO3-], we examined differences in effects between conditions via pairwise comparisons, with differences interpreted in relation to the likelihood of exceeding smallest worthwhile change thresholds for each variable. We also calculated the within-subject variation (percent typical error). There were only trivial differences in 2000-m performance between placebo (277 ± 60 W), acute bicarbonate (280 ± 65 W) and chronic bicarbonate (282 ± 65 W); however, [HCO3-] was substantially greater after acute bicarbonate, than with chronic loading and placebo. Typical error for 2000-m mean power was 2.1% (90% confidence interval 1.4 to 4.0%) for acute bicarbonate, 3.6% (2.5 to 7.0%) for chronic bicarbonate, and 1.6% (1.1 to 3.0%) for placebo. Postsupplementation [HCO3-] typical error was 7.3% (5.0 to 14.5%) for acute bicarbonate, 2.9% (2.0 to 5.7%) for chronic bicarbonate and 6.0% (1.4 to 11.9%) for placebo. Performance in 2000-m rowing ergometer trials may not substantially improve after acute or chronic bicarbonate loading. However, performances will be reliable with both acute and chronic bicarbonate loading protocols.

Identical IgM antibodies recognizing a glycine-alanine epitope are induced during acute infection with Epstein-Barr virus and cytomegalovirus.

PubMed

Rhodes, G; Smith, R S; Rubin, R E; Vaughan, J; Horwitz, C A

1990-01-01

We studied antibody production in serial serum samples from patients with acute Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. Sera were analyzed both by enzyme-linked immunosorbent assay (ELISA) using a synthetic peptide (P62) derived from the glycine-alanine repeating region of the Epstein-Barr nuclear antigen (EBNA-1) and by immunoblotting. In prior studies, we have shown that patients with acute EBV infection make IgM antibodies that react with this peptide, that recognize a viral-specific protein (EBNA-1), and that bind with a number of proteins present in uninfected cells; however, antibody binding to these autoantigens was inhibited by the peptide. IgG antibodies reactive with the peptide did not appear until months after the disease and were specific for the EBNA-1 protein. We now find that patients with acute CMV infection but not those with acute infections from a variety of other nonherpes organisms also produce IgM antibodies that recognize the EBV-derived peptide P62. These antibodies also appear to recognize the same cellular proteins as the EBV-induced IgM antibodies. The IgM antibodies appeared in all acutely infected CMV patients studied and occurred both in patients with previous EBV infections and in one patient studied who had not previously been exposed to EBV. It appears that infection with EBV or CMV can induce the synthesis of a very similar or identical set of IgM antibodies.

Gene expression and production of tumor necrosis factor alpha, interleukin 1, interleukin 6, and gamma interferon in C3H/HeN and C57BL/6N mice in acute Mycoplasma pulmonis disease.

PubMed Central

Faulkner, C B; Simecka, J W; Davidson, M K; Davis, J K; Schoeb, T R; Lindsey, J R; Everson, M P

1995-01-01

Studies were conducted to determine whether the production of various cytokines is associated with Mycoplasma pulmonis disease expression. Susceptible C3H/HeN and resistant C57BL/6N mice were inoculated intranasally with 10(7) CFU of virulent M. pulmonis UAB CT or avirulent M. pulmonis UAB T. Expression of genes for tumor necrosis factor alpha (TNF-alpha), interleukin 1 alpha (IL-1 alpha), IL-1 beta, IL-6, and gamma interferon (IFN-gamma) in whole lung tissue and TNF-alpha gene expression in bronchoalveolar lavage (BAL) cells was determined by reverse transcription-PCR using specific cytokine primers at various times postinoculation. In addition, concentrations of TNF-alpha, IL-1, IL-6, and IFN-gamma were determined in BAL fluid and serum samples at various times postinoculation. Our results showed that there was a sequential appearance of cytokines in the lungs of infected mice: TNF-alpha, produced primarily by BAL cells, appeared first, followed by IL-1 and IL-6, which were followed by IFN-gamma. Susceptible C3H/HeN mice had higher and more persistent concentrations of TNF-alpha and IL-6 in BAL fluid than did resistant C57BL/6N mice, indicating that TNF-alpha and possibly IL-6 are important factors in pathogenesis of acute M. pulmonis disease in mice. Serum concentrations of IL-6 were elevated in C3H/HeN mice, but not C57BL/6N mice, following infection with M. pulmonis, suggesting that IL-6 has both local and systemic effects in M. pulmonis disease. PMID:7558323

The OFP-6M transport jet

NASA Technical Reports Server (NTRS)

Alexander, Kelly; Heneghan, Brian; Holmes, Joules; Hughes, Bret; Kettering, Mark; Wells, Jennifer; Whelan, Todd

1994-01-01

This report presents a preliminary design of a commercial jet transport that meets the criteria of the Request For Proposal presented by the American Institute of Aeronautics and Astronauts (AIAA). The proposal requires an innovative design of a low cost domestic commercial transport that will reduce operating costs for airline companies while still meeting present and future requirements of the Federal Aviation Regulations for this type of aircraft. Specifications for the design include a mixed class, 153 passenger aircraft, traveling a range of 3000 nm. The intent of the project is to identify factors that reduce cost and to design within the limits of these constraints. The project includes techniques or options that incorporate new technologies but do not override practicality, alternative design approaches, and a comparison between the new design and current aircraft in its class. The OFP-6M is an alternative design approach to the conventional commercial transport jet and is geared towards customer satisfaction through efficiency and reliability. The goals of the OFP-6M transport design are to provide original, sensible, and practical solutions by combining essential preliminary design factors with growing technology. The design focus of the OFP-6M reduces costs by simplifying systems where significant weight or maintenance savings can be achieved, and by integrating advanced technology for improved performance. Key aspects of the OFP-6M design are efficient use of materials like composites, and efficient advanced ducted high bypass turbofan engines. The high bypass engines lower fuel consumption and aid in reducing costs and meeting future noise emission restrictions. Composites are used for most structural components, including flooring and wing box. Although composites are an emerging technology and presently, a high maintenance material, they can be cost effective and an alternative to aluminum structures when correct manufacturing and design strategies

Histone mRNA degradation in vivo: the first detectable step occurs at or near the 3' terminus.

PubMed Central

Ross, J; Peltz, S W; Kobs, G; Brewer, G

1986-01-01

The first detectable step in the degradation of human H4 histone mRNA occurs at the 3' terminus in a cell-free mRNA decay system (J. Ross and G. Kobs, J. Mol. Biol. 188:579-593, 1986). Most or all of the remainder of the mRNA is then degraded in a 3'-to-5' direction. The experiments described here were designed to determine whether a similar degradation pathway is followed in whole cells. Two sets of short-lived histone mRNA decay products were detected in logarithmically growing erythroleukemia (K562) cells. These products, designated the -5 and -12 RNAs, were generated by the loss of approximately 4 to 6 and 11 to 13 nucleotides, respectively, from the 3' terminus of histone mRNA. The same decay products were observed after a brief incubation in vitro. They were in low abundance or absent from cells that were not degrading histone mRNA. In contrast, they were readily detectable in cells that degraded the mRNA at an accelerated rate, i.e., in cells cultured with a DNA synthesis inhibitor, either cytosine arabinoside or hydroxyurea. During the initial stages of the decay process, as the 3' terminus of the mRNA was being degraded, the 5'-terminal region remained intact. These results indicate that the first detectable step in human H4 histone mRNA decay occurs at the 3' terminus and that degradation proceeds 3' to 5', both in cells and in cell-free reactions. Images PMID:3467177

Histone mRNA degradation in vivo: the first detectable step occurs at or near the 3' terminus.

PubMed

Ross, J; Peltz, S W; Kobs, G; Brewer, G

1986-12-01

The first detectable step in the degradation of human H4 histone mRNA occurs at the 3' terminus in a cell-free mRNA decay system (J. Ross and G. Kobs, J. Mol. Biol. 188:579-593, 1986). Most or all of the remainder of the mRNA is then degraded in a 3'-to-5' direction. The experiments described here were designed to determine whether a similar degradation pathway is followed in whole cells. Two sets of short-lived histone mRNA decay products were detected in logarithmically growing erythroleukemia (K562) cells. These products, designated the -5 and -12 RNAs, were generated by the loss of approximately 4 to 6 and 11 to 13 nucleotides, respectively, from the 3' terminus of histone mRNA. The same decay products were observed after a brief incubation in vitro. They were in low abundance or absent from cells that were not degrading histone mRNA. In contrast, they were readily detectable in cells that degraded the mRNA at an accelerated rate, i.e., in cells cultured with a DNA synthesis inhibitor, either cytosine arabinoside or hydroxyurea. During the initial stages of the decay process, as the 3' terminus of the mRNA was being degraded, the 5'-terminal region remained intact. These results indicate that the first detectable step in human H4 histone mRNA decay occurs at the 3' terminus and that degradation proceeds 3' to 5', both in cells and in cell-free reactions.

A Self-Diagnostic System for the M6 Accelerometer

NASA Technical Reports Server (NTRS)

Flanagan, Patrick M.; Lekki, John

2001-01-01

The design of a Self-Diagnostic (SD) accelerometer system for the Space Shuttle Main Engine is presented. This retrofit system connects diagnostic electronic hardware and software to the current M6 accelerometer system. This paper discusses the general operation of the M6 accelerometer SD system and procedures for developing and evaluating the SD system. Signal processing techniques using M6 accelerometer diagnostic data are explained. Test results include diagnostic data responding to changing ambient temperature, mounting torque and base mounting impedance.

Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia.

PubMed

Pikman, Yana; Alexe, Gabriela; Roti, Giovanni; Conway, Amy Saur; Furman, Andrew; Lee, Emily S; Place, Andrew E; Kim, Sunkyu; Saran, Chitra; Modiste, Rebecca; Weinstock, David M; Harris, Marian; Kung, Andrew L; Silverman, Lewis B; Stegmaier, Kimberly

2017-02-15

Purpose: Although significant progress has been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), many patients will require additional therapy for relapsed/refractory disease. Cyclin D3 (CCND3) and CDK6 are highly expressed in T-ALL and have been effectively targeted in mutant NOTCH1-driven mouse models of this disease with a CDK4/6 small-molecule inhibitor. Combination therapy, however, will be needed for the successful treatment of human disease. Experimental Design: We performed preclinical drug testing using a panel of T-ALL cell lines first with LEE011, a CDK4/6 inhibitor, and next with the combination of LEE011 with a panel of drugs relevant to T-ALL treatment. We then tested the combination of LEE011 with dexamethasone or everolimus in three orthotopic mouse models and measured on-target drug activity. Results: We first determined that both NOTCH1 -mutant and wild-type T-ALL are highly sensitive to pharmacologic inhibition of CDK4/6 when wild-type RB is expressed. Next, we determined that CDK4/6 inhibitors are antagonistic when used either concurrently or in sequence with many of the drugs used to treat relapsed T-ALL (methotrexate, mercaptopurine, asparaginase, and doxorubicin) but are synergistic with glucocorticoids, an mTOR inhibitor, and gamma secretase inhibitor. The combinations of LEE011 with the glucocorticoid dexamethasone or the mTOR inhibitor everolimus were tested in vivo and prolonged survival in three orthotopic mouse models of T-ALL. On-target activity was measured in peripheral blood and tissue of treated mice. Conclusions: We conclude that LEE011 is active in T-ALL and that combination therapy with corticosteroids and/or mTOR inhibitors warrants further investigation. Clin Cancer Res; 23(4); 1012-24. ©2016 AACR See related commentary by Carroll et al., p. 873 . ©2016 American Association for Cancer Research.

The SIRT1 inhibitor EX-527 suppresses mTOR activation and alleviates acute lung injury in mice with endotoxiemia.

PubMed

Huang, Jing; Tian, Rui; Yang, Yongqiang; Jiang, Rong; Dai, Jie; Tang, Li; Zhang, Li

2017-11-01

It is generally regarded that Sirtuin 1 (SIRT1), a longevity factor in mammals, acts as a negative regulator of inflammation. However, recent studies also found that SIRT1 might be a detrimental factor under certain inflammatory circumstance. In this study, the potential pathophysiological roles and the underlying mechanisms of SIRT1 in a mouse model with endotoxemia-associated acute lung injury were investigated. The results indicated that treatment with the selective SIRT1 inhibitor EX-527 suppressed LPS-induced elevation of TNF-α and IL-6 in plasma. Treatment with EX-527 attenuated LPS-induced histological abnormalities in lung tissue, which was accompanied with decreased myeloperoxidase level and suppressed induction of tissue factor and plasminogen activator inhibitor-1. Treatment with EX-527 also suppressed LPS-induced phosphorylation of eukaryotic translation initiation factor-binding protein 1 (4E-BP1). Co-administration of a mammalian target of rapamycin (mTOR) activator 3-benzyl-5-[(2-nitrophenoxy) methyl]-dihydrofuran-2 (3H)-one (3BDO) abolished the inhibitory effects of EX-527 on 4E-BP1 phosphorylation. Meanwhile, the inhibitory effects of EX-527 on IL-6 induction and the beneficial effects of EX-527 on lung injury were partially reversed by 3BDO. This study suggests that selective inhibition of SIRT1 by EX-527 might alleviate endotoxemia-associated acute lung injury partially via suppression of mTOR, which implies that SIRT1 selective inhibitors might have potential value for the pharmacological intervention of inflammatory lung injury.

Pharmacokinetics of two 6-mercaptopurine liquid formulations in children with acute lymphoblastic leukemia.

PubMed

Tolbert, Jaszianne A; Bai, Shasha; Abdel-Rahman, Susan M; August, Keith J; Weir, Scott J; Kearns, Gregory L; Neville, Kathleen A

2017-08-01

A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation. Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts. Group 1 (n = 11; five males) received a 5 mg/ml liquid formulation and the marketed 50 mg 6-MP tablet on separate occasions, and Group 2 (n = 11; five males) received a 50 mg/ml liquid formulation and the marketed tablet. The usual prescribed 6-MP dose (25-115 mg/m 2 ) was given after an 8-hr fast. Serial blood samples were collected over 8 hr postdose. Plasma 6-MP concentrations were determined using a good laboratory practice (GLP)-validated liquid chromatography-tandem mass spectrometry method. PK parameters were calculated using noncompartmental analysis and compared within and between cohorts, and thiopurine methyltransferase (TPMT) genotype was analyzed. No patient had a TPMT genotype reflective of a poor metabolizer phenotype. Comparison of PK parameters between 5 and 50 mg/ml treatments revealed significant differences (P <0.05) in AUC N (where AUC is area under the curve), C maxN , and T max . Comparisons within each group revealed significant differences in AUC 0-∞ and T max in the 5 mg/ml group. Pharmacokinetic profiles of 6-MP established in healthy adults with the approved liquid formulation may not reflect the PK profile in children with ALL. Formulation-specific differences in PK may significantly impact the dose-exposure profile in these children and must be considered. © 2017 Wiley Periodicals, Inc.

IRF5 regulates lung macrophages M2 polarization during severe acute pancreatitis in vitro.

PubMed

Sun, Kang; He, Song-Bing; Qu, Jian-Guo; Dang, Sheng-Chun; Chen, Ji-Xiang; Gong, Ai-Hua; Xie, Rong; Zhang, Jian-Xin

2016-11-14

To investigate the role of interferon regulatory factor 5 (IRF5) in reversing polarization of lung macrophages during severe acute pancreatitis (SAP) in vitro . A mouse SAP model was established by intraperitoneal (ip) injections of 20 μg/kg body weight caerulein. Pathological changes in the lung were observed by hematoxylin and eosin staining. Lung macrophages were isolated from bronchoalveolar lavage fluid. The quantity and purity of lung macrophages were detected by fluorescence-activated cell sorting and evaluated by real-time polymerase chain reaction (RT-PCR). They were treated with IL-4/IRF5 specific siRNA (IRF5 siRNA) to reverse their polarization and were evaluated by detecting markers expression of M1/M2 using RT-PCR. SAP associated acute lung injury (ALI) was induced successfully by ip injections of caerulein, which was confirmed by histopathology. Lung macrophages expressed high levels of IRF5 as M1 phenotype during the early acute pancreatitis stages. Reduction of IRF5 expression by IRF5 siRNA reversed the action of macrophages from M1 to M2 phenotype in vitro . The expressions of M1 markers, including IRF5 (S + IRF5 siRNA vs S + PBS, 0.013 ± 0.01 vs 0.054 ± 0.047, P < 0.01), TNF-α (S + IRF5 siRNA vs S + PBS, 0.0003 ± 0.0002 vs 0.019 ± 0.018, P < 0.001), iNOS (S + IRF5 siRNA vs S + PBS, 0.0003 ± 0.0002 vs 0.026 ± 0.018, P < 0.001) and IL-12 (S + IRF5 siRNA vs S + PBS, 0.000005 ± 0.00004 vs 0.024 ± 0.016, P < 0.001), were decreased. In contrast, the expressions of M2 markers, including IL-10 (S + IRF5 siRNA vs S + PBS, 0.060 ± 0.055 vs 0.0230 ± 0.018, P < 0.01) and Arg-1 (S + IRF5 siRNA vs S + PBS, 0.910 ± 0.788 vs 0.0036 ± 0.0025, P < 0.001), were increased. IRF5 siRNA could reverse the lung macrophage polarization more effectively than IL-4. Treatment with IRF5 siRNA can reverse the pancreatitis-induced activation of lung macrophages from M1 phenotype to M2 phenotype in SAP associated with ALI.

IRF5 regulates lung macrophages M2 polarization during severe acute pancreatitis in vitro

PubMed Central

Sun, Kang; He, Song-Bing; Qu, Jian-Guo; Dang, Sheng-Chun; Chen, Ji-Xiang; Gong, Ai-Hua; Xie, Rong; Zhang, Jian-Xin

2016-01-01

AIM To investigate the role of interferon regulatory factor 5 (IRF5) in reversing polarization of lung macrophages during severe acute pancreatitis (SAP) in vitro. METHODS A mouse SAP model was established by intraperitoneal (ip) injections of 20 μg/kg body weight caerulein. Pathological changes in the lung were observed by hematoxylin and eosin staining. Lung macrophages were isolated from bronchoalveolar lavage fluid. The quantity and purity of lung macrophages were detected by fluorescence-activated cell sorting and evaluated by real-time polymerase chain reaction (RT-PCR). They were treated with IL-4/IRF5 specific siRNA (IRF5 siRNA) to reverse their polarization and were evaluated by detecting markers expression of M1/M2 using RT-PCR. RESULTS SAP associated acute lung injury (ALI) was induced successfully by ip injections of caerulein, which was confirmed by histopathology. Lung macrophages expressed high levels of IRF5 as M1 phenotype during the early acute pancreatitis stages. Reduction of IRF5 expression by IRF5 siRNA reversed the action of macrophages from M1 to M2 phenotype in vitro. The expressions of M1 markers, including IRF5 (S + IRF5 siRNA vs S + PBS, 0.013 ± 0.01 vs 0.054 ± 0.047, P < 0.01), TNF-α (S + IRF5 siRNA vs S + PBS, 0.0003 ± 0.0002 vs 0.019 ± 0.018, P < 0.001), iNOS (S + IRF5 siRNA vs S + PBS, 0.0003 ± 0.0002 vs 0.026 ± 0.018, P < 0.001) and IL-12 (S + IRF5 siRNA vs S + PBS, 0.000005 ± 0.00004 vs 0.024 ± 0.016, P < 0.001), were decreased. In contrast, the expressions of M2 markers, including IL-10 (S + IRF5 siRNA vs S + PBS, 0.060 ± 0.055 vs 0.0230 ± 0.018, P < 0.01) and Arg-1 (S + IRF5 siRNA vs S + PBS, 0.910 ± 0.788 vs 0.0036 ± 0.0025, P < 0.001), were increased. IRF5 siRNA could reverse the lung macrophage polarization more effectively than IL-4. CONCLUSION Treatment with IRF5 siRNA can reverse the pancreatitis-induced activation of lung macrophages from M1 phenotype to M2 phenotype in SAP associated with ALI. PMID:27895424

The Role of Dynamic m6 A RNA Methylation in Photobiology.

PubMed

Robinson, Myles; Shah, Palak; Cui, Yan-Hong; He, Yu-Ying

2018-05-04

N 6 -methyladenosine (m 6 A) is the most abundant internal RNA modification among numerous post-transcriptional modifications identified in eukaryotic mRNA. m 6 A modification of RNA is catalyzed by the "writer" m 6 A methyltransferase enzyme complex, consisting of METTL3, METTL14, WTAP and KIAA1429. The m 6 A modification is reversible and can be removed by "eraser" m 6 A demethylase enzymes, namely, FTO and ALKBH5. The biological function of m 6 A modification on RNA is carried out by RNA-binding effector proteins called "readers." Varied functions of the reader proteins regulate mRNA metabolism by affecting stability, translation, splicing or nuclear export. The epitranscriptomic gene regulation by m 6 A RNA methylation regulates various pathways, which contribute to basic cellular processes essential for cell maintenance, development and cell fate, and affect response to external stimuli and stressors. In this review, we summarize the recent advances in the regulation and function of m 6 A RNA methylation, with a focus on UV-induced DNA damage response and the circadian clock machinery. Insights into the mechanisms of m 6 A RNA regulation and post-transcriptional regulatory function in these biological processes may facilitate the development of new preventive and therapeutic strategies for various diseases related to dysregulation of UV damage response and circadian rhythm. © 2018 The American Society of Photobiology.

Progress toward characterization of the group A Streptococcus metagenome: complete genome sequence of a macrolide-resistant serotype M6 strain.

PubMed

Banks, David J; Porcella, Stephen F; Barbian, Kent D; Beres, Stephen B; Philips, Lauren E; Voyich, Jovanka M; DeLeo, Frank R; Martin, Judith M; Somerville, Greg A; Musser, James M

2004-08-15

We describe the genome sequence of a macrolide-resistant strain (MGAS10394) of serotype M6 group A Streptococcus (GAS). The genome is 1,900,156 bp in length, and 8 prophage-like elements or remnants compose 12.4% of the chromosome. A 8.3-kb prophage remnant encodes the SpeA4 variant of streptococcal pyrogenic exotoxin A. The genome of strain MGAS10394 contains a chimeric genetic element composed of prophage genes and a transposon encoding the mefA gene conferring macrolide resistance. This chimeric element also has a gene encoding a novel surface-exposed protein (designated "R6 protein"), with an LPKTG cell-anchor motif located at the carboxyterminus. Surface expression of this protein was confirmed by flow cytometry. Humans with GAS pharyngitis caused by serotype M6 strains had antibody against the R6 protein present in convalescent, but not acute, serum samples. Our studies add to the theme that GAS prophage-encoded extracellular proteins contribute to host-pathogen interactions in a strain-specific fashion.

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia

PubMed Central

Hawwa, Ahmed F; Collier, Paul S; Millership, Jeff S; McCarthy, Anthony; Dempsey, Sid; Cairns, Carole; McElnay, James C

2008-01-01

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTThe cytotoxic effects of 6-mercaptopurine (6-MP) were found to be due to drug-derived intracellular metabolites (mainly 6-thioguanine nucleotides and to some extent 6-methylmercaptopurine nucleotides) rather than the drug itself.Current empirical dosing methods for oral 6-MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome. WHAT THIS STUDY ADDSThe first population pharmacokinetic model has been developed for 6-MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed.The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates.The developed model offers a more rational dosing approach for 6-MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype. AIMS To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m−2 day−1). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. RESULTS The developed

Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2).

PubMed

Barlow, A D; Xie, J; Moore, C E; Campbell, S C; Shaw, J A M; Nicholson, M L; Herbert, T P

2012-05-01

Rapamycin (sirolimus) is one of the primary immunosuppressants for islet transplantation. Yet there is evidence that the long-term treatment of islet-transplant patients with rapamycin may be responsible for subsequent loss of islet graft function and viability. Therefore, the primary objective of this study was to elucidate the molecular mechanism of rapamycin toxicity in beta cells. Experiments were performed on isolated rat and human islets of Langerhans and MIN6 cells. The effects of rapamycin and the roles of mammalian target of rapamycin complex 2 (mTORC2)/protein kinase B (PKB) on beta cell signalling, function and viability were investigated using cell viability assays, insulin ELISA assays, kinase assays, western blotting, pharmacological inhibitors, small interfering (si)RNA and through the overproduction of a constitutively active mutant of PKB. Rapamycin treatment of MIN6 cells and islets of Langerhans resulted in a loss of cell function and viability. Although rapamycin acutely inhibited mTOR complex 1 (mTORC1), the toxic effects of rapamycin were more closely correlated to the dissociation and inactivation of mTORC2 and the inhibition of PKB. Indeed, the overproduction of constitutively active PKB protected islets from rapamycin toxicity whereas the inhibition of PKB led to a loss of cell viability. Moreover, the selective inactivation of mTORC2 using siRNA directed towards rapamycin-insensitive companion of target of rapamycin (RICTOR), mimicked the toxic effects of chronic rapamycin treatment. This report provides evidence that rapamycin toxicity is mediated by the inactivation of mTORC2 and the inhibition of PKB and thus reveals the molecular basis of rapamycin toxicity and the essential role of mTORC2 in maintaining beta cell function and survival.

Rapid and accurate diagnosis of acute cholecystitis with /sup 99m/Tc-HIDA cholescintigraphy. [HIDA = dimethyl acetanilide iminodiacetic acid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weissmann, H.S.; Frank, M.S.; Bernstein, L.H.

1979-04-01

Technetium-99m dimethyl acetanilide iminodiacetic acid (HIDA) cholescintigraphy was performed on 90 patients with suspected acute cholecytitis. Visualization of the gallbladder established patency of the cystic duct and excluded the diagnosis of acute cholecystitis in 50 of 52 patients. Nonvisualization of the gallbladder with visualization of the common bile duct was diagnostic of acute cholecystitis in 38 patients, all subsequently proven at surgery. The observed accuracy of this procedure is 98% and specificity is 100%. The false negative rate is 5% and false positive rate is zero. Technetium-99m-HILDA has many advantages which make it the procedure of choice in evaluating amore » patient for suspected acute cholecystitis. It is a rapid, simple, safe examination which provides functional as well as anatomic information about the hepatobiliary system in individuals with a serum bilirubin level up to 8 mg/100 ml.« less

Decitabine in Treating Children With Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia

ClinicalTrials.gov

2013-01-22

Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Promyelocytic Leukemia (M3); Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

Evaluation of CMV/human herpes virus-6 positivity in bronchoalveolar lavage fluids as early detection of acute GVHD following BMT: evidence of a significant relationship.

PubMed

Takemoto, Y; Takatsuka, H; Wada, H; Mori, A; Saheki, K; Okada, M; Tamura, S; Fujimori, Y; Okamoto, T; Kakishita, E; Kanamaru, A

2000-07-01

We evaluated the relationship between CMV and human herpes virus-6 (HHV-6) reactivation and the incidence of grades 2 to 4 acute GVHD post BMT. Bronchoalveolar lavage fluid (BALF) samples extracted from 54 BMT recipients on post-BMT day 35 were analyzed by PCR for detection of CMV DNA, HHV-6 DNA and CMV plus HHV-6 DNA. CMV DNA was detected in 26 patients and 13 (50%) developed grades 2 to 4 acute GVHD. Of the 28 who were CMV negative, only six (21.4%) developed grades 2 to 4 acute GVHD. HHV-6 was detected in 18 patients, and 11 (61.1%) developed grades 2 to 4 acute GVHD. Of the 36 who were HHV-6 negative, only eight (22.2%) developed grades 2 to 4 acute GVHD. CMV and HHV-6 were detected in 13 patients, and eight (61.5%) developed grades 2 to 4 acute GVHD. Of the 23 who were negative for both CMV and HHV-6, only three (13%) developed grades 2 to 4 acute GVHD. In all experiments, the difference between the groups was significant (P<0.05, P<0.05 and P<0.01, respectively). We conclude that herpes virus infection, in particular CMV concurrent with HHV-6 reactivation, is predictive of moderate to severe acute GVHD.

Addition of m6A to SV40 late mRNAs enhances viral structural gene expression and replication

PubMed Central

Courtney, David G.

2018-01-01

Polyomaviruses are a family of small DNA tumor viruses that includes several pathogenic human members, including Merkel cell polyomavirus, BK virus and JC virus. As is characteristic of DNA tumor viruses, gene expression in polyomaviruses is temporally regulated into an early phase, consisting of the viral regulatory proteins, and a late phase, consisting of the viral structural proteins. Previously, the late transcripts expressed by the prototypic polyomavirus simian virus 40 (SV40) were reported to contain several adenosines bearing methyl groups at the N6 position (m6A), although the precise location of these m6A residues, and their phenotypic effects, have not been investigated. Here, we first demonstrate that overexpression of the key m6A reader protein YTHDF2 induces more rapid viral replication, and larger viral plaques, in SV40 infected BSC40 cells, while mutational inactivation of the endogenous YTHDF2 gene, or the m6A methyltransferase METTL3, has the opposite effect, thus suggesting a positive role for m6A in the regulation of SV40 gene expression. To directly test this hypothesis, we mapped sites of m6A addition on SV40 transcripts and identified two m6A sites on the viral early transcripts and eleven m6A sites on the late mRNAs. Using synonymous mutations, we inactivated the majority of the m6A sites on the SV40 late mRNAs and observed that the resultant viral mutant replicated more slowly than wild type SV40. Alternative splicing of SV40 late mRNAs was unaffected by the reduction in m6A residues and our data instead suggest that m6A enhances the translation of viral late transcripts. Together, these data argue that the addition of m6A residues to the late transcripts encoded by SV40 plays an important role in enhancing viral gene expression and, hence, replication. PMID:29447282

Sled Towing Acutely Decreases Acceleration Sprint Time.

PubMed

Wong, Megan A; Dobbs, Ian J; Watkins, Casey M; Barillas, Saldiam R; Lin, Anne; Archer, David C; Lockie, Robert G; Coburn, Jared W; Brown, Lee E

2017-11-01

Wong, MA, Dobbs, IJ, Watkins, C, Barillas, SR, Lin, A, Archer, DC, Lockie, RG, Coburn, JW, and Brown, LE. Sled towing acutely decreases acceleration sprint time. J Strength Cond Res 31(11): 3046-3051, 2017-Sled towing is a common form of overload training in sports to develop muscular strength for sprinting. This type of training leads to acute and chronic outcomes. Acute training potentially leads to postactivation potentiation (PAP), which is when subsequent muscle performance is enhanced after a preload stimulus. The purpose of this study was to determine differences between rest intervals after sled towing on acute sprint speed. Twenty healthy recreationally trained men (age = 22.3 ± 2.4 years, height = 176.95 ± 5.46 cm, mass = 83.19 ± 11.31 kg) who were currently active in a field sport twice a week for the last 6 months volunteered to participate. A maximal 30-meter (m) baseline (BL) body mass (BM) sprint was performed (with splits at 5, 10, 20, and 30 m) followed by 5 visits where participants sprinted 30 m towing a sled at 30% BM then rested for 2, 4, 6, 8, or 12 minutes. They were instructed to stand still during rest times. After the rest interval, they performed a maximal 30-m post-test BM sprint. Analysis of variance (ANOVA) revealed that post sled tow BM sprint times (4.47 ± 0.21 seconds) were less than BL times (4.55 ± 0.18 seconds) on an individualized rest interval basis. A follow-up 2 × 4 ANOVA showed that this decrease occurred only in the acceleration phase over the first 5 m (BL = 1.13 ± 0.08 seconds vs. Best = 1.08 ± 0.08 seconds), which may be the result of PAP and the complex relationship between fatigue and potentiation relative to the intensity of the sled tow and the rest interval. Therefore, coaches should test their athletes on an individual basis to determine optimal rest time after a 30-m 30% BM sled tow to enhance acute sprint speed.

Update: Mechanisms underlying N6-methyladenosine modification of eukaryotic mRNA

PubMed Central

Wang, Yang; Zhao, Jing Crystal

2016-01-01

Summary Eukaryotic messenger RNA (mRNA) undergoes chemical modification both at the 5′cap [1, 2] and internally [3–14]. Among internal modifications, m6A, by far the most abundant, is present in all eukaryotes examined, including mammals [3–6], flies [15], plants [16, 17] and yeast [18, 19]. m6A modification plays an essential role in diverse biological processes. Over the past few years, our knowledge relevant to establishment and function of this modification has grown rapidly. This review focuses on technologies that have facilitated m6A detection in mRNAs, identification of m6A methylation enzymes and binding proteins, and potential functions of the modification at the molecular level. Regarding m6A function at cellular or organismal levels or in disease, please refer to other recent reviews [20–23]. PMID:27793360

Risk Factors of Nicardipine-Related Phlebitis in Acute Stroke Patients.

PubMed

Kawada, Kei; Ohta, Tsuyoshi; Tanaka, Koudai; Kadoguchi, Naoto; Yamamoto, Souichi; Morimoto, Masanori

2016-10-01

Intravenous nicardipine is generally used to treat hypertension in acute stroke patients but is associated with frequent phlebitis. We aimed to identify the incidence and risk factors of phlebitis in such patients. The incidence and risk factors of phlebitis were investigated in 358 acute stroke patients from July 2014 to June 2015. In total, 138 patients received intravenous nicardipine. Of 45 (12.6%) phlebitis patients in 358 acute stroke patients, 42 (93.3%) were administered nicardipine, which was significantly associated with phlebitis occurrence (P < .01). Other candidate risk factors of phlebitis of acute stroke patients in univariate analysis were intracerebral hemorrhage (P < .01), nicardipine injection to paralyzed limbs (P = .023), dilution of nicardipine with normal saline (P < .01), higher maximum flow rate of nicardipine (7.2 ± 4.1 mg/h versus 1.6 ± 3.1 mg/h; P < .01), and higher maximum concentration of nicardipine (271.5 ± 145.0 µg/mL versus 37.6 ± 75.0 µg/mL; P < .01). The only statistically significant independent factor following multivariate logistic regression analysis, according to the optimal cutoff values defined from receiver operating characteristic curve analyses, was the maximum concentration of nicardipine greater than 130 µg/mL (OR 57.9; 95% CI 21.5-156; P < .01). A gradual decline of pH below 4.3 was observed when the concentration of nicardipine solution increased to greater than or equal to 130 µg/mL in vitro. Nicardipine-related phlebitis is frequently observed in acute stroke patients and is significantly associated with administration of a maximum concentration of nicardipine greater than 130 µg/mL. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Experimental and numerical investigations of the turbulent wake flow of a generic space launcher at $M_infty =3 M ∞ = 3 and M_infty =6$ M ∞ = 6

NASA Astrophysics Data System (ADS)

Statnikov, V.; Stephan, S.; Pausch, K.; Meinke, M.; Radespiel, R.; Schröder, W.

2016-06-01

The turbulent wake of a generic space launcher wind tunnel model with an underexpanded nozzle jet is investigated experimentally and numerically to gain insight into the variation of intricate wake flow phenomena of space vehicles at higher stages of the flight trajectory with increasing Mach number. The experiments are carried out at M_∞ =3 and M_∞ =6 in the Ludwieg tube test facility at the Institute of Fluid Mechanics at the Technische Universität Braunschweig, while the corresponding time-resolved computations are performed by the Institute of Aerodynamics at RWTH Aachen University using a zonal RANS-LES approach. A strong alteration of the wake topology with increasing Mach number due to the changing pressure ratio at the nozzle exit is found. At M_∞ =3 the moderate underexpansion rate of p_e/p_∞ ≈ 5 leads to a formation of a recirculation region with an elongated triangular cross-section reaching to the nozzle exit. At M_∞ =6 a substantially stronger afterexpansion of the jet plume (p_e/p_∞ ≈ 100) causes the formation of a cavity region with a quadrangular cross-section. The stronger deflection towards the nozzle at M_∞ =3 results in lower mean and rms wall pressure ratios than at M_∞ =6. However, due to the higher freestream pressure value at the lower Mach number the relation of absolute values is reciprocal, making the lower supersonic regime more critical with respect to dynamic structural loads. This observation is confirmed by an overall good agreement between numerical and experimental data at characteristic positions on the base and nozzle wall. Furthermore, it was shown that undesired effects of the strut support in the wake are present along the whole circumference. For M_∞ =3 the strut influence is found to be particularly intense. The spectral analysis of wall pressure fluctuations reveals fundamental differences in the dynamic behavior of the two investigated wake flow regimes. At M_∞ =3, a dominant frequency range around

Engineering of a DNA Polymerase for Direct m6 A Sequencing.

PubMed

Aschenbrenner, Joos; Werner, Stephan; Marchand, Virginie; Adam, Martina; Motorin, Yuri; Helm, Mark; Marx, Andreas

2018-01-08

Methods for the detection of RNA modifications are of fundamental importance for advancing epitranscriptomics. N 6 -methyladenosine (m 6 A) is the most abundant RNA modification in mammalian mRNA and is involved in the regulation of gene expression. Current detection techniques are laborious and rely on antibody-based enrichment of m 6 A-containing RNA prior to sequencing, since m 6 A modifications are generally "erased" during reverse transcription (RT). To overcome the drawbacks associated with indirect detection, we aimed to generate novel DNA polymerase variants for direct m 6 A sequencing. Therefore, we developed a screen to evolve an RT-active KlenTaq DNA polymerase variant that sets a mark for N 6 -methylation. We identified a mutant that exhibits increased misincorporation opposite m 6 A compared to unmodified A. Application of the generated DNA polymerase in next-generation sequencing allowed the identification of m 6 A sites directly from the sequencing data of untreated RNA samples. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

CSF drug levels for children with acute lymphoblastic leukemia treated by 5 g/m2 methotrexate. A study from the EORTC Children's Leukemia Cooperative Group.

PubMed

Milano, G; Thyss, A; Serre Debeauvais, F; Laureys, G; Benoit, Y; Deville, A; Dutour, C; Robert, A; Otten, J; Behar, C

1990-04-01

A multicenter EORTC study was conducted in children with acute lymphocytic leukemia to determine whether 5 g/m2 of methotrexate (MTX) (24 h i.v. infusion, four cycles) is an appropriate dosage for obtaining CSF drug concentrations approaching the critical cytotoxic level of 10(-6) M. A total of 193 cycles were analyzed for 58 patients. At the end of the 24 h infusion, the mean MTX serum level was 65.27 +/- 33.11 microM; the mean CSF MTX level was 1.47 +/- 1.1 microM; no significant difference in CSF MTX levels was observed between patients with (n = 20) and those without i.v. Ara-C (n = 38). The mean CSF MTX/serum MTX ratio was 0.029 +/- 0.027. CSF drug concentrations greater than or equal to 10(-6) M were achieved in 81% of the courses. The highest level was 8.4 X 10(-6) M. Only 5% of patients failed to achieve this drug concentration in at least one cycle. No significant correlation was observed between blood and CSF MTX levels. Mean CSF MTX levels were comparable from one cycle to another.

Role of Phosphatidylinositol 3-Kinase in Friend Spleen Focus-Forming Virus-Induced Erythroid Disease▿

PubMed Central

Umehara, Daigo; Watanabe, Shinya; Ochi, Haruyo; Anai, Yukari; Ahmed, Nursarat; Kannagi, Mari; Hanson, Charlotte; Ruscetti, Sandra; Nishigaki, Kazuo

2010-01-01

Infection of erythroid cells by Friend spleen focus-forming virus (SFFV) leads to acute erythroid hyperplasia in mice due to expression of its unique envelope glycoprotein, gp55. Erythroid cells expressing SFFV gp55 proliferate in the absence of their normal regulator, erythropoietin (Epo), because of interaction of the viral envelope protein with the erythropoietin receptor and a short form of the receptor tyrosine kinase Stk (sf-Stk), leading to constitutive activation of several signal transduction pathways. Our previous in vitro studies showed that phosphatidylinositol 3-kinase (PI3-kinase) is activated in SFFV-infected cells and is important in mediating the biological effects of the virus. To determine the role of PI3-kinase in SFFV-induced disease, mice deficient in the p85α regulatory subunit of class IA PI3-kinase were inoculated with different strains of SFFV. We observed that p85α status determined the extent of erythroid hyperplasia induced by the sf-Stk-dependent viruses SFFV-P (polycythemia-inducing strain of SFFV) and SFFV-A (anemia-inducing strain of SFFV) but not by the sf-Stk-independent SFFV variant BB6. Our data also indicate that p85α status determines the response of mice to stress erythropoiesis, consistent with a previous report showing that SFFV uses a stress erythropoiesis pathway to induce erythroleukemia. We further showed that sf-Stk interacts with p85α and that this interaction depends upon sf-Stk kinase activity and tyrosine 436 in the multifunctional docking site. Pharmacological inhibition of PI3-kinase blocked proliferation of primary erythroleukemia cells from SFFV-infected mice and the erythroleukemia cell lines derived from them. These results indicate that p85α may regulate sf-Stk-dependent erythroid proliferation induced by SFFV as well as stress-induced erythroid hyperplasia. PMID:20504929

A continuous arc delivery optimization algorithm for CyberKnife m6.

PubMed

Kearney, Vasant; Descovich, Martina; Sudhyadhom, Atchar; Cheung, Joey P; McGuinness, Christopher; Solberg, Timothy D

2018-06-01

This study aims to reduce the delivery time of CyberKnife m6 treatments by allowing for noncoplanar continuous arc delivery. To achieve this, a novel noncoplanar continuous arc delivery optimization algorithm was developed for the CyberKnife m6 treatment system (CyberArc-m6). CyberArc-m6 uses a five-step overarching strategy, in which an initial set of beam geometries is determined, the robotic delivery path is calculated, direct aperture optimization is conducted, intermediate MLC configurations are extracted, and the final beam weights are computed for the continuous arc radiation source model. This algorithm was implemented on five prostate and three brain patients, previously planned using a conventional step-and-shoot CyberKnife m6 delivery technique. The dosimetric quality of the CyberArc-m6 plans was assessed using locally confined mutual information (LCMI), conformity index (CI), heterogeneity index (HI), and a variety of common clinical dosimetric objectives. Using conservative optimization tuning parameters, CyberArc-m6 plans were able to achieve an average CI difference of 0.036 ± 0.025, an average HI difference of 0.046 ± 0.038, and an average LCMI of 0.920 ± 0.030 compared with the original CyberKnife m6 plans. Including a 5 s per minute image alignment time and a 5-min setup time, conservative CyberArc-m6 plans achieved an average treatment delivery speed up of 1.545x ± 0.305x compared with step-and-shoot plans. The CyberArc-m6 algorithm was able to achieve dosimetrically similar plans compared to their step-and-shoot CyberKnife m6 counterparts, while simultaneously reducing treatment delivery times. © 2018 American Association of Physicists in Medicine.

M-atrial natriuretic peptide and nitroglycerin in a canine model of experimental acute hypertensive heart failure: differential actions of 2 cGMP activating therapeutics.

PubMed

McKie, Paul M; Cataliotti, Alessandro; Ichiki, Tomoko; Sangaralingham, S Jeson; Chen, Horng H; Burnett, John C

2014-01-02

Systemic hypertension is a common characteristic in acute heart failure (HF). This increasingly recognized phenotype is commonly associated with renal dysfunction and there is an unmet need for renal enhancing therapies. In a canine model of HF and acute vasoconstrictive hypertension we characterized and compared the cardiorenal actions of M-atrial natriuretic peptide (M-ANP), a novel particulate guanylyl cyclase (pGC) activator, and nitroglycerin, a soluble guanylyl cyclase (sGC) activator. HF was induced by rapid RV pacing (180 beats per minute) for 10 days. On day 11, hypertension was induced by continuous angiotensin II infusion. We characterized the cardiorenal and humoral actions prior to, during, and following intravenous M-ANP (n=7), nitroglycerin (n=7), and vehicle (n=7) infusion. Mean arterial pressure (MAP) was reduced by M-ANP (139 ± 4 to 118 ± 3 mm Hg, P<0.05) and nitroglycerin (137 ± 3 to 116 ± 4 mm Hg, P<0.05); similar findings were recorded for pulmonary wedge pressure (PCWP) with M-ANP (12 ± 2 to 6 ± 2 mm Hg, P<0.05) and nitroglycerin (12 ± 1 to 6 ± 1 mm Hg, P<0.05). M-ANP enhanced renal function with significant increases (P<0.05) in glomerular filtration rate (38 ± 4 to 53 ± 5 mL/min), renal blood flow (132 ± 18 to 236 ± 23 mL/min), and natriuresis (11 ± 4 to 689 ± 37 mEq/min) and also inhibited aldosterone activation (32 ± 3 to 23 ± 2 ng/dL, P<0.05), whereas nitroglycerin had no significant (P>0.05) effects on these renal parameters or aldosterone activation. Our results advance the differential cardiorenal actions of pGC (M-ANP) and sGC (nitroglycerin) mediated cGMP activation. These distinct renal and aldosterone modulating actions make M-ANP an attractive therapeutic for HF with concomitant hypertension, where renal protection is a key therapeutic goal.

Acute food deprivation reverses morphine-induced locomotion deficits in M5 muscarinic receptor knockout mice.

PubMed

Steidl, Stephan; Lee, Esther; Wasserman, David; Yeomans, John S

2013-09-01

Lesions of the pedunculopontine tegmental nucleus (PPT), one of two sources of cholinergic input to the ventral tegmental area (VTA), block conditioned place preference (CPP) for morphine in drug-naïve rats. M5 muscarinic cholinergic receptors, expressed by midbrain dopamine neurons, are critical for the ability of morphine to increase nucleus accumbens dopamine levels and locomotion, and for morphine CPP. This suggests that M5-mediated PPT cholinergic inputs to VTA dopamine neurons critically contribute to morphine-induced dopamine activation, reward and locomotion. In the current study we tested whether food deprivation, which reduces PPT contribution to morphine CPP in rats, could also reduce M5 contributions to morphine-induced locomotion in mice. Acute 18-h food deprivation reversed the phenotypic differences usually seen between non-deprived wild-type and M5 knockout mice. That is, food deprivation increased morphine-induced locomotion in M5 knockout mice but reduced morphine-induced locomotion in wild-type mice. Food deprivation increased saline-induced locomotion equally in wild-type and M5 knockout mice. Based on these findings, we suggest that food deprivation reduces the contribution of M5-mediated PPT cholinergic inputs to the VTA in morphine-induced locomotion and increases the contribution of a PPT-independent pathway. The contributions of cholinergic, dopaminergic and GABAergic neurons to the effects of acute food deprivation are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Correlative mRNA and Protein Expression of Middle and Inner Ear Inflammatory Cytokines during Mouse Acute Otitis Media

PubMed Central

Trune, Dennis R.; Kempton, Beth; Hausman, Frances A.; Larrain, Barbara E.; MacArthur, Carol J.

2015-01-01

Although the inner ear has long been reported to be susceptible to middle ear disease, little is known of the inflammatory mechanisms that might cause permanent sensorineural hearing loss. Recent studies have shown inner ear tissues are capable of expressing inflammatory cytokines during otitis media. However, little quantitative information is available concerning cytokine gene expression in the inner ear and the protein products that result. Therefore, this study was conducted of mouse middle and inner ear during acute otitis media to measure the relationship between inflammatory cytokine genes and their protein products with quantitative RT-PCR and ELISA, respectively. Balb/c mice were inoculated transtympanically with heat-killed Haemophilus influenzae and middle and inner ear tissues collected for either quantitative RT-PCR microarrays or ELISA multiplex arrays. mRNA for several cytokine genes was significantly increased in both the middle and inner ear at 6 hours. In the inner ear, these included MIP-2 (448 fold), IL-6 (126 fold), IL-1β (7.8 fold), IL-10 (10.7 fold), TNFα (1.8 fold), and IL-1α (1.5 fold). The 24 hour samples showed a similar pattern of gene expression, although generally at lower levels. In parallel, the ELISA showed the related cytokines were present in the inner ear at concentrations higher by 2 to 122 fold higher at 18 hours, declining slightly from there at 24 hours. Immunohistochemistry with antibodies to a number of these cytokines demonstrated they occurred in greater amounts in the inner ear tissues. These findings demonstrate considerable inflammatory gene expression and gene products in the inner ear following acute otitis media. These higher cytokine levels suggest one potential mechanism for the permanent hearing loss seen in some cases of acute and chronic otitis media. PMID:25922207

Correlative mRNA and protein expression of middle and inner ear inflammatory cytokines during mouse acute otitis media.

PubMed

Trune, Dennis R; Kempton, Beth; Hausman, Frances A; Larrain, Barbara E; MacArthur, Carol J

2015-08-01

Although the inner ear has long been reported to be susceptible to middle ear disease, little is known of the inflammatory mechanisms that might cause permanent sensorineural hearing loss. Recent studies have shown inner ear tissues are capable of expressing inflammatory cytokines during otitis media. However, little quantitative information is available concerning cytokine gene expression in the inner ear and the protein products that result. Therefore, this study was conducted of mouse middle and inner ear during acute otitis media to measure the relationship between inflammatory cytokine genes and their protein products with quantitative RT-PCR and ELISA, respectively. Balb/c mice were inoculated transtympanically with heat-killed Haemophilus influenzae and middle and inner ear tissues collected for either quantitative RT-PCR microarrays or ELISA multiplex arrays. mRNA for several cytokine genes was significantly increased in both the middle and inner ear at 6 h. In the inner ear, these included MIP-2 (448 fold), IL-6 (126 fold), IL-1β (7.8 fold), IL-10 (10.7 fold), TNFα (1.8 fold), and IL-1α (1.5 fold). The 24 h samples showed a similar pattern of gene expression, although generally at lower levels. In parallel, the ELISA showed the related cytokines were present in the inner ear at concentrations higher by 2-122 fold higher at 18 h, declining slightly from there at 24 h. Immunohistochemistry with antibodies to a number of these cytokines demonstrated they occurred in greater amounts in the inner ear tissues. These findings demonstrate considerable inflammatory gene expression and gene products in the inner ear following acute otitis media. These higher cytokine levels suggest one potential mechanism for the permanent hearing loss seen in some cases of acute and chronic otitis media. Copyright © 2015 Elsevier B.V. All rights reserved.

External validation of a six simple variable model of stroke outcome and verification in hyper-acute stroke.

PubMed

Reid, J M; Gubitz, G J; Dai, D; Reidy, Y; Christian, C; Counsell, C; Dennis, M; Phillips, S J

2007-12-01

We aimed to validate a previously described six simple variable (SSV) model that was developed from acute and sub-acute stroke patients in our population that included hyper-acute stroke patients. A Stroke Outcome Study enrolled patients from 2001 to 2002. Functional status was assessed at 6 months using the modified Rankin Scale (mRS). SSV model performance was tested in our cohort. 538 acute ischaemic (87%) and haemorrhagic stroke patients were enrolled, 51% of whom presented to hospital within 6 h of symptom recognition. At 6 months post-stroke, 42% of patients had a good outcome (mRS < or = 2). Stroke patients presenting within 6 h of symptom recognition were significantly older with higher stroke severity. In our Stroke Outcome Study dataset, the SSV model had an area under the curve of 0.792 for 6 month outcomes and performed well for hyper-acute or post-acute stroke, age < or > or = 75 years, haemorrhagic or ischaemic stroke, men or women, moderate and severe stroke, but poorly for mild stroke. This study confirms the external validity of the SSV model in our hospital stroke population. This model can therefore be utilised for stratification in acute and hyper-acute stroke trials.

mRNA N6-methyladenosine methylation of postnatal liver development in pig.

PubMed

He, Shen; Wang, Hong; Liu, Rui; He, Mengnan; Che, Tiandong; Jin, Long; Deng, Lamei; Tian, Shilin; Li, Yan; Lu, Hongfeng; Li, Xuewei; Jiang, Zhi; Li, Diyan; Li, Mingzhou

2017-01-01

N6-methyladenosine (m6A) is a ubiquitous reversible epigenetic RNA modification that plays an important role in the regulation of post-transcriptional protein coding gene expression. Liver is a vital organ and plays a major role in metabolism with numerous functions. Information concerning the dynamic patterns of mRNA m6A methylation during postnatal development of liver has been long overdue and elucidation of this information will benefit for further deciphering a multitude of functional outcomes of mRNA m6A methylation. Here, we profile transcriptome-wide m6A in porcine liver at three developmental stages: newborn (0 day), suckling (21 days) and adult (2 years). About 33% of transcribed genes were modified by m6A, with 1.33 to 1.42 m6A peaks per modified gene. m6A was distributed predominantly around stop codons. The consensus motif sequence RRm6ACH was observed in 78.90% of m6A peaks. A negative correlation (average Pearson's r = -0.45, P < 10-16) was found between levels of m6A methylation and gene expression. Functional enrichment analysis of genes consistently modified by m6A methylation at all three stages showed genes relevant to important functions, including regulation of growth and development, regulation of metabolic processes and protein catabolic processes. Genes with higher m6A methylation and lower expression levels at any particular stage were associated with the biological processes required for or unique to that stage. We suggest that differential m6A methylation may be important for the regulation of nutrient metabolism in porcine liver.

Coordination of m6A mRNA methylation and gene transcription by ZFP217 regulates pluripotency and reprogramming

PubMed Central

Aguilo, Francesca; Zhang, Fan; Sancho, Ana; Fidalgo, Miguel; Di Cecilia, Serena; Vashisht, Ajay; Lee, Dung-Fang; Chen, Chih-Hung; Rengasamy, Madhumitha; Andino, Blanca; Jahouh, Farid; Roman, Angel; Krig, Sheryl R.; Wang, Rong; Zhang, Weijia; Wohlschlegel, James A.; Wang, Jianlong; Walsh, Martin J.

2015-01-01

SUMMARY Epigenetic and epitranscriptomic networks have important functions in maintaining pluripotency of embryonic stem cells (ESCs) and somatic cell reprogramming. However the mechanisms integrating the actions of these distinct networks are only partially understood. Here, we show that the chromatin-associated zinc finger protein 217 (ZFP217) coordinates epigenetic and epitranscriptomic regulation. ZFP217 interacts with several epigenetic regulators, activates transcription of key pluripotency genes, and modulates N6-methyladenosine (m6A) deposition on their transcripts by sequestering the enzyme m6A methyltransferase-like 3 (METTL3). Consistently, Zfp217 depletion compromises ESC self-renewal and somatic cell reprogramming, globally increases m6A RNA levels, and enhances m6A modification of Nanog, Sox2, Klf4, and c-Myc mRNAs, promoting their degradation. ZFP217 binds its own target gene mRNAs, which are also METTL3-associated, and is enriched at promoters of m6A-modified transcripts. Collectively, these findings shed light on how a transcription factor can tightly couple gene transcription to m6A RNA modification to insure ESC identity. PMID:26526723

Lipocalin 2 in cerebrospinal fluid as a marker of acute bacterial meningitis

PubMed Central

2014-01-01

Background Early differential diagnosis between acute bacterial and viral meningitis is problematic. We aimed to investigate whether the detection of lipocalin 2, a protein of the acute innate immunity response, may be used as a marker for acute bacterial meningitis. Methods Transgenic mice expressing the human transferrin were infected by intraperitoneal route and were imaged. Cerebrospinal fluid (CSF) was sampled up to 48hours post- infection to measure lipocalin 2. We also tested a collection of 90 and 44 human CSF with confirmed acute bacterial or acute viral meningitis respectively. Results Lipocalin 2 was detected after 5 h in CSF during experimental infection in mice. Lipocalin 2 levels were significantly higher (p < 0.0001) in patients with confirmed acute bacterial meningitis (mean 125 pg/mL, range 106–145 pg/mL) than in patients with acute viral meningitis (mean 2 pg/mL, range 0–6 pg/mL) with a sensitivity of 81%, a specificity of 93%, a positive predictive value of 96% and a negative predictive value of 71% in diagnosing acute bacterial meningitis. Conclusions Increased levels of lipocalin 2 in cerebrospinal fluid may discriminate between acute bacterial and viral meningitis in patients with clinical syndrome of meningitis. PMID:24885531

UP-REGULATION OF IL-6, IL-8 AND CCL2 GENE EXPRESSION AFTER ACUTE INFLAMMATION: CORRELATION TO CLINICAL PAIN

PubMed Central

Wang, Xiao-Min; Hamza, May; Wu, Tai-Xia; Dionne, Raymond A.

2012-01-01

Tissue injury initiates a cascade of inflammatory mediators and hyperalgesic substances including prostaglandins, cytokines and chemokines. Using microarray and qRT-PCR gene expression analyses, the present study evaluated changes in gene expression of a cascade of cytokines following acute inflammation and the correlation between the changes in the gene expression level and pain intensity in the oral surgery clinical model of acute inflammation. Tissue injury resulted in a significant up-regulation in the gene expression of Interleukin-6 (IL-6; 63.3-fold), IL-8 (8.1-fold), chemokine (C-C motif) ligand 2 (CCL2; 8.9-fold), chemokine (C-X-C motif) ligand 1 (CXCL1; 30.5-fold), chemokine (C-X-C motif) ligand 2 (CXCL2; 26-fold) and annexin A1 (ANXA1; 12-fold). The up-regulation of IL-6 gene expression was significantly correlated to the up-regulation on the gene expression of IL-8, CCL2, CXCL1 and CXCL2. Interestingly, the tissue injury induced up-regulation of IL-6 gene expression, IL-8 and CCL2 were positively correlated to pain intensity at 3 hours post-surgery, the onset of acute inflammatory pain. However, ketorolac treatment did not have a significant effect on the gene expression of IL-6, IL-8, CCL2, CXCL2 and ANXA1 at the same time point of acute inflammation. These results demonstrate that up-regulation of IL-6, IL-8 and CCL2 gene expression contributes to the development of acute inflammation and inflammatory pain. The lack of effect for ketorolac on the expression of these gene products may be related to the ceiling analgesic effects of non-steroidal anti-inflammatory drugs. PMID:19233564

Blocking fatty acid-fueled mROS production within macrophages alleviates acute gouty inflammation.

PubMed

Hall, Christopher J; Sanderson, Leslie E; Lawrence, Lisa M; Pool, Bregina; van der Kroef, Maarten; Ashimbayeva, Elina; Britto, Denver; Harper, Jacquie L; Lieschke, Graham J; Astin, Jonathan W; Crosier, Kathryn E; Dalbeth, Nicola; Crosier, Philip S

2018-05-01

Gout is the most common inflammatory arthritis affecting men. Acute gouty inflammation is triggered by monosodium urate (MSU) crystal deposition in and around joints that activates macrophages into a proinflammatory state, resulting in neutrophil recruitment. A complete understanding of how MSU crystals activate macrophages in vivo has been difficult because of limitations of live imaging this process in traditional animal models. By live imaging the macrophage and neutrophil response to MSU crystals within an intact host (larval zebrafish), we reveal that macrophage activation requires mitochondrial ROS (mROS) generated through fatty acid oxidation. This mitochondrial source of ROS contributes to NF-κB-driven production of IL-1β and TNF-α, which promote neutrophil recruitment. We demonstrate the therapeutic utility of this discovery by showing that this mechanism is conserved in human macrophages and, via pharmacologic blockade, that it contributes to neutrophil recruitment in a mouse model of acute gouty inflammation. To our knowledge, this study is the first to uncover an immunometabolic mechanism of macrophage activation that operates during acute gouty inflammation. Targeting this pathway holds promise in the management of gout and, potentially, other macrophage-driven diseases.

Acute haemolytic anaemia and myolysis due to G6PD deficiency.

PubMed

Mangat, Chetna; Inoue, Susumu; Saah, Elna; Sharman, Mahesh

2014-09-18

A 2-year-old African-American male patient with sickle cell trait developed cough, red coloured urine, pallor and fatigue. The patient was hospitalised. Diagnostic workup showed that he was glucose 6 phosphate dehydrogenase (G6PD) deficient in erythrocytes. He also had chest X-ray findings of pneumonia. His urine examination showed the presence of haemoglobin and myoglobin. On repeated questioning it was found that he had a moth ball in his mouth a few days prior to this medical episode. This case illustrates a rarely described complication of myolysis in G6PD deficient persons on exposure to a strong oxidant. A review of the literature showed that most people with G6PD deficiency tolerate exercise well without untoward effect in muscles. However, assay of myoglobin in urine has not been routinely performed in these patients during acute haemolytic episode, and thus it is uncertain how frequent myoglobulinaemia occurs in a similar stress situation. 2014 BMJ Publishing Group Ltd.

Comparison of (+)- and (−)-Naloxone on the Acute Psychomotor-Stimulating Effects of Heroin, 6-Acetylmorphine, and Morphine in Mice

PubMed Central

Andersen, Jannike Mørch; Boix, Fernando; Bergh, Marianne Skov-Skov; Vindenes, Vigdis; Rice, Kenner C.; Huestis, Marilyn A.; Mørland, Jørg

2016-01-01

Toll-like receptor 4 (TLR4) signaling is implied in opioid reinforcement, reward, and withdrawal. Here, we explored whether TLR4 signaling is involved in the acute psychomotor-stimulating effects of heroin, 6-acetylmorphine (6-AM), and morphine as well as whether there are differences between the three opioids regarding TLR4 signaling. To address this, we examined how pretreatment with (+)-naloxone, a TLR4 active but opioid receptor (OR) inactive antagonist, affected the acute increase in locomotor activity induced by heroin, 6-AM, or morphine in mice. We also assessed the effect of pretreatment with (−)-naloxone, a TLR4 and OR active antagonist, as well as the pharmacokinetic profiles of (+) and (−)-naloxone in the blood and brain. We found that (−)-naloxone reduced acute opioid-induced locomotor activity in a dose-dependent manner. By contrast, (+)-naloxone, administered in doses assumed to antagonize TLR4 but not ORs, did not affect acute locomotor activity induced by heroin, 6-AM, or morphine. Both naloxone isomers exhibited similar concentration versus time profiles in the blood and brain, but the brain concentrations of (−)-naloxone reached higher levels than those of (+)-naloxone. However, the discrepancies in their pharmacokinetic properties did not explain the marked difference between the two isomers’ ability to affect opioid-induced locomotor activity. Our results underpin the importance of OR activation and do not indicate an apparent role of TLR4 signaling in acute opioid-induced psychomotor stimulation in mice. Furthermore, there were no marked differences between heroin, 6-AM, and morphine regarding involvement of OR or TLR4 signaling. PMID:27278234

Requirement for CDK6 in MLL-rearranged acute myeloid leukemia

PubMed Central

Placke, Theresa; Faber, Katrin; Nonami, Atsushi; Putwain, Sarah L.; Salih, Helmut R.; Heidel, Florian H.; Krämer, Alwin; Root, David E.; Barbie, David A.; Krivtsov, Andrei V.; Armstrong, Scott A.; Hahn, William C.; Huntly, Brian J.; Sykes, Stephen M.; Milsom, Michael D.; Scholl, Claudia

2014-01-01

Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of acute myeloid leukemia (AML). Insights into MLL fusion-mediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated. We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9–driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts. PMID:24764564

Tumor necrosis factor-inducible gene 6 promotes liver regeneration in mice with acute liver injury.

PubMed

Wang, Sihyung; Lee, Ji-Seon; Hyun, Jeongeun; Kim, Jieun; Kim, Seung U; Cha, Hyuk-Jin; Jung, Youngmi

2015-03-11

Tumor necrosis factor-inducible gene 6 protein (TSG-6), one of the cytokines released by human mesenchymal stem/stromal cells (hMSC), has an anti-inflammatory effect and alleviates several pathological conditions; however, the hepatoprotective potential of TSG-6 remains unclear. We investigated whether TSG-6 promoted liver regeneration in acute liver failure. The immortalized hMSC (B10) constitutively over-expressing TSG-6 or empty plasmid (NC: Negative Control) were established, and either TSG-6 or NC-conditioned medium (CM) was intraperitoneally injected into mice with acute liver damage caused by CCl4. Mice were sacrificed at 3 days post-CM treatment. Higher expression and the immunosuppressive activity of TSG-6 were observed in CM from TSG-6-hMSC. The obvious histomorphological liver injury and increased level of liver enzymes were shown in CCl4-treated mice with or without NC-CM, whereas those observations were markedly ameliorated in TSG-6-CM-treated mice with CCl4. Ki67-positive hepatocytic cells were accumulated in the liver of the CCl4+TSG-6 group. RNA analysis showed the decrease in both of inflammation markers, tnfα, il-1β, cxcl1 and cxcl2, and fibrotic markers, tgf-β1, α-sma and collagen α1, in the CCl4+TSG-6 group, compared to the CCl4 or the CCl4+NC group. Protein analysis confirmed the lower expression of TGF-β1 and α-SMA in the CCl4+TSG-6 than the CCl4 or the CCl4+NC group. Immunostaining for α-SMA also revealed the accumulation of the activated hepatic stellate cells in the livers of mice in the CCl4 and CCl4+NC groups, but not in the livers of mice from the CCl4+TSG-6 group. The cultured LX2 cells, human hepatic stellate cell line, in TSG-6-CM showed the reduced expression of fibrotic markers, tgf-β1, vimentin and collagen α1, whereas the addition of the TSG-6 antibody neutralized the inhibitory effect of TSG-6 on the activation of LX2 cells. In addition, cytoplasmic lipid drops, the marker of inactivated hepatic stellate cell, were

The 2001 January 13th M {W}7.7 and February 13th M {W}6.6 El Salvador Earthquakes: Deformation and Stress Triggering

NASA Astrophysics Data System (ADS)

Hreinsdóttir, S.; Freymueller, J. T.

2001-12-01

On the 13th of January 2001, an M {W} 7.7 normal fault earthquake occurred offshore El Salvador. The earthquake occurred in the subducting Cocos plate and was followed by high seismic activity and several earthquakes exceeding magnitude 5. On the 13th of February, an M {W} 6.6 strike slip earthquake occurred in the overriding Caribbean plate, about 75 km NNW from the epicenter of the large January earthquake. Deformation due to these earthquakes was observed at six continuous CORS GPS stations in Central America. In the M {W} 7.7 earthquake about 10 mm displacement was measured at GPS stations in El Salvador and Honduras. A smaller but significant dispacement was also observed at GPS stations in Nicaragua, more then 200 km from the earthquake's epicenter. In the M {W} 6.6 earthquake 41+/- 1 mm displacement in direction N111oE was measured at the GPS station in San Salvador, El Salvador. Other CORS GPS stations were not affected by that earthquake. A postsesmic signal is detectable at the San Salvador GPS station, strongest right after the earthquake and then decays. On average we see 0.3 +/- 0.1 mm/day of SSW motion of the station in the first twenty days following the earthquake. Using seismic and geodetic data, we calculated Coulomb stress changes following the January 13th, M {W} 7.7 earthquake. Of special interest were six 5.4 <= {M} {W}<=5.8 thrust events that presumably occurred on the interface between the Caribean and Cocos plate, and the M {W} 6.6 strike slip earthquake that occurred in the overriding Caribean plate. The location and focal mechanism of these earthquakes correlate with areas of calculated increase in static stress thus indicating stress triggering. The thrust events occurred 2 to 20 days after the M {W} 7.7 earthquake, in increasing distance from the M {W} 7.7 event with time.

IL-6 signalling in patients with acute ST-elevation myocardial infarction

PubMed Central

Ritschel, Vibeke N.; Seljeflot, Ingebjørg; Arnesen, Harald; Halvorsen, Sigrun; Weiss, Thomas; Eritsland, Jan; Andersen, Geir Ø

2013-01-01

Cytokines of the IL-6 family have been related to infarct size and prognosis in patients with myocardial infarction. The aims of the present study were to elucidate possible associations between myocardial necrosis and left ventricular impairment and members of the IL-6 transsignalling system including soluble (s) IL-6R and (s) glycoprotein 130 (sgp130) in patients with ST-elevation myocardial infarction (STEMI) treated with primary PCI. In blood samples from 1028 STEMI patients, collected in-hosptial, we found significant correlations between peak TnT and IL-6 and CRP (p < 0.001, all) and between IL-6 and CRP and LV ejection fraction and NT-proBNP (p < 0.001, all). On the contrary, no significant associations were found between peak TnT and sgp130 or sIL-6R. Furthermore sgp130 was significantly elevated in diabetic patients and also associated with the glucometabolic state. In conclusion, circulating levels of IL-6 and CRP, but not the soluble forms of the receptor (sIL-6R) or the receptor signalling subunit (sgp130) were associated with the extent of myocardial necrosis. The biological importance of the IL-6/gp130-mediated signalling pathways in patients with acute myocardial infarction and dysglycemia should be further elucidated. PMID:24707455

Transcallosal Projections Require Glycoprotein M6-Dependent Neurite Growth and Guidance.

PubMed

Mita, Sakura; de Monasterio-Schrader, Patricia; Fünfschilling, Ursula; Kawasaki, Takahiko; Mizuno, Hidenobu; Iwasato, Takuji; Nave, Klaus-Armin; Werner, Hauke B; Hirata, Tatsumi

2015-11-01

The function of mature neurons critically relies on the developmental outgrowth and projection of their cellular processes. It has long been postulated that the neuronal glycoproteins M6a and M6b are involved in axon growth because these four-transmembrane domain-proteins of the proteolipid protein family are highly enriched on growth cones, but in vivo evidence has been lacking. Here, we report that the function of M6 proteins is required for normal axonal extension and guidance in vivo. In mice lacking both M6a and M6b, a severe hypoplasia of axon tracts was manifested. Most strikingly, the corpus callosum was reduced in thickness despite normal densities of cortical projection neurons. In single neuron tracing, many axons appeared shorter and disorganized in the double-mutant cortex, and some of them were even misdirected laterally toward the subcortex. Probst bundles were not observed. Upon culturing, double-mutant cortical and cerebellar neurons displayed impaired neurite outgrowth, indicating a cell-intrinsic function of M6 proteins. A rescue experiment showed that the intracellular loop of M6a is essential for the support of neurite extension. We propose that M6 proteins are required for proper extension and guidance of callosal axons that follow one of the most complex trajectories in the mammalian nervous system. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

No Effect of Acute and 6-Day Nitrate Supplementation on VO2 and Time-Trial Performance in Highly Trained Cyclists.

PubMed

Nyakayiru, Jean M; Jonvik, Kristin L; Pinckaers, Philippe J M; Senden, Joan; van Loon, Luc J C; Verdijk, Lex B

2017-02-01

While the majority of studies reporting ergogenic effects of dietary nitrate have used a multiday supplementation protocol, some studies suggest that a single dose of dietary nitrate before exercise can also improve subsequent performance. We aimed to compare the impact of acute and 6-day sodium nitrate supplementation on oxygen uptake (V̇O 2 ) and time-trial performance in trained cyclists. Using a randomized, double-blind, cross-over design, 17 male cyclists (25 ± 4 y, V̇O 2peak 65 ± 4 ml·kg -1 ·min -1 , W max 411 ± 35 W) were subjected to 3 different trials; 5 days placebo and 1 day sodium nitrate supplementation (1-DAY); 6 days sodium nitrate supplementation (6-DAY); 6 days placebo supplementation (PLA). Nitrate was administered as 1097 mg sodium nitrate providing 800 mg (~12.9 mmol) nitrate per day. Three hours after ingestion of the last supplemental bolus, indirect calorimetry was performed while subjects performed 30 min of exercise at 45% W max and 30 min at 65% W max on a cycle ergometer, followed by a 10 km time-trial. Immediately before exercise, plasma [nitrate] and [nitrite] increased to a similar extent during the 6-DAY and 1-DAY trial, but not with PLA (plasma nitrite: 501 ± 205, 553 ± 278, and 239 ± 74 nM, respectively; p < .001). No differences were observed between interventions in V̇O 2 during submaximal exercise, or in time to complete the time-trial (6-DAY: 1004 ± 61, 1-DAY: 1022 ± 72, PLA: 1017 ± 71 s; p = .28). We conclude that both acute and 6-days of sodium nitrate supplementation do not alter V̇O 2 during submaximal exercise or improve time-trial performance in highly trained cyclists, despite increasing plasma [nitrate] and [nitrite].

6-PACK programme to decrease fall injuries in acute hospitals: cluster randomised controlled trial

PubMed Central

Morello, Renata T; Wolfe, Rory; Brand, Caroline A; Haines, Terry P; Hill, Keith D; Brauer, Sandra G; Botti, Mari; Cumming, Robert G; Livingston, Patricia M; Sherrington, Catherine; Zavarsek, Silva; Lindley, Richard I; Kamar, Jeannette

2016-01-01

Objective To evaluate the effect of the 6-PACK programme on falls and fall injuries in acute wards. Design Cluster randomised controlled trial. Setting Six Australian hospitals. Participants All patients admitted to 24 acute wards during the trial period. Interventions Participating wards were randomly assigned to receive either the nurse led 6-PACK programme or usual care over 12 months. The 6-PACK programme included a fall risk tool and individualised use of one or more of six interventions: “falls alert” sign, supervision of patients in the bathroom, ensuring patients’ walking aids are within reach, a toileting regimen, use of a low-low bed, and use of a bed/chair alarm. Main outcome measures The co-primary outcomes were falls and fall injuries per 1000 occupied bed days. Results During the trial, 46 245 admissions to 16 medical and eight surgical wards occurred. As many people were admitted more than once, this represented 31 411 individual patients. Patients’ characteristics and length of stay were similar for intervention and control wards. Use of 6-PACK programme components was higher on intervention wards than on control wards (incidence rate ratio 3.05, 95% confidence interval 2.14 to 4.34; P<0.001). In all, 1831 falls and 613 fall injuries occurred, and the rates of falls (incidence rate ratio 1.04, 0.78 to 1.37; P=0.796) and fall injuries (0.96, 0.72 to 1.27; P=0.766) were similar in intervention and control wards. Conclusions Positive changes in falls prevention practice occurred following the introduction of the 6-PACK programme. However, no difference was seen in falls or fall injuries between groups. High quality evidence showing the effectiveness of falls prevention interventions in acute wards remains absent. Novel solutions to the problem of in-hospital falls are urgently needed. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12611000332921. PMID:26813674

Preclinical evaluation of WYE-687, a mTOR kinase inhibitor, as a potential anti-acute myeloid leukemia agent

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Feng; Wang, Lingling; Shen, Yunfeng

Mammalian target of rapamycin (mTOR) as a potential drug target for treatment of acute myeloid leukemia (AML). Here, we investigated the potential anti-leukemic activity by WYE-687, a potent mTOR kinase inhibitor. We demonstrated that WYE-687 potently inhibited survival and proliferation of established (HL-60, U937, AML-193 and THP-1 lines) and human AML progenitor cells. Yet, same WYE-687 treatment was non-cytotoxic to the primary peripheral blood mononuclear leukocytes (PBMCs) isolated from healthy donors. WYE-687 induced caspase-dependent apoptotic death in above AML cells/progenitor cells. On the other hand, the pan-caspase inhibitor (Z-VAD-FMK), the caspase-3 specific inhibitor (Z-DEVD-FMK) or the caspase-9 specific inhibitor (z-LEHD-fmk)more » attenuated WYE-687-induced cytotoxicity. At the molecular level, WYE-687 concurrently inhibited activation of mTORC1 (p70S6K1 and S6 phosphorylations) and mTORC2 (AKT Ser-473 and FoxO1/3a phosphorylations), whiling downregulating mTORC1/2-regulated genes (Bcl-xL and hypoxia-inducible factor 1/2α) in both HL-60/U937 cells and human AML progenitor cells. In vivo, oral administration of WYE-687 potently inhibited U937 leukemic xenograft tumor growth in severe combined immunodeficient (SCID) mice, without causing significant toxicities. In summary, our results demonstrate that targeting mTORC1/2 by WYE-687 leads to potent antitumor activity in preclinical models of AML. - Highlights: • WYE-687 inhibits survival and proliferation of human AML cells/progenitor cells. • WYE-687 induces apoptotic death of human AML cells/progenitor cells. • WYE-687 inhibits mTORC1/2 activation in human AML cells/progenitor cells. • WYE-687 inhibits U937 xenograft growth in SCID mice.« less

Emphysema induced by elastase alters the mRNA relative levels from DNA repair genes in acute lung injury in response to sepsis induced by lipopolysaccharide administration in Wistar rats.

PubMed

Sergio, Luiz Philippe S; Lucinda, Leda M F; Reboredo, Maycon M; de Paoli, Flavia; Fonseca, Lídia M C; Pinheiro, Bruno V; Mencalha, Andre L; Fonseca, Adenilson S

2018-03-01

Purpose/Aim of the study: Patients suffering from chronic obstructive pulmonary disease (COPD) in association with acute respiratory distress syndrome (ARDS) present oxidative stress in lung cells, with production of free radicals and DNA lesions in pulmonary and adjacent cells. Once the DNA molecule is damaged, a set of enzymatic mechanisms are trigged to preserve genetic code integrity and cellular homeostasis. These enzymatic mechanisms include the base and the nucleotide excision repair pathways, as well as telomere regulation. Thus, the aim of this work was to evaluate the mRNA levels from APEX1, ERCC2, TP53, and TRF2 genes in lung tissue from Wistar rats affected by acute lung injury in response to sepsis and emphysema. Adult male Wistar rats were randomized into 4 groups (n = 6, for each group): control, emphysema, sepsis, and emphysema with sepsis. Pulmonary emphysema was induced by intratracheal instillation of elastase (12 IU/animal) and sepsis induced by intraperitoneal Escherichia coli lipopolysaccharide (LPS) injection (10 mg/kg). Lungs were removed, and samples were withdrawn for histological analysis and total RNA extraction, cDNA synthesis, and mRNA level evaluation by real time quantitative polymerase chain reaction. Data show acute lung injury by LPS and emphysema by elastase and that APEX1, ERCC2, TP53, and TRF2 mRNA levels are increased significantly (p < 0.01) in emphysema with sepsis group. Our results suggest that alteration in mRNA levels from DNA repair and genomic stability could be part of cell response to acute lung injury in response to emphysema and sepsis.

A role for the membrane protein M6 in the Drosophila visual system.

PubMed

Zappia, María Paula; Bernabo, Guillermo; Billi, Silvia C; Frasch, Alberto C; Ceriani, María Fernanda; Brocco, Marcela Adriana

2012-07-04

Members of the proteolipid protein family, including the four-transmembrane glycoprotein M6a, are involved in neuronal plasticity in mammals. Results from our group previously demonstrated that M6, the only proteolipid protein expressed in Drosophila, localizes to the cell membrane in follicle cells. M6 loss triggers female sterility, which suggests a role for M6 in follicular cell remodeling. These results were the basis of the present study, which focused on the function and requirements of M6 in the fly nervous system. The present study identified two novel, tissue-regulated M6 isoforms with variable N- and C- termini, and showed that M6 is the functional fly ortholog of Gpm6a. In the adult brain, the protein was localized to several neuropils, such as the optic lobe, the central complex, and the mushroom bodies. Interestingly, although reduced M6 levels triggered a mild rough-eye phenotype, hypomorphic M6 mutants exhibited a defective response to light. Based on its ability to induce filopodium formation we propose that M6 is key in cell remodeling processes underlying visual system function. These results bring further insight into the role of M6/M6a in biological processes involving neuronal plasticity and behavior in flies and mammals.

mTORC1 Inhibition Induces Resistance to Methotrexate and 6-Mercaptopurine in Ph+ and Ph-like B-ALL.

PubMed

Vo, Thanh-Trang T; Lee, J Scott; Nguyen, Duc; Lui, Brandon; Pandori, William; Khaw, Andrew; Mallya, Sharmila; Lu, Mengrou; Müschen, Markus; Konopleva, Marina; Fruman, David A

2017-09-01

Elevated activity of mTOR is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high-risk B-ALL subtypes. Therefore, we tested whether mTOR inhibition can augment the efficacy of current chemotherapy agents in Ph + and Ph-like B-ALL models. Surprisingly, inhibiting mTOR complex 1 (mTORC1) protected B-ALL cells from killing by methotrexate and 6-mercaptopurine, two antimetabolite drugs used in maintenance chemotherapy. The cytoprotective effects correlated with decreased cell-cycle progression and were recapitulated using cell-cycle inhibitors, palbociclib or aphidicolin. Dasatinib, a tyrosine kinase inhibitor currently used in Ph + patients, inhibits ABL kinase upstream of mTOR. Dasatinib resistance is mainly caused by ABL kinase mutations, but is also observed in a subset of ABL unmutated cases. We identified dasatinib-resistant Ph+ cell lines and patient samples in which dasatinib can effectively reduce ABL kinase activity and mTORC1 signaling without causing cell death. In these cases, dasatinib protected leukemia cells from killing by 6-mercaptopurine. Using xenograft models, we observed that mTOR inhibition or dasatinib increased the numbers of leukemia cells that emerge after cessation of chemotherapy treatment. These results demonstrate that inhibitors targeting mTOR or upstream signaling nodes should be used with caution when combined with chemotherapeutic agents that rely on cell-cycle progression to kill B-ALL cells. Mol Cancer Ther; 16(9); 1942-53. ©2017 AACR . ©2017 American Association for Cancer Research.

Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation.

PubMed

Geula, Shay; Moshitch-Moshkovitz, Sharon; Dominissini, Dan; Mansour, Abed AlFatah; Kol, Nitzan; Salmon-Divon, Mali; Hershkovitz, Vera; Peer, Eyal; Mor, Nofar; Manor, Yair S; Ben-Haim, Moshe Shay; Eyal, Eran; Yunger, Sharon; Pinto, Yishay; Jaitin, Diego Adhemar; Viukov, Sergey; Rais, Yoach; Krupalnik, Vladislav; Chomsky, Elad; Zerbib, Mirie; Maza, Itay; Rechavi, Yoav; Massarwa, Rada; Hanna, Suhair; Amit, Ido; Levanon, Erez Y; Amariglio, Ninette; Stern-Ginossar, Noam; Novershtern, Noa; Rechavi, Gideon; Hanna, Jacob H

2015-02-27

Naïve and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here, we identify Mettl3, an N(6)-methyladenosine (m(6)A) transferase, as a regulator for terminating murine naïve pluripotency. Mettl3 knockout preimplantation epiblasts and naïve embryonic stem cells are depleted for m(6)A in mRNAs, yet are viable. However, they fail to adequately terminate their naïve state and, subsequently, undergo aberrant and restricted lineage priming at the postimplantation stage, which leads to early embryonic lethality. m(6)A predominantly and directly reduces mRNA stability, including that of key naïve pluripotency-promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo and identifies regulatory modules that functionally influence naïve and primed pluripotency in an opposing manner. Copyright © 2015, American Association for the Advancement of Science.

M2 macrophages coexist with a Th1-driven profile in periapical cysts.

PubMed

Ribeiro, C M; de Carli, M L; Nonogaki, S; Nogueira, D A; Pereira, A A C; Sperandio, F F; Hanemann, J A C

2018-02-01

To evaluate the participation of both Th1 and Th2 responses in periapical cysts by assessing the presence of M2 macrophages, as well as acute IL-1 β, TNF-α and IL-6 cytokines. Twenty-four cases of periapical cysts were selected. Immuno-expressions of IL-1 β, IL-6, TNF-α and CD163 were analysed in the cystic capsules in both superficial and deeper regions. Data were analysed with paired Wilcoxon test and Spearman correlation coefficient (P ≤ 0.05). There was a higher expression of IL-1β, IL-6, TNF-α and M2 macrophages in the superficial region (P < 0.001) of cystic capsules. All acute cytokines had significant positive correlations amongst them regardless of the cystic capsule region. Regarding CD163, positive correlations occurred only with TNF-α (P = 0.007; r = 0.537) and IL-6 (P = 0.018; r = 0.478) in the superficial regions of the cystic capsule. M2 macrophages participated actively in the inflammatory response of periapical cysts and correlated with the expression of certain acute Th1-related cytokines. This illustrates the coexistence of an acute and chronic Th2-driven immune response in these lesions. Although M2 macrophages favour the healing process, their presence is not sufficient for periapical cyst regression, once an acute active response has occurred due to an infectious stimuli. © 2017 International Endodontic Journal. Published by John Wiley & Sons Ltd.

Immunoglobulin M (IgM)-Glycoinositolphospholipid Enzyme-Linked Immunosorbent Assay: an Immunoenzymatic Assay for Discrimination between Patients with Acute Toxoplasmosis and Those with Persistent Parasite-Specific IgM Antibodies

PubMed Central

Giraldo, Mónica; Portela, Ricardo W. D.; Snege, Mirian; Leser, Paulo G.; Camargo, Mário E.; Mineo, José Roberto; Gazzinelli, Ricardo T.

2002-01-01

In the present study we developed an enzyme-linked immunosorbent assay (ELISA) to measure immunoglobulin M (IgM) specific for glycoinositolphospholipids (GIPL) derived from tachyzoite membrane (IgM-GIPL ELISA). The sensitivity and specificity of the assay were compared with those of commercially available Toxoplasma-specific IgM serological tests, namely, immunofluorescence assay (IFA) with fixed tachyzoites and capture ELISA employing tachyzoite extracts. Our results show that all patients with acute toxoplasmosis, as determined by clinical data and conventional serological tests, were also positive by the IgM-GIPL ELISA. Interestingly, many patients that were classified as indeterminate, who had IgG with high avidity but positive results in the IgM-specific IFA and capture ELISA, were negative by the IgM-GIPL ELISA. Finally, we tested the sera from patients with rheumatoid arthritis and various parasitic infections and found no evidence of false positives in the IgM-GIPL ELISA. PMID:11923364

The combination of urinary IL - 6 and renal biometry as useful diagnostic tools to differentiate acute pyelonephritis from lower urinary tract infection.

PubMed

Azab, Sherif; Zakaria, Mostafa; Raafat, Mona; Seief, Hadeel

2016-01-01

To evaluate the role of renal ultrasound (RUS) and urinary IL-6 in the differentiation between acute pyelonephritis (APN) and lower urinary tract infection (LUTI). This prospective study was carried out at the Pediatric and urology outpatient and inpatient departments of Cairo University Children's Hospital as well as October 6 University Hospital and it included 155 children between one month and fourteen years old with positive culture UTI. Patients were categorized into APN and LUTI based on their clinical features and laboratory parameters. Thirty healthy children, age and sex matched constituted the control group. Children with positive urine cultures were treated with appropriate antibiotics. Before treatment, urinary IL-6 was measured by enzyme immunoassay technique (ELISA), and renal ultrasound (RUS) was done. CRP (C-reactive protein), IL-6 and RUS were repeated on the 14th day of antibiotic treatment to evaluate the changes in their levels in response to treatment. UIL-6 levels were more significantly higher in patients with APN than in patients with LUTI (24.3±19.3pg/mL for APN vs. 7.3±2.7pg/mL in LUTI (95% CI: 2.6-27.4; p< 0.01). Similarly, serum CRP was more significantly higher in patients with APN than in children with LUTI (19.7±9.1μg/mL vs. 5.5±2.3μg/mL (p< 0.01). IL-6 levels >20pg/mL and serum CRP >20μg/mL were highly reliable markers of APN. Mean renal volume and mean volume difference between the two kidneys in the APN group were more than that of the LUTI and control groups (P< 0.001). Renal volume between 120-130% of normal was the best for differentiating APN from LUTI. RUS and urinary IL-6 levels have a highly dependable role in the differentiation between APN and LUTI especially in places where other investigations are not available and/ or affordable. Copyright© by the International Brazilian Journal of Urology.

An Outbreak of Acute Hepatitis in a Medical Facility of Bangladesh

PubMed Central

Mohammad Fazle Akbar, Sheikh; chandra Podder, Dulal; Kumar Saha, Paban; Jahan, Munira; Begum, Lovely; Afrose, Tanjina; chowdhury, Farzana; Rahman, Salimur

2014-01-01

ABSTRACT A total of 45 patients with acute hepatitis were detected in a medical facility of Bangladesh over a period of 6 months. All of them were physicians, nurses, students or employees of the hospital. About 50% of these patients suffered from acute hepatitis within a period of 2 months. All of them had clinical and biochemical evidences of acute hepatitis. All of them shared common working places as well as common dining and cooking facilities. Although the disease was supposed to be caused by hepatitis viruses, none of them were expressing IgM type antibody to hepatitis B core antigen (IgM anti-HBc) or hepatitis C virus (IgM anti-HCV). IgM type antibody to hepatitis A virus (IgM HAV) was detected in one patient and IgM type antibody to hepatitis E virus (anti-HEV IgM) were found in 14 patients. In conclusion, diagnosis of etiological agent of viral acute hepatitis constitutes a formidable challenge to the existing health care delivery system in developing countries as available serological and routine screening fails to find the proper etiological agent. How to cite this article: Mahtab MA, Akbar SMF, Podder DC, Saha PK, Jahan M, Begum L, Afrose T, Chowdhury F, Rahman S. An Outbreak of Acute Hepatitis in a Medical Facility of Bangladesh. Euroasian J Hepato-Gastroenterol 2014;4(1):66-67. PMID:29264325

An Outbreak of Acute Hepatitis in a Medical Facility of Bangladesh.

PubMed

Al Mahtab, Mamun; Mohammad Fazle Akbar, Sheikh; Chandra Podder, Dulal; Kumar Saha, Paban; Jahan, Munira; Begum, Lovely; Afrose, Tanjina; Chowdhury, Farzana; Rahman, Salimur

2014-01-01

A total of 45 patients with acute hepatitis were detected in a medical facility of Bangladesh over a period of 6 months. All of them were physicians, nurses, students or employees of the hospital. About 50% of these patients suffered from acute hepatitis within a period of 2 months. All of them had clinical and biochemical evidences of acute hepatitis. All of them shared common working places as well as common dining and cooking facilities. Although the disease was supposed to be caused by hepatitis viruses, none of them were expressing IgM type antibody to hepatitis B core antigen (IgM anti-HBc) or hepatitis C virus (IgM anti-HCV). IgM type antibody to hepatitis A virus (IgM HAV) was detected in one patient and IgM type antibody to hepatitis E virus (anti-HEV IgM) were found in 14 patients. In conclusion, diagnosis of etiological agent of viral acute hepatitis constitutes a formidable challenge to the existing health care delivery system in developing countries as available serological and routine screening fails to find the proper etiological agent. How to cite this article: Mahtab MA, Akbar SMF, Podder DC, Saha PK, Jahan M, Begum L, Afrose T, Chowdhury F, Rahman S. An Outbreak of Acute Hepatitis in a Medical Facility of Bangladesh. Euroasian J Hepato-Gastroenterol 2014;4(1):66-67.

A role for the membrane protein M6 in the Drosophila visual system

PubMed Central

2012-01-01

Background Members of the proteolipid protein family, including the four-transmembrane glycoprotein M6a, are involved in neuronal plasticity in mammals. Results from our group previously demonstrated that M6, the only proteolipid protein expressed in Drosophila, localizes to the cell membrane in follicle cells. M6 loss triggers female sterility, which suggests a role for M6 in follicular cell remodeling. These results were the basis of the present study, which focused on the function and requirements of M6 in the fly nervous system. Results The present study identified two novel, tissue-regulated M6 isoforms with variable N- and C- termini, and showed that M6 is the functional fly ortholog of Gpm6a. In the adult brain, the protein was localized to several neuropils, such as the optic lobe, the central complex, and the mushroom bodies. Interestingly, although reduced M6 levels triggered a mild rough-eye phenotype, hypomorphic M6 mutants exhibited a defective response to light. Conclusions Based on its ability to induce filopodium formation we propose that M6 is key in cell remodeling processes underlying visual system function. These results bring further insight into the role of M6/M6a in biological processes involving neuronal plasticity and behavior in flies and mammals. PMID:22762289

Co-occurrence of biphenotypic acute leukaemia, glucose 6-phosphate dehydrogenase deficiency and haemoglobin E trait in a single child.

PubMed

Mallick, Debkrishna; Thapa, Rajoo; Biswas, Biswajit

2016-02-01

Acute leukaemias occur as the result of clonal expansion subsequent to transformation and arrest at a normal differentiation stage of haematopoietic precursors, which commit to a single lineage, such as myeloid or B-lymphoid or T-lymphoid cells. Biphenotypic acute leukaemia (BAL) constitutes a biologically different group of leukaemia arising from a precursor stem cell and co-expressing more than one lineage specific marker. The present report describes a child with unusual co-occurrence of biphenotypic (B-precursor cell and Myeloid) acute leukaemia, haemoglobin E trait and glucose 6-phosphate dehydrogenase (G6-PD) deficiency. To the best of our knowledge, this constellation of haematological conditions in a single child has never been described before. 2016 BMJ Publishing Group Ltd.

[Clinical Efficacy of NOPHO-AML 2004 Regimen for Treatment of Children with Acute Myelocytic Leukemia (Non-M3)].

PubMed

Qiu, Kun-Yin; Liao, Xiong-Yu; Huang, Ke; Li, Yang; Weng, Wen-Jun; Xu, Hong-Gui; Fang, Jian-Pei; Wu, Ruo-Hao; Zhou, Dun-Hua

2018-04-01

To investigate the efficacy and safety of NOPHO-AML 2004 chemotherapy regimen for treatment of children with acute myelocytic leukemia(non-M3). Thirty-three patients aged 1-13 with acute myelocytic leukemia (non-M3) were diagnosed from January 2013 to June 2017. FAB typing showed that 1 case in M0, 4 cases in M1, 12 cases in M2, 5 cases in M4, 8 cases in M5, 1 case in M6, and 2 cases in M7; Risk stratification showed that: 19 cases in standard risk, and 14 cases in high risk. All patients were treated with NOPHO-AML 2004 chemotherapy regimen. SPSS 22.0 software was used, the Kaplan-Meier survival analysis method and Cox regression model were used for statistical analysis. In the first course of treatment (AIET), among 33 child patients there were 27 cases with complete remission, and 5 cases with non-remission, thus the remission rate was 81.8%. Out of the 5 child patients without remission, 4 cases reached to the complete remission after the second course (AM), and 1 case did not remission, thus the total remission rate was 96.9%.9 cases (27.3%) underwent bone marrow recurrence and the median recurrence time was 30 months after complete continuous remission. Univariate analysis showed that age and erythrocyte transfusion frequency were significant factors to affect the early treatment response; the multiple Cox regression analysis showed that: age >7, MRD positive, erythrocyte transfusion >4 times and poor response to early treatment were independent risk factors for recurrence; Allogeneic hematopoietic stem cell transplantation(HSCT) in 8 high-risk children received enhanced chemotherapy had better efficacy as compared with the chemotherapy alone. The 3-year event-free survival rate was 59.9%, and 3-year overall survival rate was 69.2%. 33 children patients experienced varying degrees of infection and myelosuppression, or drug-related gastrointestinal reactions and allergic reactions, patients were tolerable to these side reactions after active symptomatic

Administration of human recombinant activated protein C is not associated with pancreatic parenchymal haemorrhage in L-arginine-induced experimental acute pancreatitis.

PubMed

Jamdar, Saurabh; Babu, Benoy I; Nirmalan, Mahesh; Jeziorska, Maria; McMahon, Raymond F T; Siriwardena, Ajith K

2013-11-10

Microvascular thrombosis is a critical event in severe acute pancreatitis. Human recombinant activated protein C (Xigris®, Eli Lilly, Indianapolis, IN, USA) modulates the interplay between pro-inflammatory and pro-coagulant pathways and maintains microvascular patency. However, the anticoagulant properties of Xigris® may precipitate bleeding from the inflamed pancreas. This study tests the hypothesis that Xigris® can ameliorate experimental acute pancreatitis without causing pancreatic haemorrhage. Sprague Dawley rats were allocated as follows: Group 1: control (n=7); Group 2: acute pancreatitis (n=6); Group 3: administration of Xigris® 500 µg/kg body weight before induction of acute pancreatitis (n=6); and Group 4: Administration of Xigris® 500 µg/kg body weight 30 minutes after induction of acute pancreatitis (n=6). Acute pancreatitis was induced by intraperitoneal administration of L-arginine 300 mg/100 g body weight. Animals were sacrificed at 48 hours and biochemical, haematological, and histological markers of pancreatic haemorrhage and inflammation assessed. Median lipase in animals with acute pancreatitis was 10 U/mL (range: 7-16 U/mL) compared to 5.5 (range: 3-8 U/mL) in controls (P=0.028). Lipase was also elevated in animals given Xigris® both before (12 U/mL, range: 8-22 U/mL; P=0.031 vs. control group) and after (46 U/mL, range: 9-71 U/mL; P=0.015 vs. control group) induction of acute pancreatitis). Haemoglobin levels were similar among all groups (P=0.323). There was no histological evidence of pancreatic haemorrhage in animals treated with Xigris®. Pre-treatment with Xigris® was associated with a significant reduction in pancreatic injury. This effect was absent when Xigris® was administered after induction of acute pancreatitis. Xigris® did not lead to pancreatic haemorrhage in experimental acute pancreatitis. Administration of Xigris® prior to induction of acute pancreatitis was associated with amelioration of injury. This effect was

Acute toxicity of 6 neonicotinoid insecticides to freshwater invertebrates.

PubMed

Raby, Melanie; Nowierski, Monica; Perlov, Dmitri; Zhao, Xiaoming; Hao, Chunyan; Poirier, David G; Sibley, Paul K

2018-05-01

Neonicotinoids are a group of insecticides commonly used in agriculture. Due to their high water solubility, neonicotinoids can be transported to surface waters and have the potential to be toxic to aquatic life. The present study assessed and compared the acute (48- or 96-h) toxicity of 6 neonicotinoids (acetamiprid, clothianidin, dinotefuran, imidacloprid, thiacloprid, and thiamethoxam) to 21 laboratory-cultured and field-collected aquatic invertebrates spanning 10 aquatic arthropod orders. Test conditions mimicked species' habitat, with lentic taxa exposed under static conditions, and lotic taxa exposed under recirculating systems. Median lethal concentrations (LC50s) and median effect concentrations (EC50s; immobility) were calculated and used to construct separate lethal- and immobilization-derived species sensitivity distributions for each neonicotinoid, from which 5th percentile hazard concentrations (HC5s) were calculated. The results showed that the most sensitive invertebrates were insects from the orders Ephemeroptera (Neocloeon triangulifer) and Diptera (Chironomus dilutus), whereas cladocerans (Daphnia magna, Ceriodaphnia dubia) were the least sensitive. The HC5s were compared with neonicotinoid environmental concentrations from Ontario (Canada) monitoring studies. For all neonicotinoids except imidacloprid, the resulting hazard quotients indicated little to no hazard in terms of acute toxicity to aquatic communities in Ontario freshwater streams. For the neonicotinoid imidacloprid, a moderate hazard was found when only invertebrate immobilization, and not lethality, data were considered. Environ Toxicol Chem 2018;37:1430-1445. © 2018 SETAC. © 2018 SETAC.

Epigallocatechin gallate targets FTO and inhibits adipogenesis in an mRNA m6A-YTHDF2-dependent manner.

PubMed

Wu, Ruifan; Yao, Yongxi; Jiang, Qin; Cai, Min; Liu, Qing; Wang, Yizhen; Wang, Xinxia

2018-05-24

N 6 -methyladenosine (m 6 A) modification of mRNA plays a role in regulating adipogenesis. However, its underlying mechanism remains largely unknown. Epigallocatechin gallate (EGCG), the most abundant catechin in green tea, plays a critical role in anti-obesity and anti-adipogenesis. High-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (HPLC-QqQ-MS/MS) was performed to determine the m 6 A levels in 3T3-L1 preadipocytes. The effects of EGCG on the m 6 A levels in specific genes were determined by methylated RNA immunoprecipitation coupled with quantitative real-time PCR (meRIP-qPCR). Several adipogenesis makers and cell cycle genes were analyzed by quantitative real-time PCR (qPCR) and western blotting. Lipid accumulation was evaluated by oil red O staining. All measurements were performed at least for three times. Here we showed that EGCG inhibited adipogenesis by blocking the mitotic clonal expansion (MCE) at the early stage of adipocyte differentiation. Exposing 3T3-L1 cells to EGCG reduced the expression of fat mass and obesity-associated (FTO) protein, an m 6 A demethylase, which led to increased overall levels of RNA m 6 A methylation. Cyclin A2 (CCNA2) and cyclin dependent kinase 2 (CDK2) play vital roles in MCE. The m 6 A levels of CCNA2 and CDK2 mRNA were dramatically enhanced by EGCG. Interestingly, EGCG increased the expression of YTH N 6 -methyladenosine RNA binding protein 2 (YTHDF2), which recognized and decayed methylated mRNAs, resulting in decreased protein levels of CCNA2 and CDK2. As a result, MCE was blocked and adipogenesis was inhibited. FTO overexpression and YTHDF2 knockdown in 3T3-L1 cells significantly increased CCNA2 and CDK2 protein levels and ameliorated the EGCG-induced adipogenesis inhibition. Thus, m 6 A-dependent CCNA2 and CDK2 expressions mediated by FTO and YTHDF2 contributed to EGCG-induced adipogenesis inhibition. Our findings provide mechanistic insights into how m 6 A is involved in the

Acute Penicillium marneffei infection stimulates host M1/M2a macrophages polarization in BALB/C mice.

PubMed

Dai, Xiaoying; Mao, Congzheng; Lan, Xiuwan; Chen, Huan; Li, Meihua; Bai, Jing; Deng, Jingmin; Liang, Qiuli; Zhang, Jianquan; Zhong, Xiaoning; Liang, Yi; Fan, Jiangtao; Luo, Honglin; He, Zhiyi

2017-08-18

Penicillium marneffei (P. marneffei) is a thermally dimorphic fungus pathogen that causes fatal infection. Alveolar macrophages are innate immune cells that have critical roles in protection against pulmonary fungal pathogens and the macrophage polarization state has the potential to be a deciding factor in disease progression or resolution. The aim of this study was to investigate mouse alveolar macrophage polarization states during P. marneffei infection. We used enzyme-linked immunosorbent (ELISA) assays, quantitative real-time PCR (qRT-PCR), and Griess, arginase activity to evaluate the phenotypic markers of alveolar macrophages from BALB/C mice infected with P. marneffei. We then treated alveolar macrophages from infected mice with P. marneffei cytoplasmic yeast antigen (CYA) and investigated alveolar macrophage phenotypic markers in order to identify macrophage polarization in response to P. marneffei antigens. Our results showed: i) P. marneffei infection significantly enhanced the expression of classically activated macrophage (M1)-phenotypic markers (inducible nitric oxide synthase [iNOS] mRNA, nitric oxide [NO], interleukin-12 [IL-12], tumor necrosis factor-alpha [TNF-α]) and alternatively activated macrophage (M2a)-phenotypic markers (arginase1 [Arg1] mRNA, urea) during the second week post-infection. This significantly decreased during the fourth week post-infection. ii) During P. marneffei infection, CYA stimulation also significantly enhanced the expression of M1 and M2a-phenotypic markers, consistent with the results for P. marneffei infection and CYA stimulation preferentially induced M1 subtype. The data from the current study demonstrated that alveolar macrophage M1/M2a subtypes were present in host defense against acute P. marneffei infection and that CYA could mimic P. marneffei to induce a host immune response with enhanced M1 subtype. This could be useful for investigating the enhancement of host anti-P. marneffei immune responses and to

Corneal tissue ablation using 6.1 μm quantum cascade laser

NASA Astrophysics Data System (ADS)

Huang, Yong; Kang, Jin U.

2012-03-01

High absorption property of tissues in the IR range (λ> 2 μm) results in effective tissue ablation, especially near 3 μm. In the mid-infrared range, wavelengths of 6.1 μm and 6.45 μm fall into the absorption bands of the amide protein groups Amide-I and Amide-II, respectively. They also coincide with the deformation mode of water, which has an absorption peak at 6.1 μm. This coincidence makes 6.1 μm laser a better ablation tool that has promising effectiveness and minimum collateral damages than 3 μm lasers. In this work, we performed bovine corneal ablation test in-vitro using high-power 6.1μm quantum cascade laser (QCL) operated at pulse mode. Quantum cascade laser has the advantages of low cost, compact size and tunable wavelength, which makes it great alternative Mid-IR light source to conventional tunable free-electron lasers (FEL) for medical applications. Preliminary results show that effective corneal stroma craters were achieved with much less collateral damage in corneal tissue that contains less water. Future study will focus on optimizing the control parameters of QCL to attain neat and precise ablation of corneal tissue and development of high peak power QCL.

Chronic resuscitation after trauma-hemorrhage and acute fluid replacement improves hepatocellular function and cardiac output.

PubMed

Remmers, D E; Wang, P; Cioffi, W G; Bland, K I; Chaudry, I H

1998-01-01

To determine whether prolonged (chronic) resuscitation has any beneficial effects on cardiac output and hepatocellular function after trauma-hemorrhage and acute fluid replacement. Acute fluid resuscitation after trauma-hemorrhage restores but does not maintain the depressed hepatocellular function and cardiac output. Male Sprague-Dawley rats underwent a 5-cm laparotomy (i.e., trauma was induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximal bleed-out volume was returned in the form of Ringer's lactate (RL). The animals were acutely resuscitated with RL using 4 times the volume of maximum bleed-out over 60 minutes, followed by chronic resuscitation of 0, 5, or 10 mL/kg/hr RL for 20 hours. Hepatocellular function was determined by an in vivo indocyanine green clearance technique. Hepatic microvascular blood flow was assessed by laser Doppler flowmetry. Plasma levels of interleukin-6 (IL-6) were determined by bioassay. Chronic resuscitation with 5 mL/kg/hr RL, but not with 0 or 10 mL/kg/hr RL, restored cardiac output, hepatocellular function, and hepatic microvascular blood flow at 20 hours after hemorrhage. The regimen above also reduced plasma IL-6 levels. Because chronic resuscitation with 5 mL/kg/hr RL after trauma-hemorrhage and acute fluid replacement restored hepatocellular function and hepatic microvascular blood flow and decreased plasma levels of IL-6, we propose that chronic fluid resuscitation in addition to acute fluid replacement should be routinely used in experimental studies of trauma-hemorrhage.

AthMethPre: a web server for the prediction and query of mRNA m6A sites in Arabidopsis thaliana.

PubMed

Xiang, Shunian; Yan, Zhangming; Liu, Ke; Zhang, Yaou; Sun, Zhirong

2016-10-18

N 6 -Methyladenosine (m 6 A) is the most prevalent and abundant modification in mRNA that has been linked to many key biological processes. High-throughput experiments have generated m 6 A-peaks across the transcriptome of A. thaliana, but the specific methylated sites were not assigned, which impedes the understanding of m 6 A functions in plants. Therefore, computational prediction of mRNA m 6 A sites becomes emergently important. Here, we present a method to predict the m 6 A sites for A. thaliana mRNA sequence(s). To predict the m 6 A sites of an mRNA sequence, we employed the support vector machine to build a classifier using the features of the positional flanking nucleotide sequence and position-independent k-mer nucleotide spectrum. Our method achieved good performance and was applied to a web server to provide service for the prediction of A. thaliana m 6 A sites. The server also provides a comprehensive database of predicted transcriptome-wide m 6 A sites and curated m 6 A-seq peaks from the literature for query and visualization. The AthMethPre web server is the first web server that provides a user-friendly tool for the prediction and query of A. thaliana mRNA m 6 A sites, which is freely accessible for public use at .

Motor-neuron pool excitability of the lower leg muscles after acute lateral ankle sprain.

PubMed

Klykken, Lindsey W; Pietrosimone, Brian G; Kim, Kyung-Min; Ingersoll, Christopher D; Hertel, Jay

2011-01-01

Neuromuscular deficits in leg muscles that are associated with arthrogenic muscle inhibition have been reported in people with chronic ankle instability, yet whether these neuromuscular alterations are present in individuals with acute sprains is unknown. To compare the effect of acute lateral ankle sprain on the motor-neuron pool excitability (MNPE) of injured leg muscles with that of uninjured contralateral leg muscles and the leg muscles of healthy controls. Case-control study. Laboratory. Ten individuals with acute ankle sprains (6 females, 4 males; age= 19.2 ± 3.8 years, height= 169.4 ± 8.5 cm, mass= 66.3 ± 11.6 kg) and 10 healthy individuals(6 females,4 males; age= 20.6 ± 4.0 years, height = 169.9 ± 10.6 cm, mass= 66.3 ± 10.2 kg) participated. The independent variables were group (acute ankle sprain, healthy) and limb (injured, uninjured). Separate dependent t tests were used to determine differences in MNPE between legs. The MNPE of the soleus, fibularis longus, and tibialis anterior was measured by the maximal Hoffmann reflex (H(max)) and maximal muscle response (M(max)) and was then normalized using the H(max):M(max) ratio. The soleus MNPE in the ankle-sprain group was higher in the injured limb (H(max):M(max) = 0.63; 95% confidence interval [Cl],0.46, 0.80) than the uninjured limb (H(max):M(max) = 0.47; 95%Cl, 0.08, 0.93)(t(6) = 3.62,P =.01).In the acute ankle-sprain group, tibialis anterior MNPE tended to be lower in the injured ankle (H(max):M(max) =0.06; 95% Cl, 0.01, 0.10) than in the uninjured ankle (H(max):M(max) =0.22; 95%Cl, 0.09, 0.35),but this finding was not different (t(9) =-2.01, P =.07). No differences were detected between injured (0.22; 95% Cl, 0.14, 0.29) and uninjured (0.25; 95%Cl, 0.12, 0.38) ankles for the fibularis longus in the ankle-sprain group (t(9) =-0.739, P =.48). We found no side-to-side differences in any muscle among the healthy group. Facilitated MNPE was present in the involved soleus muscle of patients with acute

6-mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia.

PubMed

Schmiegelow, K; Bretton-Meyer, U

2001-01-01

Through inhibition of purine de novo synthesis and enhancement of 6-mercaptopurine (6MP) bioavailability high-dose methotrexate (HDM) may increase the incorporation into DNA of 6-thioguanine nucleotides (6TGN), the cytoxic metabolites of 6MP. Thus, coadministration of 6MP could increase myelotoxicity following HDM. Twenty-one children with standard risk (SR) and 25 with intermediate risk (IR) acute lymphoblastic leukemia (ALL) were studied. During consolidation therapy they received either three courses of HDM at 2 week intervals without concurrent oral 6MP (SR-ALL) or four courses of HDM given at 2 week intervals with 25 mg/m2 of oral 6MP daily (IR-ALL). During the first year of maintenance with oral 6MP (75 mg/m2/day) and oral MTX (20 mg/m2/week) they all received five courses of HDM at 8 week intervals. In all cases, HDM consisted of 5,000 mg of MTX/m2 given over 24 h with intraspinal MTX and leucovorin rescue. Erythrocyte levels of 6TGN (E-6TGN) and methotrexate (E-MTX) were, on average, measured every second week during maintenance therapy. When SR consolidation (6MP: 0 mg), IR consolidation (6MP: 25 mg/m2), and SR/IR maintenance therapy (6MP: 75 mg/m2) were compared, white cell and absolute neutrophil count (ANC) nadir, lymphocyte count nadir, thrombocyte count nadir, and hemoglobin nadir after HDM decreased significantly with increasing doses of oral 6MP. Three percent of the HDM courses given without oral 6MP (SR consolidation) were followed by an ANC nadir <0.5 x 10(9)/l compared to 50% of the HDM courses given during SR/IR maintenance therapy. Similarly, only 13% of the HDM courses given as SR-ALL consolidation induced a thrombocyte count nadir <100 x 10(9)/l compared to 58% of the HDM courses given during maintenance therapy. The best-fit model to predict the ANC nadir following HDM during maintenance therapy included the dose of 6MP prior to HDM (beta = -0.017, P= 0.001), the average ANC level during maintenance therapy (beta = 0.82, P = 0.004), and E-6

Acute high-intensity interval exercise induces comparable levels of circulating cell-free DNA and Interleukin-6 in obese and normal-weight individuals.

PubMed

Ferrandi, Peter J; Fico, Brandon G; Whitehurst, Michael; Zourdos, Michael C; Bao, Fanchen; Dodge, Katelyn M; Rodriguez, Alexandra L; Pena, Gabriel; Huang, Chun-Jung

2018-06-01

Obesity is associated with lipid aggregation in adipocytes and macrophage infiltration, leading to increased oxidative stress and inflammation. Increased cell-free DNA (cfDNA) concentrations have been observed in clinical conditions of systemic inflammation. While the beneficial effects of regular physical activity on the release of circulating cfDNA still remain unknown, acute intense exercise has been shown to increase inflammatory cytokines and cfDNA concentrations in normal-weight individuals. Therefore, the primary purpose of this study was to examine the effect of acute high-intensity interval Exercise (HIIE) on plasma cfDNA and interleukin-6 (IL-6) responses in obese and normal-weight subjects. Fourteen male subjects (7 obese and 7 normal-weight) participated in an acute HIIE protocol (30 min, 4x4min @ 80% - 90% of VO 2max ) on a treadmill. Between HIIE intervals, subjects performed 3 min of active recovery at 50-60% VO 2max . Blood samples were collected prior to, immediately following exercise, and one hour into recovery for measurements of plasma cfDNA and IL-6. Our results demonstrated a significant elevation in plasma cfDNA immediately following acute HIIE in both obese and normal-weight subjects. A comparable elevation in the concentration of plasma IL-6 was also found between two groups in response to acute HIIE. Furthermore, the level of plasma cfDNA was not correlated with IL-6 either at baseline or in response to acute HIIE. These findings may support the utilization of HIIE as a time-efficient exercise protocol to understand the obesity-associated cfDNA and inflammatory responses. Published by Elsevier Inc.

Glucose-6-phosphate dehydrogenase deficiency: an unusual cause of acute jaundice after paracetamol overdose.

PubMed

Phillpotts, Simon; Tash, Elliot; Sen, Sambit

2014-11-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest human enzyme defect causing haemolytic anaemia after exposure to specific triggers. Paracetamol-induced haemolysis in G6PD deficiency is a rare complication and mostly reported in children. We report the first case (to the best of our knowledge) of acute jaundice without overt clinical features of a haemolytic crisis, in an otherwise healthy adult female following paracetamol overdose, due to previously undiagnosed G6PD deficiency. It is important that clinicians consider this condition when a patient presents following a paracetamol overdose with significant and disproportionate jaundice, without transaminitis or coagulopathy. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Early blood pressure lowering treatment in acute stroke. Ordinal analysis of vascular events in the Scandinavian Candesartan Acute Stroke Trial (SCAST).

PubMed

Jusufovic, Mirza; Sandset, Else Charlotte; Bath, Philip M; Berge, Eivind

2016-08-01

Early blood pressure-lowering treatment appears to be beneficial in patients with acute intracerebral haemorrhage and potentially in ischaemic stroke. We used a new method for analysis of vascular events in the Scandinavian Candesartan Acute Stroke Trial to see if the effect was dependent on the timing of treatment. Scandinavian Candesartan Acute Stroke Trial was a randomized controlled and placebo-controlled trial of candesartan within 30 h of ischaemic or haemorrhagic stroke. Of 2029 patients, 231 (11.4%) had a vascular event (vascular death, nonfatal stroke or nonfatal myocardial infarction) during the first 6 months. The modified Rankin Scale (mRS) score following a vascular event was used to categorize vascular events in order of severity: no event (n = 1798), minor (mRS 0-2, n = 59), moderately severe (mRS 3-4, n = 57) and major event (mRS 5-6, n = 115). We used ordinal logistic regression for analysis and adjusted for predefined prognostic variables. Candesartan had no overall effect on vascular events (adjusted common odds ratio 1.11, 95% confidence interval 0.84-1.47, P = 0.48), and the effects were the same in ischaemic and haemorrhagic stroke. Among the patients treated within 6 h, the adjusted common odds ratio for vascular events was 0.37, 95% confidence interval 0.16-0.84, P = 0.02, and there was no heterogeneity of effect between ischaemic and haemorrhagic strokes. Ordinal analysis of vascular events showed no overall effect of candesartan in the subacute phase of stroke. The effect of treatment given within 6 h of stroke onset appears promising, and will be addressed in ongoing trials. Ordinal analysis of vascular events is feasible and can be used in future trials.

YKL-40 expression in CD14+ liver cells in acute and chronic injury

PubMed Central

Pizano-Martínez, Oscar; Yañez-Sánchez, Irinea; Alatorre-Carranza, Pilar; Miranda-Díaz, Alejandra; Ortiz-Lazareno, Pablo C; García-Iglesias, Trinidad; Daneri-Navarro, Adrian; Mercado, Mónica Vázquez-Del; Fafutis-Morris, Mary; Delgado-Rizo, Vidal

2011-01-01

AIM: To demonstrate that CD14+ cells are an important source of the growth factor YKL-40 in acute and chronic liver damage. METHODS: Rats were inoculated with one dose of CCl4 to induce acute damage. Liver biopsies were obtained at 0, 6, 12, 24, 48 and 72 h. For chronic damage, CCl4 was administered three days per week for 6 or 8 wk. Tissue samples were collected, and cellular populations were isolated by liver digestion and purified by cell sorting. YKL-40 mRNA and protein expression were evaluated by real-time polymerase chain reaction and western blot. RESULTS: Acute liver damage induced a rapid increase of YKL-40 mRNA beginning at 12 h. Expression peaked at 24 h, with a 26-fold increase over basal levels. By 72 h however, YKL-40 expression levels had nearly returned to control levels. On the other hand, chronic damage induced a sustained increase in YKL-40 expression, with 7- and 9-fold higher levels at 6 and 8 wk, respectively. The pattern of YKL-40 expression in different subpopulations showed that CD14+ cells, which include Kupffer cells, are a source of YKL-40 after acute damage at 72 h [0.09 relative expression units (REU)] as well as after chronic injury at 6 wk (0.11 REU). Hepatocytes, in turn, accounted for 0.06 and 0.01 REU after 72 h (acute) or 6 wk (chronic), respectively. The rest of the CD14- cells (including T lymphocytes, B lymphocytes, natural killer and natural killer T cells) yielded 0.07 and 0.15 REU at 72 h and 6 wk, respectively. YKL-40 protein expression in liver was detected at 72 h as well as 6 and 8 wk, with the highest expression relative to controls (11-fold; P ≤ 0.05) seen at 6 wk. Macrophages were stimulated by lipopolysaccharide. We demonstrate that under these conditions, these cells showed maximum expression of YKL-40 at 12 h, with P < 0.05 compared with controls. CONCLUSION: Hepatic CD14+ cells are an YKL-40 mRNA and protein source in acute and chronic liver injury, with expression patterns similar to growth factors implicated

Direct suppressive effect of acute metabolic and respiratory alkalosis on parathyroid hormone secretion in the dog.

PubMed

Lopez, Ignacio; Rodriguez, Mariano; Felsenfeld, Arnold J; Estepa, Jose Carlos; Aguilera-Tejero, Escolastico

2003-08-01

Acute alkalosis may directly affect PTH secretion. The effect of acute metabolic and respiratory alkalosis was studied in 20 dogs. PTH values were lower in the metabolic (5.6 +/- 0.8 pg/ml) and respiratory (1.8 +/- 0.6 pg/ml) alkalosis groups than in the control group (27 +/- 5 pg/ml). Acute alkalosis is an independent factor that decreases PTH values during normocalcemia and delays the PTH response to hypocalcemia. We recently showed that acute metabolic and respiratory acidosis stimulated PTH secretion. This study was designed to evaluate whether acute metabolic and respiratory alkalosis suppressed parathyroid hormone (PTH) secretion. Three groups of 10 dogs were studied: control, acute metabolic alkalosis, and acute respiratory alkalosis. Metabolic alkalosis was induced with an infusion of sodium bicarbonate and respiratory alkalosis by hyperventilation. Calcium chloride was infused to prevent alkalosis-induced hypocalcemia during the first 60 minutes. During the next 30 minutes, disodium EDTA was infused to induce hypocalcemia and to evaluate the PTH response to hypocalcemia. Because the infusion of sodium bicarbonate resulted in hypernatremia, the effect of hypernatremia was studied in an additional group that received hypertonic saline. After 60 minutes of a normocalcemic clamp, PTH values were less (p < 0.05) in the metabolic (5.6 +/- 0.8 pg/ml) and respiratory (1.8 +/- 0.6 pg/ml) alkalosis groups than in the control group (27 +/- 5 pg/ml); the respective blood pH values were 7.61 +/- 0.01, 7.59 +/- 0.02, and 7.39 +/- 0.02. The maximal PTH response to hypocalcemia was similar among the three groups. However, the maximal PTH response was observed after a decrease in ionized calcium of 0.20 mM in the control group but not until a decrease of 0.40 mM in the metabolic and respiratory alkalosis groups. In contrast to the metabolic alkalosis group, hypernatremia (157 +/- 2 mEq/liter) in the hypertonic saline group was associated with an increased PTH value (46

Role of loop L5-6 connecting transmembrane segments M5 and M6 in biogenesis and functioning of yeast Pma1 H+-ATPase.

PubMed

Petrov, V V

2015-01-01

The L5-6 loop is a short extracytoplasmic stretch (714-DNSLDID) connecting transmembrane segments M5 and M6 and forming along with segments M4 and M8 the core through which cations are transported by H+-, Ca2+-, K+,Na+-, H+,K+-, and other P2-ATPases. To study structure-function relationships within this loop of the yeast plasma membrane Pma1 H+-ATPase, alanine- and cysteine-scanning mutagenesis has been employed. Ala and Cys substitutions for the most conserved residue (Leu717) led to complete block in biogenesis preventing the enzyme from reaching secretory vesicles. The Ala replacement at Asp714 led to five-fold decrease in the mutant expression and loss of its activity, while the Cys substitution blocked biogenesis completely. Replacements of other residues did not lead to loss of enzymatic activity. Additional replacements were made for Asp714 and Asp720 (Asp®Asn/Glu). Of the substitutions made at Asp714, only D714N partially restored the mutant enzyme biogenesis and functioning. However, all mutant enzymes with substituted Asp720 were active. The expressed mutants (34-95% of the wild-type level) showed activity high enough (35-108%) to be analyzed in detail. One of the mutants (I719A) had three-fold reduced coupling ratio between ATP hydrolysis and H+ transport; however, the I719C mutation was rather indistinguishable from the wild-type enzyme. Thus, substitutions at two of the seven positions seriously affected biogenesis and/or functioning of the enzyme. Taken together, these results suggest that the M5-M6 loop residues play an important role in protein stability and function, and they are probably responsible for proper arrangement of transmembrane segments M5 and M6 and other domains of the enzyme. This might also be important for the regulation of the enzyme.

Far-infrared laser diagnostics on the HT-6M tokamak

NASA Astrophysics Data System (ADS)

Gao, X.; Lu, H. J.; Guo, Q. L.; Wan, Y. X.; Tong, X. D.

1995-01-01

A multichannel far-infrared (FIR) hydrogen cyanide (HCN) laser interferometer was developed to measure plasma electron density profile on the HT-6M tokamak. The structure of the seven-channel FIR laser interferometer is described. The laser source used in the interferometer was a continuous-wave glow discharge HCN laser with a cavity length of 3.4 m and power output of about 100 mW at 337 μm. The detection sensitivity was 1/15 fringe with a temporal resolution of 0.1 ms. Experimental results were measured by the seven-channel FIR HCN laser interferometer with edge Ohmic heating, a pumping limiter, and ion cyclotron resonant heating on the HT-6M tokamak are reported.

Factor H binds to the hypervariable region of many Streptococcus pyogenes M proteins but does not promote phagocytosis resistance or acute virulence.

PubMed

Gustafsson, Mattias C U; Lannergård, Jonas; Nilsson, O Rickard; Kristensen, Bodil M; Olsen, John E; Harris, Claire L; Ufret-Vincenty, Rafael L; Stålhammar-Carlemalm, Margaretha; Lindahl, Gunnar

2013-01-01

Many pathogens express a surface protein that binds the human complement regulator factor H (FH), as first described for Streptococcus pyogenes and the antiphagocytic M6 protein. It is commonly assumed that FH recruited to an M protein enhances virulence by protecting the bacteria against complement deposition and phagocytosis, but the role of FH-binding in S. pyogenes pathogenesis has remained unclear and controversial. Here, we studied seven purified M proteins for ability to bind FH and found that FH binds to the M5, M6 and M18 proteins but not the M1, M3, M4 and M22 proteins. Extensive immunochemical analysis indicated that FH binds solely to the hypervariable region (HVR) of an M protein, suggesting that selection has favored the ability of certain HVRs to bind FH. These FH-binding HVRs could be studied as isolated polypeptides that retain ability to bind FH, implying that an FH-binding HVR represents a distinct ligand-binding domain. The isolated HVRs specifically interacted with FH among all human serum proteins, interacted with the same region in FH and showed species specificity, but exhibited little or no antigenic cross-reactivity. Although these findings suggested that FH recruited to an M protein promotes virulence, studies in transgenic mice did not demonstrate a role for bound FH during acute infection. Moreover, phagocytosis tests indicated that ability to bind FH is neither sufficient nor necessary for S. pyogenes to resist killing in whole human blood. While these data shed new light on the HVR of M proteins, they suggest that FH-binding may affect S. pyogenes virulence by mechanisms not assessed in currently used model systems.

Factor H Binds to the Hypervariable Region of Many Streptococcus pyogenes M Proteins but Does Not Promote Phagocytosis Resistance or Acute Virulence

PubMed Central

Kristensen, Bodil M.; Olsen, John E.; Harris, Claire L.; Ufret-Vincenty, Rafael L.; Stålhammar-Carlemalm, Margaretha; Lindahl, Gunnar

2013-01-01

Many pathogens express a surface protein that binds the human complement regulator factor H (FH), as first described for Streptococcus pyogenes and the antiphagocytic M6 protein. It is commonly assumed that FH recruited to an M protein enhances virulence by protecting the bacteria against complement deposition and phagocytosis, but the role of FH-binding in S. pyogenes pathogenesis has remained unclear and controversial. Here, we studied seven purified M proteins for ability to bind FH and found that FH binds to the M5, M6 and M18 proteins but not the M1, M3, M4 and M22 proteins. Extensive immunochemical analysis indicated that FH binds solely to the hypervariable region (HVR) of an M protein, suggesting that selection has favored the ability of certain HVRs to bind FH. These FH-binding HVRs could be studied as isolated polypeptides that retain ability to bind FH, implying that an FH-binding HVR represents a distinct ligand-binding domain. The isolated HVRs specifically interacted with FH among all human serum proteins, interacted with the same region in FH and showed species specificity, but exhibited little or no antigenic cross-reactivity. Although these findings suggested that FH recruited to an M protein promotes virulence, studies in transgenic mice did not demonstrate a role for bound FH during acute infection. Moreover, phagocytosis tests indicated that ability to bind FH is neither sufficient nor necessary for S. pyogenes to resist killing in whole human blood. While these data shed new light on the HVR of M proteins, they suggest that FH-binding may affect S. pyogenes virulence by mechanisms not assessed in currently used model systems. PMID:23637608

Multiple lipopolysaccharide (LPS) injections alter interleukin 6 (IL-6), IL-7, IL-10 and IL-6 and IL-7 receptor mRNA in CNS and spleen.

PubMed

Szot, Patricia; Franklin, Allyn; Figlewicz, Dianne P; Beuca, Timothy Petru; Bullock, Kristin; Hansen, Kim; Banks, William A; Raskind, Murray A; Peskind, Elaine R

2017-07-04

Neuroinflammation is proposed to be an important component in the development of several central nervous system (CNS) disorders including depression, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. However, exactly how neuroinflammation leads to, or contributes to, these central disorders is unclear. The objective of the study was to examine and compare the expression of mRNAs for interleukin-6 (IL-6), IL-7, IL-10 and the receptors for IL-6 (IL-6R) and IL-7 (IL-7R) using in situ hybridization in discrete brain regions and in the spleen after multiple injections of 3mg/kg lipopolysaccharide (LPS), a model of neuroinflammation. In the spleen, LPS significantly elevated IL-6 mRNA expression, then IL-10 mRNA, with no effect on IL-7 or IL-7R mRNA, while significantly decreasing IL-6R mRNA expression. In the CNS, LPS administration had the greatest effect on IL-6 and IL-6R mRNA. LPS increased IL-6 mRNA expression only in non-neuronal cells throughout the brain, but significantly elevated IL-6R mRNA in neuronal populations, where observed, except the cerebellum. LPS resulted in variable effects on IL-10 mRNA, and had no effect on IL-7 or IL-7R mRNA expression. These studies indicate that LPS-induced neuroinflammation has substantial but variable effects on the regional and cellular patterns of CNS IL-6, IL-7 and IL-10, and for IL-6R and IL-7R mRNA expression. It is apparent that administration of LPS can affect non-neuronal and neuronal cells in the brain. Further research is required to determine how CNS inflammatory changes associated with IL-6, IL-10 and IL-6R could in turn contribute to the development of CNS neurological disorders. Published by Elsevier Ltd.

Single-leg drop landing movement strategies 6 months following first-time acute lateral ankle sprain injury.

PubMed

Doherty, C; Bleakley, C; Hertel, J; Caulfield, B; Ryan, J; Delahunt, E

2015-12-01

No research exists predicating a link between acute ankle sprain injury-affiliated movement patterns and those of chronic ankle instability (CAI) populations. The aim of the current study was to perform a biomechanical analysis of participants, 6 months after they sustained a first-time acute lateral ankle sprain (LAS) injury to establish this link. Fifty-seven participants with a 6-month history of first-time LAS and 20 noninjured participants completed a single-leg drop landing task on both limbs. Three-dimensional kinematic (angular displacement) and sagittal plane kinetic (moment of force) data were acquired for the joints of the lower extremity, from 200 ms pre-initial contact (IC) to 200 ms post-IC. Individual joint stiffnesses and the peak magnitude of the vertical component of the ground reaction force (GRF) were also computed. LAS participants displayed increases in hip flexion and ankle inversion on their injured limb (P < 0.05); this coincided with a reduction in the net flexion-extension moment at the hip joint, with an increase in its stiffness (P < 0.05). There was no difference in the magnitude of the peak vertical GRF for either limb compared with controls. These results demonstrate that altered movement strategies persist in participants, 6 months following acute LAS, which may precipitate the onset of CAI. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Genome-wide maps of m6A circRNAs identify widespread and cell-type-specific methylation patterns that are distinct from mRNAs

PubMed Central

Zhou, Chan; Molinie, Benoit; Daneshvar, Kaveh; Pondick, Joshua V.; Wang, Jinkai; Van Wittenberghe, Nicholas O.; Xing, Yi; Giallourakis, Cosmas C.; Mullen, Alan C.

2017-01-01

Summary N6-methyladenosine (m6A) is the most abundant internal modification of mRNAs and is implicated in all aspects of post-transcriptional RNA metabolism. However, little is known about m6A modifications to circular (circ) RNAs. We developed a computational pipeline (AutoCirc) that together with depletion of ribosomal RNA and m6A immunoprecipitation defined thousands of m6A-circRNAs, with cell-type-specific expression. The presence of m6A-circRNAs is corroborated by interaction between circRNAs and YTHDF1/YTHDF2, proteins that read m6A sites in mRNAs, and by reduced m6A levels upon depletion of METTL3, the m6A writer. Despite sharing m6A readers and writers, m6A-circRNAs are frequently derived from exons that are not methylated in mRNAs, while mRNAs that are methylated on the same exons that compose m6A-circRNAs exhibit less stability, in a process regulated by YTHDF2. These results expand our understanding of the breadth of m6A modifications and uncover regulation of circRNAs through m6A modification. PMID:28854373

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. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

m6A RNA Degradation Products are Catabolized by an Evolutionarily Conserved N6-methyl-AMP Deaminase in Plant and Mammalian Cells.

PubMed

Chen, Mingjia; Urs, Mounashree J; Sánchez-González, Ismael; Olayioye, Monilola A; Herde, Marco; Witte, Claus-Peter

2018-06-08

N6-methylated adenine (m6A) is the most frequent posttranscriptional modification in eukaryotic mRNA. Turnover of RNA generates N6-methylated AMP (N6-mAMP), which has an unclear metabolic fate. We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate (IMP) in vivo by hydrolytically removing the aminomethyl group. A phylogenetic, structural, and biochemical analysis revealed that many fungi partially or fully lack MAPDA, which coincides with a minor role of N6A-RNA methylation in these organisms. MAPDA likely protects RNA from m6A mis-incorporation. This is required because eukaryotic RNA polymerase can use N6-mATP as a substrate. Upon abrogation of MAPDA, root growth is slightly reduced, and the N6-methyladenosine, N6-mAMP, and N6-mATP concentrations are increased in Arabidopsis. Although this will potentially lead to m6A mis-incorporation into RNA, we show that the frequency is too low to be reliably detected in vivo. Since N6-mAMP was several fold more abundant than N6-mATP in MAPDA mutants, we speculate that additional molecular filters suppress the generation of N6-mATP. Enzyme kinetic data indicate that adenylate kinases represent such filters being highly selective for AMP versus N6-mAMP phosphorylation. We conclude that a multilayer molecular protection system is in place preventing N6-mAMP accumulation and salvage. © 2018 American Society of Plant Biologists. All rights reserved.

Acute inflammatory neuropathy with monoclonal anti-GM2 IgM antibodies, IgM-κ paraprotein and additional autoimmune processes in association with a diffuse large B-cell non-Hodgkin's lymphoma.

PubMed

Milnik, Annette; Roggenbuck, Dirk; Conrad, Karsten; Bartels, Claudius

2013-01-21

Lymphoproliferative disorders are often associated with autoimmune processes preceding or following the occurrence of a lymphoma. Here, we describe a patient with a history of recurrent diffuse large B-cell non-Hodgkin's lymphoma who suffered from an acute inflammatory neuropathy with specific monoclonal anti-GM2 IgM antibodies and associated IgM-κ paraprotein. It was possible in this case to prove that both, anti-GM2 IgM antibodies and IgM-κ paraprotein, share the same binding characteristic. In addition, the patient possibly suffered from an immune thrombocytopenia and an early-stage bullous pemphigoid with anti-BP-230 IgG antibodies. Intravenous immunoglobulin and plasmapheresis alleviated the acute neuropathy and thrombocytopenia, while the bullous pemphigoid has been aggravated. In summary, the simultaneous occurrence of multiple autoimmune processes was a sign of a dysfunctional immune system preceding the relapse of a B-cell non-Hodgkin's lymphoma.

Accurate diagnosis of acute abdomen in FMF and acute appendicitis patients: how can we use procalcitonin?

PubMed

Kisacik, Bunyamin; Kalyoncu, Umut; Erol, M Fatih; Karadag, Omer; Yildiz, Mustafa; Akdogan, Ali; Kaptanoglu, Bugra; Hayran, Mutlu; Ureten, Kemal; Ertenli, Ihsan; Kiraz, Sedat; Calguneri, Meral

2007-12-01

This study was conducted to define the value of procalcitonin (PCT) levels in the differential diagnosis of abdominal familial Mediterranean fever (FMF) attacks from acute appendicitis. From October 2006 to January 2007, 28 FMF (12 males, 16 females) patients with acute abdominal attacks and 34 patients (18 males) with acute abdomen who underwent operation with the clinical diagnosis of acute appendicitis were consecutively enrolled in this study. FMF patients with concurrent infectious diseases were excluded. PCT values were measured by an immunofluorescent method using the B.R.A.H.M.S. PCT kit (B.R.A.H.M.S. Diagnostica, Berlin, Germany). Erythrocyte sedimentation rate (ESR), C-reactive proteins (CRP) and leucocyte levels were also noted. Mean disease duration in FMF patients was 9.6 +/- 8.1 years (range 2-33 years) and all were on colchicine therapy with a mean colchicine dosage of 1.2 +/- 0.4 mg/day. Among the operated patients, 5 were excluded: 3 patients had normal findings and 2 had intestinal perforation (PCT levels were 2.69 and 4.93 ng/ml, respectively) at operative and pathologic evaluation. There were no significant differences between the two groups with respect to gender and age (p was not significant (NS) for all). Acute phase reactants and PCT levels were increased in patients with FMF compared to patients with acute appendicitis (0.529[0.12 +/- 0.96] vs 0.095 [0.01-0.80] p < 0.001, respectively). PCT levels higher than 0.5 ng/ml were found in 11% (3/28) of FMF patients compared to 62% (18/29) of acute appendicitis patients (p < 0.001). Our results suggest that PCT could be a useful test in the differentiation of abdominal FMF attacks from acute appendicitis, though it should not supplant more conventional investigations.

The 1999 Ji-Ji (Taiwan) earthquake as a trigger for acute myocardial infarction.

PubMed

Tsai, Ching-Hong; Lung, For-Wey; Wang, Shing-Yaw

2004-01-01

The authors evaluated the effect of stress due to the Ji-Ji, Taiwan, earthquake, which occurred at 1:47 a.m. on September 21, 1999, on the onset of acute myocardial infarction in six counties near the earthquake epicenter. The rate of hospitalization due to acute myocardial infarction increased during the 6 weeks after the earthquake, and a significantly higher number of patients were hospitalized with acute myocardial infarction during that period, compared with the same 6-week period in the previous year (99 and 65 patients, respectively). The findings suggest that extreme emotional stress due to the natural disaster, superimposed on the stress of awakening, increased the incidence of acute myocardial infarction in this population.

Antiplatelet and invasive treatment in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and acute coronary syndrome. The safety of aspirin.

PubMed

Kafkas, N V; Liakos, C I; Mouzarou, A G

2015-06-01

Aspirin is an important drug in acute coronary syndromes (ACS) and percutaneous coronary interventions (PCI). However, its use is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency (risk for haemolytic anaemia). We report the management of 2 patients with class II G6PD deficiency and non-ST-segment elevation ACS (NSTE-ACS). The two patients were safely and efficiently treated with dual antiplatelet treatment (DAPT, aspirin plus ticagrelor) and PCI using new-generation drug-eluting stent (DES) despite G6PD deficiency. NSTE-ACS management with DAPT and DES is probably safe and effective in class II G6PD-deficient patients. © 2015 John Wiley & Sons Ltd.

Effects of clopidogrel and clarithromycin on the disposition of sibutramine and its active metabolites M1 and M2 in relation to CYP2B6*6 polymorphism.

PubMed

Pan, Wei; Bae, Soo-Kyung; Shim, Eon-Jeong; Park, Sung-Eun; Lee, Sang-Seop; Park, Soo-Jin; Yeo, Chang-Woo; Zhou, Hong-Hao; Shon, Ji-Hong; Shin, Jae-Gook

2013-02-01

Plasma concentrations of sibutramine and its two active metabolites after single oral dose of sibutramine were determined in Korean healthy male subjects with different CYP2B6 genotypes (CYP2B6*1/*1, *1/*6 and *6/*6), either alone or after four-day pretreatment with clopidogrel or clarithromycin. The pretreatment with clopidogrel and clarithromycin raised the mean area under the concentration-time curve (AUC) of sibutramine by 163% and 255%, respectively. Co-administration of clarithromycin, combined with CYP2B6*6/*6 genotype, led to highest concentration of sibutramine. The molar sum AUC (M1 + M2) was raised by 35% in the clopidogrel phase but not significantly affected by clarithromycin or CYP2B6 genotype. The CYP2B6*6/*6 subjects in the clopidogrel phase showed the highest molar AUC (M1 + M2) among three genotype groups throughout the three phases. The exposure of sibutramine and its metabolites seemed to be associated with the CYP2B6 genotype. The treatment of clopidogrel significantly altered the disposition of active metabolites as well as sibutramine, but clarithromycin only affects the disposition of sibutramine. These results suggest that the perturbation of CYP2B6 activity may contribute to the inter-individual variation of sibutramine drug responses although the clinical relevance is remained to be established.

High-performance thermoelectric minerals: Colusites Cu26V2M6S32 (M = Ge, Sn)

NASA Astrophysics Data System (ADS)

Suekuni, Koichiro; Kim, Fiseong S.; Nishiate, Hirotaka; Ohta, Michihiro; Tanaka, Hiromi I.; Takabatake, Toshiro

2014-09-01

We report thermoelectric (TE) properties of dense samples of colusites Cu26V2M6S32 (M = Ge, Sn), most of which are composed of earth-abundant elements; Cu and S. The combination of p-type metallic conduction and large thermopowers greater than 200 μV/K leads to high TE power factors of 0.61 and 0.48 mW/K2 m at 663 K for M = Ge and Sn samples, respectively. Furthermore, the lattice thermal conductivity is smaller than 0.6 W/Km over the temperature range from 350 K to 663 K due to the structural complexity. As a consequence, the values of dimensionless TE figure of merit ZT for M = Ge and Sn reach 0.73 and 0.56 at 663 K, respectively. Thus, the colusites are promising candidates for environmental friendly TE materials usable in the range of 500-700 K.

[Electrophysiological study on rat conduit pulmonary artery smooth muscle cells under normoxia and acute hypoxia].

PubMed

Hu, Ying; Zou, Fei; Cai, Chun-Qing; Wu, Hang-Yu; Yun, Hai-Xia; Chen, Yun-Tian; Jin, Guo-En; Ge, Ri-Li

2006-10-25

The present study was designed to investigate the electrophysiological characteristics of rat conduit pulmonary artery smooth muscle cells (PASMCs) and the response to acute hypoxia. PASMCs of the 1st to 2nd order branches in the conduit pulmonary arteries were obtained by enzymatic isolation. The PASMCs were divided into acute hypoxia preconditioned group and normoxia group. Hypoxia solutions were achieved by bubbling with 5% CO2 plus 95% N2 for at least 30 min before cell perfusion. Potassium currents were compared between these two groups using whole-cell patch clamp technique. The total outward current of PASMCs was measured under normoxia condition when iBTX [specific blocking agent of large conductance Ca-activated K(+) (BK(Ca)) channel] and 4-AP [specific blocking agent of delayed rectifier K(+) (K(DR)) channel] were added consequently into bath solution. PASMCs were classified into three types according to their size, shape and electrophysiological characteristics. Type I cells are the smallest with spindle shape, smooth surface and discrete perinuclear bulge. Type II cells show the biggest size with banana-like appearance. Type III cells have the similar size with type I, and present intermediary shape between type I and type II. iBTX had little effect on the total outward current in type I cells, while 4-AP almost completely blocked it. Most of the total outward current in type II cells was inhibited by iBTX, and the remaining was sensitive to 4-AP. In type III cells, the total outward current was sensitive to both iBTX and 4-AP. Acute hypoxia reduced the current in all three types of cells: (1614.8+/-62.5) pA to (892.4+/-33.6) pA for type I cells (P<0.01); (438.3+/-42.8) pA to (277.5+/-44.7) pA for type II cells (P<0.01); (1 042.0+/-37.2) pA to (613.6+/-23.8) pA for type III (P<0.01), and raised the resting membrane potentials (E(m)) in all these three types of cells: (-41.6+/-1.6) mV to (-18.6+/-1.5) mV (P<0.01), (-42.3+/-3.8) mV to (-30.6+/-3.0) mV (P

Human herpesvirus 6 encephalitis followed by acute disseminated encephalomyelitis in an immunocompetent adult.

PubMed

Horie, Junichi; Suzuki, Keisuke; Nakamura, Toshiki; Okamura, Madoka; Iwasaki, Akio; Hirata, Koichi

2017-04-28

A 26-year-old, otherwise healthy man presented with visual abnormality followed by loss of consciousness and convulsion. The patient then developed headache and fever 14 days later. Brain MRI showed hyperintensities in the left cingulate cortex. The cerrebrospinal fluid examinations showed mononuclear pleocytosis and positive PCR results for human herpesvirus 6 (HHV-6). A diagnosis of HHV-6 encephalitis and symptomatic epilepsy was made. The patient's clinical symptoms improved promptly following acyclovir treatment. However, 3 months later the patient noticed dysesthesia in the trunk, the left upper limb and the right lower limb. Brain and spine MRI showed multiple brain white matter lesions, the middle cerebellar peduncle and cervical spinal lesions. The symptoms resolved following methylprednisolone pulse therapy only. We report an adult patient with HHV-6 encephalitis followed by acute disseminated encephalomyelitis whose initial presentation was epilepsy. HHV-6 encephalitis should be included in the differential diagnosis of encephalitis of unknown etiology in an immunocompetent adult.

Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response

PubMed Central

Liuzzi, Juan P.; Lichten, Louis A.; Rivera, Seth; Blanchard, Raymond K.; Aydemir, Tolunay Beker; Knutson, Mitchell D.; Ganz, Tomas; Cousins, Robert J.

2005-01-01

Infection and inflammation produce systemic responses that include hypozincemia and hypoferremia. The latter involves regulation of the iron transporter ferroportin 1 by hepcidin. The mechanism of reduced plasma zinc is not known. Transcripts of the two zinc transporter gene families (ZnT and Zip) were screened for regulation in mouse liver after turpentine-induced inflammation and LPS administration. Zip14 mRNA was the transporter transcript most up-regulated by inflammation and LPS. IL-6 knockout (IL-6–/–) mice did not exhibit either hypozincemia or the induction of Zip14 with turpentine inflammation. However, in IL-6–/– mice, LPS produced a milder hypozincemic response but no Zip14 induction. Northern analysis showed Zip14 up-regulation was specific for the liver, with one major transcript. Immunohistochemistry, using an antibody to an extracellular Zip14 epitope, showed both LPS and turpentine increased abundance of Zip14 at the plasma membrane of hepatocytes. IL-6 produced increased expression of Zip14 in primary hepatocytes cultures and localization of the protein to the plasma membrane. Transfection of mZip14 cDNA into human embryonic kidney cells increased zinc uptake as measured by both a fluorescent probe for free Zn2+ and 65Zn accumulation, as well as by metallothionein mRNA induction, all indicating that Zip14 functions as a zinc importer. Zip14 was localized in plasma membrane of the transfected cells. These in vivo and in vitro experiments demonstrate that Zip14 expression is up-regulated through IL-6, and that this zinc transporter most likely plays a major role in the mechanism responsible for hypozincemia that accompanies the acute-phase response to inflammation and infection. PMID:15863613

Pediatric Acute Lung Injury Epidemiology and Natural History study: Incidence and outcome of the acute respiratory distress syndrome in children.

PubMed

López-Fernández, Yolanda; Azagra, Amelia Martínez-de; de la Oliva, Pedro; Modesto, Vicent; Sánchez, Juan I; Parrilla, Julio; Arroyo, María José; Reyes, Susana Beatriz; Pons-Ódena, Martí; López-Herce, Jesús; Fernández, Rosa Lidia; Kacmarek, Robert M; Villar, Jesús

2012-12-01

The incidence and outcome of the acute respiratory distress syndrome in children are not well-known, especially under current ventilatory practices. The goal of this study was to determine the incidence, etiology, and outcome of acute respiratory distress syndrome in the pediatric population in the setting of lung protective ventilation. A 1-yr, prospective, multicenter, observational study in 12 geographical areas of Spain (serving a population of 3.77 million ≤ 15 yrs of age) covered by 21 pediatric intensive care units. All consecutive pediatric patients receiving invasive mechanical ventilation and meeting American-European Consensus Criteria for acute respiratory distress syndrome. None. Data on ventilatory management, gas exchange, hemodynamics, and organ dysfunction were collected. A total of 146 mechanically ventilated patients fulfilled the acute respiratory distress syndrome definition, representing a incidence of 3.9/100,000 population ≤ 15 yrs of age/yr. Pneumonia and sepsis were the most common causes of acute respiratory distress syndrome. At the time of meeting acute respiratory distress syndrome criteria, mean PaO2/FIO2 was 99 mm Hg ± 41 mm Hg, mean tidal volume was 7.6 mL/kg ± 1.8 mL/kg predicted body weight, mean plateau pressure was 27 cm H2O ± 6 cm H2O, and mean positive end-expiratory pressure was 8.9 cm ± 2.9 cm H2O. Overall pediatric intensive care unit and hospital mortality were 26% (95% confidence interval 19.6-33.7) and 27.4% (95% confidence interval 20.8-35.1), respectively. At 24 hrs, after the assessment of oxygenation under standard ventilatory settings, 118 (80.8%) patients continued to meet acute respiratory distress syndrome criteria (PaO2/FIO2 104 mm Hg ± 36 mm Hg; pediatric intensive care units mortality 30.5%), whereas 28 patients (19.2%) had a PaO2/FIO2 >200 mm Hg (pediatric intensive care units mortality 7.1%) (p = .014). This is the largest study to estimate prospectively the pediatric population-based acute

mStroke: "Mobile Stroke"-Improving Acute Stroke Care with Smartphone Technology.

PubMed

Andrew, Benjamin Y; Stack, Colleen M; Yang, Julian P; Dodds, Jodi A

2017-07-01

This study aimed to evaluate the effect of method and time of system activation on clinical metrics in cases utilizing the Stop Stroke (Pulsara, Inc.) mobile acute stroke care coordination application. A retrospective cohort analysis of stroke codes at 12 medical centers using Stop Stroke from March 2013 to May 2016 was performed. Comparison of metrics (door-to-needle time [DTN] and door-to-CT time [DTC], and rate of DTN ≤ 60 minutes [goal DTN]) was performed between subgroups based on method (emergency medical service [EMS] versus emergency department [ED]) and time of activation. Effects were adjusted for confounders (age, sex, National Institutes of Health Stroke Scale [NIHSS] score) using multiple linear and logistic regression. The final dataset included 2589 cases. Cases activated by EMS were more severe (median NIHSS score 8 versus 4, P < .0001) and more likely to receive recombinant tissue plasminogen activator (20% versus 12%, P < .0001) than those with ED activation. After adjustment, cases with EMS activation had shorter DTC (6.1 minutes shorter, 95% CI [-10.3, -2]) and DTN (12.8 minutes shorter, 95% CI [-21, -4.6]) and were more likely to meet goal DTN (OR 1.83, 95% CI [1.1, 3]). Cases between 1200 and 1800 had longer DTC (7.7 minutes longer, 95% CI [2.4, 13]) and DTN (21.1 minutes longer, 95% CI [9.3, 33]), and reduced rate of goal DTN (OR .3, 95% CI [.15, .61]) compared to those between 0000 and 0600. Incorporating real-time prehospital data obtained via smartphone technology provides unique insight into acute stroke codes. Activation of mobile electronic stroke coordination in the field appears to promote a more expedited and successful care process. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Elevation of Serum Acid Sphingomyelinase Activity in Children with Acute Respiratory Syncytial Virus Bronchiolitis.

PubMed

Yoshida, Shuichiro; Noguchi, Atsuko; Kikuchi, Wataru; Fukaya, Hiroshi; Igarashi, Kiyoshi; Takahashi, Tsutomu

2017-12-01

Acid sphingomyelinase (ASM) is a lysosomal enzyme that hydrolyzes sphingomyelin into ceramide, a bioactive lipid to regulate cellular physiological functions. Thus, ASM activation has been reported as a key event in pathophysiological reactions including inflammation, cytokine release, oxidative stress, and endothelial damage in human diseases. Since ASM activation is associated with extracellular ASM secretion through unknown mechanisms, it can be detected by recognizing the elevation of secretory ASM (S-ASM) activity. Serum S-ASM activity has been reported to increase in chronic diseases, acute cardiac diseases, and systemic inflammatory diseases. However, the serum S-ASM has not been investigated in common acute illness. This study was designed to evaluate serum S-ASM activity in children with common acute illness. Fifty children with common acute illness and five healthy children were included in this study. The patients were categorized into five groups based on clinical diagnoses: acute respiratory syncytial virus (RSV) bronchiolitis, adenovirus infection, streptococcal infection, asthma, and other infections due to unknown origin. The serum S-ASM activity was significantly elevated at 6.9 ± 1.6 nmol/0.1 mL/6 h in the group of acute RSV bronchiolitis patients compared with healthy children who had a mean level of 1.8 ± 0.8 nmol/0.1 mL/6 h (p < 0.05). In the other illness groups, the serum S-ASM activity was not significantly elevated. The results suggest an association of ASM activation with RSV infection, a cause for common acute illness. This is the first report to describe the elevation of serum S-ASM activity in respiratory tract infection.

Plasma levels of soluble CD30 in kidney graft recipients as predictors of acute allograft rejection.

PubMed

Ayed, K; Abdallah, T B; Bardi, R; Abderrahim, E; Kheder, A

2006-09-01

In renal transplant recipients elevated soluble serum CD30 levels are associated with increased rejection and graft loss. We sought to determine the sCD30 plasma levels before and after kidney transplantation and to assess whether sCD30 was a predictive factor of immunological risk. sCD30 plasma levels were determined by an enzyme-linked immunosorbent assay assay in 52 kidney graft recipients before as well as 7, 15, and 21 days after transplantation. Eighteen patients developed acute allograft rejection (group I) and 34 patients showed uneventful courses (group II). Before transplantation sCD30 plasma levels were elevated in both groups (mean: 162.6 +/- 89.5 U/mL). After transplantation, group I recipients with acute rejection showed higher relative levels of plasma sCD30 on days 7 and 15 (120.8 +/- 74.6 U/mL and 210.6 +/- 108.7 U/mL respectively) compared with group II patients without rejection (95 +/- 45 U/mL and 59.4 +/- 31.6 U/mL), a difference that was significant for group I (P = .0003) and not significant for group II (P = .09). On day 21, sCD30 decreased in the two groups but remained higher among group I patients (120.6 +/- 92.7 U/mL). HLA antibodies were positive in 18 patients (34.6%) with 9 (50%) experiencing at last one episode of acute rejection. Among 34 patients negative for anti-HLA antibodies, nine displayed acute rejection only (26.4%), a difference that was not significant (P > .05). If we consider 100 U/mL as the minimum predictive level for allograft rejection, our results suggested that levels of sCD30 should be taken into consideration with the presence of HLA-antibodies detectable before and after transplantation, especially in patients with more than three HLA mismatches [RR = 3.20 (0.94 < RR < 10.91)]. These data suggested that measurement of plasma sCD30 is a useful procedure for the recognition of rejection in its earliest stages.

Association Between Interleukin-6 and Striatal Prediction-Error Signals Following Acute Stress in Healthy Female Participants.

PubMed

Treadway, Michael T; Admon, Roee; Arulpragasam, Amanda R; Mehta, Malavika; Douglas, Samuel; Vitaliano, Gordana; Olson, David P; Cooper, Jessica A; Pizzagalli, Diego A

2017-10-15

Stress is widely known to alter behavioral responses to rewards and punishments. It is believed that stress may precipitate these changes through modulation of corticostriatal circuitry involved in reinforcement learning and motivation, although the intervening mechanisms remain unclear. One candidate is inflammation, which can rapidly increase following stress and can disrupt dopamine-dependent reward pathways. Here, in a sample of 88 healthy female participants, we first assessed the effect of an acute laboratory stress paradigm on levels of plasma interleukin-6 (IL-6), a cytokine known to be both responsive to stress and elevated in depression. In a second laboratory session, we examined the effects of a second laboratory stress paradigm on reward prediction error (RPE) signaling in the ventral striatum. We show that individual differences in stress-induced increases in IL-6 (session 1) were associated with decreased ventral striatal RPE signaling during reinforcement learning (session 2), though there was no main effect of stress on RPE. Furthermore, changes in IL-6 following stress predicted intraindividual variability in perceived stress during a 4-month follow-up period. Taken together, these data identify a novel link between IL-6 and striatal RPEs during reinforcement learning in the context of acute psychological stress, as well as future appraisal of stressful life events. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.