[Migraine in SLE: role of antiphospholipid antibodies and Raynaud's phenomenon].

PubMed

Annese, Virginia; Tomietto, Paola; Venturini, Paolo; D'Agostini, Serena; Ferraccioli, Gianfranco

2006-01-01

To determine the role of antiphospholipid antibodies (aPL) and of Raynaud's phenomenon (RP) in the development of migraine in patients with systemic lupus erythematosus (SLE). 50 unselected SLE patients and 20 rheumatoid arthritis (RA) controls underwent an interview to define the presence of migraine according to the guidelines of the International Headache Society (1988). Serological tests for aPL were performed in all patients. SLE patients were divided according to positivity for RP and/or aPL into 4 subsets: R-/aPL-, R-/aPL+, R+/aPL- and R+/aPL+. Data were analysed using Fisher's exact test, Chi-square test and U Mann-Whitney test. SLE and RA patients were similar for demographic and clinical features; aPL positivity was found in a greater proportion of SLE patients versus RA controls (68% vs 25%, p=0.0036). 31 of the 50 lupic patients (62%) and 7 of the 20 RA controls (35%) suffered from migraine (OR=3, CI:1-8.9). Among SLE and RA patients, migraine was associated with aPL positivity (p=0.027 and p=0.019). Analysing the combined effect of aPL and RP on migraine, in R+/aPL+ patients we detected an higher frequency of migraine (85.7%) with respect to the patients negative for these two features (27%, p=0.0051, OR=16, CI:2.2-118) and to the patients positive only for aPL (65%, p=0.0031, OR=6.2, CI:1.2-32). Migraine in SLE and RA associates with aPL positivity. The simultaneous presence of RP increases by 2,5 times the probability of having migraine, suggesting that cerebral vasospasm might be more common in patients with peripheral vasospasm, given the presence of aPL.

Biophysical Analysis of Anopheles gambiae Leucine-Rich Repeat Proteins APL1A1, APL1B and APL1C and Their Interaction with LRIM1

DOE PAGES

Williams, Marni; Summers, Brady J.; Baxter, Richard H. G.; ...

2015-03-16

Natural infection of Anopheles gambiae by malaria-causing Plasmodium parasites is significantly influenced by the APL1 genetic locus. The locus contains three closely related leucine-rich repeat (LRR) genes, APL1A, APL1B and APL1C. Multiple studies have reported the participation of APL1A—C in the immune response of A. gambiae to invasion by both rodent and human Plasmodium isolates. APL1C forms a heterodimer with the related LRR protein LRIM1 via a C-terminal coiled-coil domain that is also present in APL1A and APL1B. The LRIM1/APL1C heterodimer protects A. gambiae from infection by binding the complement-like protein TEP1 to form a stable and active immune complex.more » We report solution x-ray scatting data for the LRIM1/APL1C heterodimer, the oligomeric state of LRIM1/APL1 LRR domains in solution and the crystal structure of the APL1B LRR domain. The LRIM1/APL1C heterodimeric complex has a flexible and extended structure in solution. In contrast to the APL1A, APL1C and LRIM1 LRR domains, the APL1B LRR domain is a homodimer. The crystal structure of APL1B-LRR shows that the homodimer is formed by an N-terminal helix that complements for the absence of an N-terminal capping motif in APL1B, which is a unique distinction within the LRIM1/APL1 protein family. Full-length APL1A 1 and APL1B form a stable complex with LRIM1. Our results support a model in which APL1A 1, APL1B and APL1C can all form an extended, flexible heterodimer with LRIM1, providing a repertoire of functional innate immune complexes to protect A. gambiae from a diverse array of pathogens.« less

Biophysical Analysis of Anopheles gambiae Leucine-Rich Repeat Proteins APL1A1, APL1B and APL1C and Their Interaction with LRIM1

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

Williams, Marni; Summers, Brady J.; Baxter, Richard H. G.

Natural infection of Anopheles gambiae by malaria-causing Plasmodium parasites is significantly influenced by the APL1 genetic locus. The locus contains three closely related leucine-rich repeat (LRR) genes, APL1A, APL1B and APL1C. Multiple studies have reported the participation of APL1A—C in the immune response of A. gambiae to invasion by both rodent and human Plasmodium isolates. APL1C forms a heterodimer with the related LRR protein LRIM1 via a C-terminal coiled-coil domain that is also present in APL1A and APL1B. The LRIM1/APL1C heterodimer protects A. gambiae from infection by binding the complement-like protein TEP1 to form a stable and active immune complex.more » We report solution x-ray scatting data for the LRIM1/APL1C heterodimer, the oligomeric state of LRIM1/APL1 LRR domains in solution and the crystal structure of the APL1B LRR domain. The LRIM1/APL1C heterodimeric complex has a flexible and extended structure in solution. In contrast to the APL1A, APL1C and LRIM1 LRR domains, the APL1B LRR domain is a homodimer. The crystal structure of APL1B-LRR shows that the homodimer is formed by an N-terminal helix that complements for the absence of an N-terminal capping motif in APL1B, which is a unique distinction within the LRIM1/APL1 protein family. Full-length APL1A 1 and APL1B form a stable complex with LRIM1. Our results support a model in which APL1A 1, APL1B and APL1C can all form an extended, flexible heterodimer with LRIM1, providing a repertoire of functional innate immune complexes to protect A. gambiae from a diverse array of pathogens.« less

Metabolomics profiles delineate uridine deficiency contributes to mitochondria-mediated apoptosis induced by celastrol in human acute promyelocytic leukemia cells

PubMed Central

Li, Lei; Huan, Fei; Li, Aiping; Liu, Yanqing; Xia, Yankai; Duan, Jin-ao; Ma, Shiping

2016-01-01

Celastrol, extracted from “Thunder of God Vine”, is a promising anti-cancer natural product. However, its effect on acute promyelocytic leukemia (APL) and underlying molecular mechanism are poorly understood. The purpose of this study was to explore its effect on APL and underlying mechanism based on metabolomics. Firstly, multiple assays indicated that celastrol could induce apoptosis of APL cells via p53-activated mitochondrial pathway. Secondly, unbiased metabolomics revealed that uridine was the most notable changed metabolite. Further study verified that uridine could reverse the apoptosis induced by celastrol. The decreased uridine was caused by suppressing the expression of gene encoding Dihydroorotate dehydrogenase, whose inhibitor could also induce apoptosis of APL cells. At last, mouse model confirmed that celastrol inhibited tumor growth through enhanced apoptosis. Celastrol could also decrease uridine and DHODH protein level in tumor tissues. Our in vivo study also indicated that celastrol had no systemic toxicity at pharmacological dose (2 mg/kg, i.p., 21 days). Altogether, our metabolomics study firstly reveals that uridine deficiency contributes to mitochondrial apoptosis induced by celastrol in APL cells. Celastrol shows great potential for the treatment of APL. PMID:27374097

Making Decisions about Adult Learners Based on Performances on Functional Competency Measures.

ERIC Educational Resources Information Center

Bunch, Michael B.

The validity and dependability of functional competency tests for adults are examined as they relate to the information needs of instructional decision makers. Test data from the Adult Performance Level (APL) Program (funded by the U.S. Office of Education at the University of Texas at Austin) is used to illustrate key points. In the discussion of…

Commonly dysregulated genes in murine APL cells

PubMed Central

Yuan, Wenlin; Payton, Jacqueline E.; Holt, Matthew S.; Link, Daniel C.; Watson, Mark A.; DiPersio, John F.; Ley, Timothy J.

2007-01-01

To identify genes that are commonly dysregulated in a murine model of acute promyelocytic leukemia (APL), we first defined gene expression patterns during normal murine myeloid development; serial gene expression profiling studies were performed with primary murine hematopoietic progenitors that were induced to undergo myeloid maturation in vitro with G-CSF. Many genes were reproducibly expressed in restricted developmental “windows,” suggesting a structured hierarchy of expression that is relevant for the induction of developmental fates and/or differentiated cell functions. We compared the normal myeloid developmental transcriptome with that of APL cells derived from mice expressing PML-RARα under control of the murine cathepsin G locus. While many promyelocyte-specific genes were highly expressed in all APL samples, 116 genes were reproducibly dysregulated in many independent APL samples, including Fos, Jun, Egr1, Tnf, and Vcam1. However, this set of commonly dysregulated genes was expressed normally in preleukemic, early myeloid cells from the same mouse model, suggesting that dysregulation occurs as a “downstream” event during disease progression. These studies suggest that the genetic events that lead to APL progression may converge on common pathways that are important for leukemia pathogenesis. PMID:17008535

Biochar enables anaerobic digestion of aqueous phase from intermediate pyrolysis of biomass.

PubMed

Torri, Cristian; Fabbri, Daniele

2014-11-01

Intermediate pyrolysis produces a two-phase liquid whose aqueous phase is characterized by low heating value and high water content (aqueous pyrolysis liquid, APL). Anaerobic digestion can be the straightest way to produce a fuel (methane) from this material. Batch tests showed poor performance in anaerobic digestion of APL, which underlined the inhibition of biological process. Nutrient supplementation was ineffective, whereas biochar addition increased yield of methane (60±15% of theoretical) with respect to pure APL (34±6% of theoretical) and improved the reaction rate. On the basis of batch results, a semi-continuous biomethanation test was set up, by adding an increasingly amount of APL in a 30ml reactor preloaded with biochar (0.8gml(-1)). With a daily input of 5gd(-1)l(-1) of APL (corresponding to overall amount of 0.1kgl(-1) added before the end of the study) the yield of methane was 65±5% of the theoretical. Copyright © 2014 Elsevier Ltd. All rights reserved.

Multi-octave analog photonic link with improved second- and third-order SFDRs

NASA Astrophysics Data System (ADS)

Tan, Qinggui; Gao, Yongsheng; Fan, Yangyu; He, You

2018-03-01

The second- and third-order spurious free dynamic ranges (SFDRs) are two key performance indicators for a multi-octave analogy photonic link (APL). The linearization methods for either second- or third-order intermodulation distortion (IMD2 or IMD3) have been intensively studied, but the simultaneous suppression for the both were merely reported. In this paper, we propose an APL with improved second- and third-order SFDRs for multi-octave applications based on two parallel DPMZM-based sub-APLs. The IMD3 in each sub-APL is suppressed by properly biasing the DPMZM, and the IMD2 is suppressed by balanced detecting the two sub-APLs. The experiment demonstrates significant suppression ratios for both the IMD2 and IMD3 after linearization in the proposed link, and the measured second- and third-order SFDRs with the operating frequency from 6 to 40 GHz are above 91 dB ṡHz 1 / 2 and 116 dB ṡHz 2 / 3, respectively.

Opposite effects of Agrimonia pilosa Ledeb aqueous extracts on blood coagulation function

PubMed Central

Yuan, Wufeng; Jiang, Lei; Wang, Huan

2017-01-01

Background Agrimonia pilosa Ledeb (APL) has showed anticoagulant and antithrombotic activities in some studies, whereas its actual effects on blood coagulation are still unclear. This study was designed to observe the in vitro effects of APL aqueous extracts on blood coagulation, as well as to investigate the underlying mechanisms. Methods Studies were divided into four groups: 0, 4, 20, and 80 g/L of APL aqueous extracts mixed with plasma or whole blood samples. Clotting time of whole blood, plasma coagulation tests, activities of plasma coagulation factors, plasma calcium ion, platelet aggregation test, and platelet fibrinogen receptor as well as the blood viscosity were measured. Results It was observed that the APL aqueous extracts in 4 g/L significantly prolonged the whole blood clotting time and activated partial thromboplastin time, shortened prothrombin time, decreased activities of coagulation factor VIII, IX and XI, and levels of platelet aggregation and fibrinogen receptor expression. However, coagulation factor VII activity, and blood viscosity were increased after the extracts treatment. And the effects of APL extracts were in a concentration-dependent manner (0–80 g/L). Conclusions The results suggest that APL aqueous extracts have a total anticoagulant activity, whereas they exhibit opposite effects of greater anticoagulant activity than pro-coagulant activity. PMID:28480193

A Pediatric Acute Promyelocytic Leukemia With a Rare Karyotype of ider(17)(q10)t(15;17) and Favorable Outcome: A Case Report.

PubMed

He, Yanli; Wang, Ping; Liang, Kaiwei; Chen, Xiangjun; Du, Wen; Li, Juan; Hu, Yanjie; Bai, Yan; Liu, Wei; Li, Xiaoqing; Jin, Runming; Zhang, Min; Zheng, Jine

2015-10-01

Acute promyelocytic leukemia (APL) is a specific malignant hematological disorder with a diagnostic hallmark of chromosome translocation t(15;17)(q22;q21). As a very rare secondary cytogenetic aberration in pediatric APL, ider(17q) (q10)t(15;17) was suggested to be a poor prognostic factor based on previous case reports.Here, we report a pediatric APL case with a rare karyotype of ider(17)(q10)t(15;17). Bone marrow aspiration, immunophenotyping, molecular biology, cytogenetic, and fluorescence in situ hybridization (FISH) analyses were performed at initial diagnosis and during the treatment.A 6-year-old boy was brought to our hospital with the chief complaint of bleeding gums twice and intermittent fever for 3 days in January 2013. He was diagnosed as low-risk APL according to the 2012 NCCN guideline on APL, with the expression of PML-RARA (bcr3 subtype) and the karyotype of 46,XY, der(15)t(15;17)(q22;q21),ider(17)(q10)t(15;17), which was further verified by FISH. The patient was treated through combination all-trans retinoic acid (ATRA) and arsenic with daunorubicin according to the 2012 NCCN guideline for APL. Continuous hematological completed remission (HCR) and major molecular remission (MMR) were achieved with normal karyotype for >28 months after induction chemotherapy.Different from previously reported cases, this pediatric APL patient with ider(17)(q10)t(15;17) displays favorable clinical outcomes, which might be related to the low-risk classification and arsenic treatment during the treatment. It suggests that ider(17)(q10)t(15;17) may not be the sole determinant for worse outcomes in pediatric APL and implies that more contributed factors should be considered for pediatric APL prognosis.

Dose-adjusted arsenic trioxide for acute promyelocytic leukaemia in chronic renal failure.

PubMed

Firkin, Frank; Roncolato, Fernando; Ho, Wai Khoon

2015-10-01

To determine the potential for arsenic trioxide (ATO) to be safely and effectively incorporated into induction therapy of newly diagnosed acute promyelocytic leukaemia (APL) in patients with severe chronic renal failure (CRF) by reduction of the ATO dosage to compensate for reduced renal elimination of arsenic in CRF. Two of the four CRF patients with APL in the study were dialysis-dependent, and two had eGFRs of 18 and 19 mL/min/1.73 m(2) . ATO dosage schedules were adjusted to obtain comparable whole-blood arsenic levels to those in APL patients with normal renal function who achieved molecular remission (MR) while receiving 10 mg ATO daily for 28 d. Average ATO administered per day in CRF patients ranged from 36 to 50% of the ATO administered to APL patients with normal renal function. No clinically significant cardiac, hepatic or other toxicities were detected. RT-PCR-negative MR was achieved after one treatment course in two patients and after two courses in the others. Relapse-free survival is 155, 60, 43 and 5 months. The observations in this pilot study have demonstrated whole-blood arsenic levels can provide a guide to adjustments of ATO dosage schedules that permit safe and effective therapeutic outcomes in APL patients with severely compromised renal function. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Interstitial insertion of RARα gene into PML gene in a patient with acute promyelocytic leukemia (APL) lacking the classic t(15;17).

PubMed

Goldschmidt, Neta; Yehuda-Gafni, Orly; Abeliovich, Deborah; Slyusarevsky, Elena; Rund, Deborah

2010-10-01

The diagnosis of APL is based on clinical and morphological tests though the final diagnosis is at the molecular level. An accurate diagnosis is important as it mandates targeted therapy to improve survival. We report a case of APL without t(15;17) in conventional cytogenetic study and with initially negative fluorescence in situ hybridization (FISH) study on cells in interphase. Reverse transcription polymerase chain reaction (RT-PCR) for the promyelocytic/retinoic acid receptor alpha gene (PML/RARα) fusion oncogene proved the clinical diagnosis as well as FISH study on cells in metaphase. The cause was a cryptic translocation of the RARα gene into PML. We reviewed 36 additional cases of APL diagnosed in our hospital since 1992. This was the only case that failed to show t(15;17) in cytogenetics. However, three cases with t(15;17) in cytogenetics had negative RT-PCR for PML/RARα. Our case emphasizes that cytogenetics, FISH and RT-PCR studies are complementary studies for the molecular diagnosis of APL.

Suppression of glucose-6-phosphate-isomerase induced arthritis by oral administration of transgenic rice seeds expressing altered peptide ligands of glucose-6-phosphate-isomerase.

PubMed

Hirota, Tomoya; Tsuboi, Hiroto; Iizuka-Koga, Mana; Takahashi, Hiroyuki; Asashima, Hiromitsu; Yokosawa, Masahiro; Kondo, Yuya; Ohta, Masaru; Wakasa, Yuhya; Matsumoto, Isao; Takaiwa, Fumio; Sumida, Takayuki

2017-05-01

To investigate the effects of transgenic rice seeds expressing the altered peptide ligand (APL) of human glucose-6-phosphate-isomerase (hGPI 325-339 ) in mice model of GPI-induced arthritis (GIA). We generated transgenic rice expressing T-cell epitope of hGPI 325-339 and APL12 contained in the seed endosperm. The transgenic rice seeds were orally administered prophylactically before the induction of GIA. The severity of arthritis and titers of serum anti-GPI antibodies were evaluated. We examined for IL-17 production in splenocytes and inguinal lymph node (iLN) cells, and analyzed the expression levels of functional molecules in splenocytes. Prophylactic treatment of GIA mice with APL12 transgenic (APL12-TG) rice seeds significantly reduced the severity of arthritis and titers of serum anti-GPI antibodies compared with non-transgenic (Non-TG) rice-treated mice. APL12-TG and hGPI 325-339 transgenic (hGPI 325-339 -TG) rice seeds improved the histopathological arthritis scores and decreased IL-17 production compared with non-TG rice-treated mice. APL12-TG rice-treated GIA mice showed upregulation of Foxp3 and GITR protein in CD4  +  CD25  +  Foxp3 +  cells in the spleen compared with non-TG rice- and hGPI 325-339 -TG rice-treated mice. APL12-TG rice seeds improved the severity of GIA through a decrease in production of IL-17 and anti-GPI antibodies via upregulation of Foxp3 and GITR expression on Treg cells in spleen.

Antiphospholipid Antibodies and Recurrent Thrombotic Events: Persistence and Portfolio

PubMed Central

Amory, Colum F.; Levine, Steve R.; Brey, Robin L.; Gebregziabher, Mulugeta; Tuhrim, Stanley; Tilley, Barbara C.; Simpson, Ann-Catherin N.; Sacco, Ralph L.; Mohr, J.P.

2015-01-01

Background There are very limited prospective data on the significance of persistent of antiphospholipid antibodies (aPL) and recurrent thrombo-occlusive events (TOEs). We investigated the prognostic value of (1) two newer aPL assays, (2) an aPL portfolio, and (3) persistent aPL positivity following stroke. Methods 1,770 subjects from the APASS-WARSS study underwent further aPL testing for antibodies to phosphatidylserine (aPS) and β2-glycoprotein-I (anti-β2GPI) from stored sera. Follow-up aPL status was also tested in a subset of subjects. Primary analysis was based on time to any TOE (ischemic stroke, MI, TIA, DVT, PE, or systemic arterial occlusion)/death at 2 years. Cox proportional hazard analyses assessed whether aPL independently related to outcome. Results Persistent anti-β2GPI decreased the time to TOE/death after adjustment for potential confounders (HR=2.86, CI 1.21-6.76, p=0.017). When persistent anti-β2GPI was combined with another persistently positive aPL, time to TOE/death was also reduced (HR=3.79, CI 1.18-12.14, p=0.025). Neither persistent aCL, persistent aPS alone, nor a single positive anti-β2GPI or aPS was associated with decreased time to TOE/death. No single positive aPL, portfolio of baseline aPL, or any persistent aPL increased the rate of TOE/death. Conclusions Rates of TOE/death were not influenced by aPL results at baseline or follow-up. Persistent anti-β2GPI alone and with persistent second aPL were independently associated with decreased time to TOE/death. Persistent aPL, an aPL portfolio, and newer aPL in ischemic stroke patients are not helpful in predicting an increased rate of recurrent TOEs. PMID:26513489

A Low-Cost Audio Prescription Labeling System Using RFID for Thai Visually-Impaired People.

PubMed

Lertwiriyaprapa, Titipong; Fakkheow, Pirapong

2015-01-01

This research aims to develop a low-cost audio prescription labeling (APL) system for visually-impaired people by using the RFID system. The developed APL system includes the APL machine and APL software. The APL machine is for visually-impaired people while APL software allows caregivers to record all important information into the APL machine. The main objective of the development of the APL machine is to reduce costs and size by designing all of the electronic devices to fit into one print circuit board. Also, it is designed so that it is easy to use and can become an electronic aid for daily living. The developed APL software is based on Java and MySQL, both of which can operate on various operating platforms and are easy to develop as commercial software. The developed APL system was first evaluated by 5 experts. The APL system was also evaluated by 50 actual visually-impaired people (30 elders and 20 blind individuals) and 20 caregivers, pharmacists and nurses. After using the APL system, evaluations were carried out, and it can be concluded from the evaluation results that this proposed APL system can be effectively used for helping visually-impaired people in terms of self-medication.

Project Link-Four: Pre-Vocational Education for Adults through Community Linkages.

ERIC Educational Resources Information Center

Stedman, Deborah S.

The Texas adult performance level (APL) project LINK-FOUR implemented a curriculum based on functional competencies at four sites (Austin, Texarkana, Texas City, and Abilene) and formed linkages with local organizations involved in adult vocational education. The concept on which the project was based was that a set of prevocational skills, plus a…

Incorporation of Consumer Education [Lessons] in Adult Basic Education Programs in North Dakota. Final Report.

ERIC Educational Resources Information Center

Shurr, Harriet

Two North Dakota home economists developed consumer education curricula based on adult performance level (APL) objectives and the perceived needs of their vocational students. They worked with local directors of adult basic and secondary education (ABSE) to incorporate the curricula into regular ABSE classes. Project objectives were to (1)…

Lithium Chloride Promotes Apoptosis in Human Leukemia NB4 Cells by Inhibiting Glycogen Synthase Kinase-3 Beta.

PubMed

Li, Liu; Song, Hao; Zhong, Liang; Yang, Rong; Yang, Xiao-Qun; Jiang, Kai-Ling; Liu, Bei-Zhong

2015-01-01

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML). With the application of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), APL becomes one of best prognosis of leukemia. However, ATRA and ATO are not effective against all APLs. Therefore, a new strategy for APL treatment is necessary. Here, we investigated whether lithium chloride (LiCl), a drug used for the treatment of mental illness, could promote apoptosis in human leukemia NB4 cells. We observed that treatment with LiCl significantly accelerated apoptosis in NB4 cells and led to cell cycle arrest at G2/M phase. Moreover, LiCl significantly increased the level of Ser9-phosphorylated glycogen synthase kinase 3β(p-GSK-3β), and decreased the level of Akt1 protein in a dose-dependent manner. In addition, LiCl inhibition of c-Myc also enhanced cell death with a concomitant increase in β-catnin. Taken together, these findings demonstrated that LiCl promoted apoptosis in NB4 cells through the Akt signaling pathway and that G2/M phase arrest was induced by increase of p-GSK-3β(S9).

Aloe vera (Aloe barbadensis Miller) supplemented probiotic lassi prevents Shigella infiltration from epithelial barrier into systemic blood flow in mice model.

PubMed

Hussain, Shaik Abdul; Patil, Girdhari Ramdas; Reddi, Srinu; Yadav, Vidhu; Pothuraju, Ramesh; Singh, Ram Ran Bijoy; Kapila, Suman

2017-01-01

The aim of present work was to investigate preventive role of orally administered Aloe vera supplemented probiotic lassi (APL) on Shigella dysenteriae infection in mice. At the end of experimental period (2, 5 and 7 days of challenging), different organs such as spleen, liver, small intestine, large intestine, and peritoneal fluid were collected and assessed for Shigella colonization. Secretary IgA was estimated in intestinal fluid. Blood was collected in heparinized tubes for various haematological studies. Oral administration of APL showed a significant (p < 0.05) reduction in the Shigella counts (log cfu/mL) in all organs as compared to other treatment groups at different intervals after post feeding. Similarly, secretary IgA antibody levels (μg/mL) in intestinal fluid were significantly (p < 0.05) increased in case of APL fed mice. Further, feeding of APL also demonstrated a positive effect on different haematological parameters viz. Hb (gm %), RBC and WBC count. The results indicated the immunoprotective effects of APL against Shigella dysenteriae induced infection in mice. Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical and electronic studies of CoFeB / MgO / CoFeB magnetic tunnel junctions

NASA Astrophysics Data System (ADS)

Read, J.; Cha, J.; Huang, P.; Egelhoff, W.; Muller, D.; Buhrman, R.

2008-03-01

MgO based magnetic tunnel junctions (MTJs), particularly the CoFeB/MgO/CoFeB system, exhibit large tunneling magnetoresistance (TMR) which makes them viable for MRAM [1] and sensor applications. Careful engineering of the MgO tunnel barriers, CoFeB electrodes, and their interfaces is essential for optimizing device performance [2,3], which motivates investigation of the chemical and electronic properties of high quality MTJs. We correlate scanning tunneling (STS), x-ray photoelectron (XPS) [4], and electron energy loss (EELS) [5] spectroscopies with current-in-plane tunneling (CIPT) measurements to gain insight on the electronic structure and chemistry of MgO MTJ structures. The measurements reveal that quite high TMR (>200%) can be obtained when there is substantial boron in the tunnel barrier, showing that proper doping of the MgO layer plays a significant role in the performance of such MTJs. We will discuss the impact of materials properties upon transport measurements and provide suggestions for greater control over MTJ device characteristics. [1] Parkin, Nat. Mater. 3, 862 (2004). [2] Nagamine, APL 89, 162507 (2006). [3] Lee, APL 90, 212507 (2007). [4] Read, APL 90, 132503 (2007). [5] Cha, APL 91, 062516 (2007).

Antiphospholipid Antibodies and Recurrent Thrombotic Events: Persistence and Portfolio.

PubMed

Amory, Colum F; Levine, Steven R; Brey, Robin L; Gebregziabher, Mulugeta; Tuhrim, Stanley; Tilley, Barbara C; Simpson, Ann-Catherin C; Sacco, Ralph L; Mohr, Jay P

2015-01-01

There are very limited prospective data on the significance of persistent antiphospholipid antibodies (aPL) and recurrent thrombo-occlusive events (TOEs). We investigated the prognostic value of (1) 2 newer aPL assays, (2) an aPL portfolio and (3) persistent aPL positivity following stroke. A total of 1,770 subjects from the APASS-WARSS study underwent further aPL testing for antibodies to phosphatidylserine (aPS) and anti-β2-glycoprotein-I (anti-β2GPI) from stored sera. Follow-up aPL status was also tested in a subset of subjects. Primary analysis was based on time to any TOE (ischemic stroke, myocardial infarction, transient ischemic attack, deep vein thrombosis, pulmonary embolism or systemic arterial occlusion)/death at 2 years. Cox proportional hazard analyses assessed whether aPL independently related to outcome. Persistent anti-β2GPI decreased the time to TOE/death after adjustment for potential confounders (hazards ratio (HR) 2.86, 95% CI 1.21-6.76, p = 0.017). When persistent anti-β2GPI was combined with another persistently positive aPL, time to TOE/death was also reduced (HR 3.79, 95% CI 1.18-12.14, p = 0.025). Neither persistent anticardiolipin antibodies nor persistent aPS alone nor a single positive anti-β2GPI nor aPS was associated with decreased time to TOE/death. No single positive aPL, portfolio of baseline aPL or any persistent aPL increased the rate of TOE/death. Rates of TOE/death were not influenced by aPL results at baseline or follow-up. Persistent anti-β2GPI alone, and with persistent second aPL, was independently associated with decreased time to TOE/death. Persistent aPL, an aPL portfolio and newer aPL in ischemic stroke patients are not helpful in predicting an increased rate of recurrent TOEs. © 2015 S. Karger AG, Basel.

Impact of Cerebrospinal Fluid Shunting for Idiopathic Normal Pressure Hydrocephalus on the Amyloid Cascade

PubMed Central

Moriya, Masao; Miyajima, Masakazu; Nakajima, Madoka; Ogino, Ikuko; Arai, Hajime

2015-01-01

The aim of this study was to determine whether the improvement of cerebrospinal fluid (CSF) flow dynamics by CSF shunting, can suppress the oligomerization of amyloid β-peptide (Aβ), by measuring the levels of Alzheimer’s disease (AD)-related proteins in the CSF before and after lumboperitoneal shunting. Lumbar CSF from 32 patients with idiopathic normal pressure hydrocephalus (iNPH) (samples were obtained before and 1 year after shunting), 15 patients with AD, and 12 normal controls was analyzed for AD-related proteins and APLP1-derived Aβ-like peptides (APL1β) (a surrogate marker for Aβ). We found that before shunting, individuals with iNPH had significantly lower levels of soluble amyloid precursor proteins (sAPP) and Aβ38 compared to patients with AD and normal controls. We divided the patients with iNPH into patients with favorable (improvement ≥ 1 on the modified Rankin Scale) and unfavorable (no improvement on the modified Rankin Scale) outcomes. Compared to the unfavorable outcome group, the favorable outcome group showed significant increases in Aβ38, 40, 42, and phosphorylated-tau levels after shunting. In contrast, there were no significant changes in the levels of APL1β25, 27, and 28 after shunting. After shunting, we observed positive correlations between sAPPα and sAPPβ, Aβ38 and 42, and APL1β25 and 28, with shifts from sAPPβ to sAPPα, from APL1β28 to 25, and from Aβ42 to 38 in all patients with iNPH. Our results suggest that Aβ production remained unchanged by the shunt procedure because the levels of sAPP and APL1β were unchanged. Moreover, the shift of Aβ from oligomer to monomer due to the shift of Aβ42 (easy to aggregate) to Aβ38 (difficult to aggregate), and the improvement of interstitial-fluid flow, could lead to increased Aβ levels in the CSF. Our findings suggest that the shunting procedure can delay intracerebral deposition of Aβ in patients with iNPH. PMID:25821958

[Establishment of diagnostic model to monitor minimal residual disease of acute promyelocytic leukemia by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry].

PubMed

Zhang, Lin-lin; Xu, Zhi-fang; Tan, Yan-hong; Chen, Xiu-hua; Xu, Ai-ning; Ren, Fang-gang; Wang, Hong-wei

2013-01-01

To screen the potential protein biomarkers in minimal residual disease (MRD) of the acute promyelocytic leukemia (APL) by comparison of differentially expressed serum protein between APL patients at diagnosis and after complete remission (CR) and healthy controls, and to establish and verify a diagnostic model. Serum proteins from 36 cases of primary APL, 29 cases of APL during complete remission and 32 healthy controls were purified by magnetic beads and then analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The spectra were analyzed statistically using FlexAnalysis(TM) and ClinProt(TM) software. Two prediction model of primary APL/healthy control, primary APL/APL CR were developed. Thirty four statistically significant peptide peaks were obtained with the m/z value ranging from 1000 to 10 000 (P < 0.001) in primary APL/healthy control model. Seven statistically significant peptide peaks were obtained in primary APL/APL CR model (P < 0.001). Comparison of the protein profiles between the two models, three peptides with m/z 4642, 7764 and 9289 were considered as the protein biomarker of APL MRD. A diagnostic pattern for APL CR using m/z 4642 and 9289 was established. Blind validation yielded correct classification of 6 out of 8 cases. The MALDI-TOF MS analysis of APL patients serum protein can be used as a promising dynamic method for MRD detection and the two peptides with m/z 4642 and 9289 may be better biomarkers.

Sparse, decorrelated odor coding in the mushroom body enhances learned odor discrimination.

PubMed

Lin, Andrew C; Bygrave, Alexei M; de Calignon, Alix; Lee, Tzumin; Miesenböck, Gero

2014-04-01

Sparse coding may be a general strategy of neural systems for augmenting memory capacity. In Drosophila melanogaster, sparse odor coding by the Kenyon cells of the mushroom body is thought to generate a large number of precisely addressable locations for the storage of odor-specific memories. However, it remains untested how sparse coding relates to behavioral performance. Here we demonstrate that sparseness is controlled by a negative feedback circuit between Kenyon cells and the GABAergic anterior paired lateral (APL) neuron. Systematic activation and blockade of each leg of this feedback circuit showed that Kenyon cells activated APL and APL inhibited Kenyon cells. Disrupting the Kenyon cell-APL feedback loop decreased the sparseness of Kenyon cell odor responses, increased inter-odor correlations and prevented flies from learning to discriminate similar, but not dissimilar, odors. These results suggest that feedback inhibition suppresses Kenyon cell activity to maintain sparse, decorrelated odor coding and thus the odor specificity of memories.

Users guide for information retrieval using APL

NASA Technical Reports Server (NTRS)

Shapiro, A.

1974-01-01

A Programming Language (APL) is a precise, concise, and powerful computer programming language. Several features make APL useful to managers and other potential computer users. APL is interactive; therefore, the user can communicate with his program or data base in near real-time. This, coupled with the fact that APL has excellent debugging features, reduces program checkout time to minutes or hours rather than days or months. Of particular importance is the fact that APL can be utilized as a management science tool using such techniques as operations research, statistical analysis, and forecasting. The gap between the scientist and the manager could be narrowed by showing how APL can be used to do what the scientists and the manager each need to do, retrieve information. Sometimes, the information needs to be retrieved rapidly. In this case APL is ideally suited for this challenge.

Coexistence of antiphospholipid antibodies and cephalalgia.

PubMed

Islam, Md Asiful; Alam, Fahmida; Gan, Siew Hua; Cavestro, Cinzia; Wong, Kah Keng

2018-03-01

Background The occurrence of antiphospholipid antibodies (aPLs) and headache comorbidity in the presence or absence of underlying autoimmune diseases remains unclear. Aim The aim of this review was to summarize the relationship between headache and aPLs based on evidences from cohort studies and case reports, in addition to examining the treatment strategies that resolved headache in aPLs-positive individuals. Methods A comprehensive literature search was conducted through PubMed, ISI Web of Science and Google Scholar. A total of 559 articles were screened and the appropriate articles were selected based on quality and level of evidence. Results Cohort studies (n = 27) from Europe, North America and Asia demonstrated comorbidity of aPLs and headache in antiphospholipid syndrome, systemic lupus erythematosus (SLE) and neuropsychiatric SLE patients. Significantly higher association between migraine and aPLs was observed (n = 170/779; p < 0.0001) in individuals without any underlying diseases. Our analysis of shortlisted case reports (n = 17) showed that a higher frequency of anticardiolipin antibodies were present in subjects with different autoimmune disorders (70.6%). Corticosteroids were highly effective in resolving headache in aPLs-positive individuals. Conclusion Higher frequency of comorbidity between aPLs and headache was observed in healthy individuals and patient cases. Therefore, experimental studies are warranted to evaluate the aPLs-induced pathogenic mechanism of headache.

Computer-aided linear-circuit design.

NASA Technical Reports Server (NTRS)

Penfield, P.

1971-01-01

Usually computer-aided design (CAD) refers to programs that analyze circuits conceived by the circuit designer. Among the services such programs should perform are direct network synthesis, analysis, optimization of network parameters, formatting, storage of miscellaneous data, and related calculations. The program should be embedded in a general-purpose conversational language such as BASIC, JOSS, or APL. Such a program is MARTHA, a general-purpose linear-circuit analyzer embedded in APL.

Global Characteristics of Childhood Acute Promyelocytic Leukemia

PubMed Central

Zhang, L; Samad, A; Pombo-de-Oliveira, MS; Scelo, G; Smith, MT; Feusner, J; Wiemels, JL; Metayer, C

2014-01-01

Acute promyelocytic leukemia (APL) comprises approximately 5–10% of childhood acute myeloid leukemia (AML) cases in the US. While variation in this percentage among other populations was noted previously, global patterns of childhood APL have not been thoroughly characterized. In this comprehensive review of childhood APL, we examined its geographic pattern and the potential contribution of environmental factors to observed variation. In 142 studies (spanning >60 countries) identified, variation was apparent—de novo APL represented from 2% (Switzerland) to >50% (Nicaragua) of childhood AML in different geographic regions. Because a limited number of previous studies addressed specific environmental exposures that potentially underlie childhood APL development, we gathered 28 childhood cases of therapy-related APL, which exemplified associations between prior exposures to chemotherapeutic drugs/radiation and APL diagnosis. Future population-based studies examining childhood APL patterns and the potential association with specific environmental exposures and other risk factors are needed. PMID:25445717

Beyond Price Comparisons: Towards a More Critical Consumer Education for Adults through Informal Sites of Learning

ERIC Educational Resources Information Center

Sandlin, Jennifer A.

2004-01-01

Over a decade ago, Oduran (1993) argued that consumer education was an emerging frontier of adult education. While the Adult Performance Level (APL) project in the 1970s sparked some interest in consumer and life skills within adult basic education and English as a second language (Lankshear, 1993; Levine, 1986; Sandlin, 2000), and while this push…

Therapy-induced PML/RARA proteolysis and acute promyelocytic leukemia cure.

PubMed

Nasr, Rihab; Lallemand-Breitenbach, Valérie; Zhu, Jun; Guillemin, Marie-Claude; de Thé, Hugues

2009-10-15

Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosomal translocation that yields the PML/RARA fusion gene. Clinically, besides chemotherapy, two drugs induce clinical remissions: retinoic acid (RA) and arsenic trioxide (As). Both agents directly target PML/RARA-mediated transcriptional repression and protein stability, inducing to various extent promyelocyte differentiation and clinical remission of APL patients. RA targets the RARA moiety of the fusion, whereas arsenic targets its PML part. PML/RARA expression in the mouse is sufficient to initiate APL. The RA-As association, which synergizes for PML/RARA degradation but not for differentiation, rapidly clears leukemia initiating cells (LIC), resulting in APL eradication in murine APL models, but also in several APL clinical trials. Cyclic AMP triggered PML/RARA phosphorylation also enhances RA-induced APL regression, PML/RARA degradation, and LIC clearance, raising new options for therapy-resistant patients. Although differentiation has a major role in debulking of the tumor, PML/RARA degradation seems to be the primary basis for APL eradication by the RA-As association. Oncoprotein degradation could be a general therapeutic strategy that may be extended beyond APL.

Opposite beta2-glycoprotein I requirement for the binding of infectious and autoimmune antiphospholipid antibodies to cardiolipin liposomes is associated with antibody avidity.

PubMed

Celli, C M; Gharavi, A E; Chaimovich, H

1999-01-12

The aim of this study was to investigate the interaction of antiphospholipid antibodies (aPL) from two different populations (patients with autoimmune or infectious disorders) with cardiolipin (CL) arranged in a defined bilayer. beta2-Glycoprotein I (beta2GPI), an apolipoprotein that plays a critical role in the aPL binding to phospholipids, was quantified by dot blot in purified IgG-aPL samples, further classified according to apparent avidity to CL. In solid-phase assays, beta2GPI increased, preferentially, the binding of low-avidity autoimmune aPL to CL but inhibited the binding of low-avidity syphilitic aPL. In the absence of beta2GPI, both autoimmune and infectious aPL induced the leakage of the entrapped fluorescent probe, carboxyfluorescein (CF), from small unilamellar vesicles containing CL. aPL-induced probe leakage was protein concentration-dependent and characterized by a lag-phase onset of 100-120 min. beta2GPI increased the leakage rate induced by low-avidity autoimmune aPL only and inhibited the leakage induced by all syphilitic aPL. The following conclusions were provided: (1) in the absence of beta2GPI, autoimmune and infectious aPL bind to CL in a bilayer, inducing liposome leakage; (2) the leakage mechanism induced by aPL is suggested to be intravesicular; (3) beta2GPI requirement for phospholipid binding in both solid and fluid phase is associated to aPL avidity; (4) CL alone or the CL-beta2GPI complex are the most likely epitopes for autoimmune aPL; (5) aPL from syphilis patients can only form the CL-aPL complex, supporting that beta2GPI is not (part of) the target epitope.

Antiphospholipid antibodies: Paradigm in transition

PubMed Central

Horstman, Lawrence L; Jy, Wenche; Bidot, Carlos J; Ahn, Yeon S; Kelley, Roger E; Zivadinov, Robert; Maghzi, Amir H; Etemadifar, Masoud; Mousavi, Seyed Ali; Minagar, Alireza

2009-01-01

Objectives This is a critical review of anti-phospholipid antibodies (aPL). Most prior reviews focus on the aPL syndrome (APS), a thrombotic condition often marked by neurological disturbance. We bring to attention recent evidence that aPL may be equally relevant to non-thrombotic autoimmune conditions, notably, multiple sclerosis and ITP. Organization After a brief history, the recent proliferation of aPL target antigens is reviewed. The implication is that many more exist. Theories of aPL in thrombosis are then reviewed, concluding that all have merit but that aPL may have more diverse pathological consequences than now recognized. Next, conflicting results are explained by methodological differences. The lupus anticoagulant (LA) is then discussed. LA is the best predictor of thrombosis, but why this is true is not settled. Finally, aPL in non-thrombotic disorders is reviewed. Conclusion The current paradigm of aPL holds that they are important in thrombosis, but they may have much wider clinical significance, possibly of special interest in neurology. PMID:19154576

Biocompatibility Assessment of a Long-Term Wearable Artificial Pump-Lung in Sheep

PubMed Central

Zhou, Kang; Niu, Shuqiong; Bianchi, Giacomo; Wei, Xufeng; Garimella, Narayana; Griffith, Bartley P; Wu, Zhongjun J

2013-01-01

The purpose of this study was to assess the biocompatibility of a newly developed long-term wearable artificial pump-lung (APL) in a clinically relevant ovine animal mode. The wearable APL device was implanted in five sheep through a left thoracotomy. The device was connected between the right atrium (RA) and pulmonary artery (PA) and evaluated for 30 days. Three sheep were used as the sham control. Platelet activation was assessed by measuring platelet surface P-selectin (CD62P) expression with flow cytometry and plasma soluble P-selectin with an enzyme-linked immunosorbent assay (ELISA). Thrombotic deposition on the device components and hollow fiber membranes (HFM) were analyzed with digital imaging and scanning electron microscopy (SEM). Surface P-selectin of the APL and sham groups changed significantly over the study period, but without significant differences between the two groups. Soluble P-selectin for the two groups peaked in the first 24 hours after the surgery. Soluble P-selectin of the APL group remained slightly elevated over the study period compared to the pre-surgical baseline value and was slightly higher compared to that of the sham group. Plasma free hemoglobin (PFH) remained in the normal ranges in all the animals. In spite of the surgery related alteration in laboratory tests and elevation of platelet activation status, the APL devices in all the animals functioned normally (oxygen transfer and blood pumping) during the 30 day study period. The device flow path and membrane surface were free of gross thrombus. Electron microscopy images showed only scattered thrombi on the fibers (membrane surface and weft). In summary, the APL exhibited excellent biocompatibility. Two forms of platelet activation, surgery related and device induced, in the animals implanted with the wearable APL were observed. The limited device-induced platelet activation did not cause gross thrombosis and impair the long-term device performance. PMID:23452221

[Basic and clinical studies of the gene product-targeting therapy based on leukemogenesis--editorial].

PubMed

Chen, Sai-Juan; Chen, Li-Juan; Zhou, Guang-Biao

2005-02-01

In the last twenty years, using all-trans retinoic acid (ATRA) as a differentiation inducer, Shanghai Institute of Hematology has achieved an important breakthrough in the treatment of acute promyelocytic leukemia (APL), which realized the theory of reversing phenotype of cells and provided a successful model of differentiation therapy in cancers. Our group first discovered in the world the variant chromosome translocation t(11;17)(q23;q21) of APL, and cloned the PML-RAR alpha, PLZF-RAR alpha and NPM-RAR alpha fusion genes corresponding to the characterized chromosome translocations t(15;17); t(11;17) and t(5;17) in APL. Moreover, establishment of transgenic mice model of APL proved their effects on leukemogenesis. The ability of ATRA to modify the recruitment of nuclear receptor co-repressor with PML-RAR alpha but not PLZF-RAR alpha caused by the variant chromosome translocation elucidated the therapeutic mechanism of ATRA from the molecular level and provides new insight into transcription-modulating therapy. Since 1994, our group has successfully applied arsenic trioxide (As(2)O(3)) in treating relapsed APL patients, with the complete remission rate of 70% - 80%. The molecular mechanism study revealed that As(2)O(3) exerts a dose-dependent dual effect on APL. Low-dose As(2)O(3) induced partial differentiation of APL cells, while the higher dose induced apoptosis. As(2)O(3) binds ubiquitin like SUMO-1 through the lysine 160 of PML, resulting in the degradation of PML-RAR alpha. Taken together, ATRA and As(2)O(3) target the transcription factor PML-RAR alpha, the former by retinoic acid receptor and the latter by PML sumolization, both induce PML-RAR alpha degradation and APL cells differentiation and apoptosis. Because of the different acting pathways, ATRA and As(2)O(3) have no cross-resistance and can be used as combination therapy. Clinical trial in newly diagnosed APL patients showed that ATRA/As(2)O(3) in combination yields a longer disease-free survival time. With the median survival of 18 months, none of the 20 cases in combination treatment relapsed, whereas 7 relapsed in 37 cases in mono-treatment. This is the best clinical effect achieved in treating adult acute leukemia to this day, possibly making APL the first adult curable leukemia. Based on the great success of the pathogenetic gene target therapy in APL, this strategy may extend to other leukemias. Combination of Gleevec and arsenic agents in treating chronic myeloid leukemia has already make a figure both in clinical and laboratory research, aiming at counteracting the abnormal tyrosine kinase activity of ABL and the degradating BCR-ABL fusion protein. In acute myeloid leukemia M(2b), using new target therapy degradating AML1-ETO fusion protein and reducing the abnormal tyrosine kinase activity of c-kit will also lead to new therapeutic management in acute leukemias.

[Comparison of Curative Effect between Fu Fang Huang Dai Pian and Arsenic Trioxide in Treatment of 45 Patients with Acute Promyelocytic Leukaemia].

PubMed

Wang, Jian; Huang, Jun-Bin; Liu, Zu-Lin; Zhang, Bi-Hong; Xu, Hong-Gui; Xue, Hong-Man; Chen, Chun

2017-12-01

To investigate the clinical efficacy of Fu Fan Huang Dai Pian(RIF) and arsenic trioxide (ATO) regimens for treatment of children with acute promyelocytic leukemia (APL) and to explore the risk factors affecting the prognosis of patients. The clinical data of 45 newly diagnosed APL children admitted in our hospital from January 2004 to May 2017 were analyzed retrospectively. Among 45 APL children, 25 children were treated by chemotherapetic regimen including RIF (RIF group), another 20 children were treated by chemotherapeutic regimen including ATO (ATO group). The follow-up was performed in all APL children. The prognosis and incidence of side reactions from drugs in 2 groups were compared, and the high risk factors affecting the prognosis of patients were analyzed. The median follow-up time was 49.8% months. In RIF group, no early death occured in 25 APL children; 5 cases did not achieve complete remission (CR) after induction therapy, CR rate was 88%. Out of 25 cases 2 caes relapsed, 3 cases died, 20 cases maintained contined CR (CCR), 2 cases failed to be followed-up. In ATO group, 2 cases suffered from early death, 5 cases did not achieve CR after induction therapy, CR rate was 90%, 2 caese relapsed and died, 15 cases maintained CCR, the follow-up failed in 1 caes. The 5 year- OS and EFS rate in all the patients were predicted as (82.2±6.2)% and (76.4±6.6)% respectively. The OS and EFS rate in RIF group were (86.1±7.4)% and (78.4±8.6)% respectively, which were significantly different from OS and EFS rate (76.4%±10.6%) and (74.0%±10.1%) respectively in ATO group (all P>0.05). As for the side reaction from drug, except for the cardiac damage (P<0.05), incidence of other side reactions was not significantly different between 2 groups (P>0.05). In addition, the 5 year-OS and EFS rates in APL children with CNSL were significantly lower than those in APL children without CNSL (all P<0.05), the 5 year OS and EFS rate in APL children did not reache M1 and with high risk were significantly lower than those in APL children reached M1 after induction therapy and with low and standerd risk (P<0.05 and P<0.05); the 5 year-OS and EFS rates did not correlate with age and sex. The Fu Fang Huang Dai Pian shows the therapeutic efficacy on APL children same as ATO, moreover, no obvious enhancement in incidence of side reactions is observed, therefore, the Fu Fang Huang Dai Pian is effective and safe for treatment of APL children. The CNSL, poor respond to treatment, high risk in clinical stratification are high risk factors affecting prognosis of patients.

Absolute quantitation of low abundance plasma APL1β peptides at sub-fmol/mL Level by SRM/MRM without immunoaffinity enrichment.

PubMed

Sano, Shozo; Tagami, Shinji; Hashimoto, Yuuki; Yoshizawa-Kumagaye, Kumiko; Tsunemi, Masahiko; Okochi, Masayasu; Tomonaga, Takeshi

2014-02-07

Selected/multiple reaction monitoring (SRM/MRM) has been widely used for the quantification of specific proteins/peptides, although it is still challenging to quantitate low abundant proteins/peptides in complex samples such as plasma/serum. To overcome this problem, enrichment of target proteins/peptides is needed, such as immunoprecipitation; however, this is labor-intense and generation of antibodies is highly expensive. In this study, we attempted to quantify plasma low abundant APLP1-derived Aβ-like peptides (APL1β), a surrogate marker for Alzheimer's disease, by SRM/MRM using stable isotope-labeled reference peptides without immunoaffinity enrichment. A combination of Cibacron Blue dye mediated albumin removal and acetonitrile extraction followed by C18-strong cation exchange multi-StageTip purification was used to deplete plasma proteins and unnecessary peptides. Optimal and validated precursor ions to fragment ion transitions of APL1β were developed on a triple quadruple mass spectrometer, and the nanoliquid chromatography gradient for peptide separation was optimized to minimize the biological interference of plasma. Using the stable isotope-labeled (SI) peptide as an internal control, absolute concentrations of plasma APL1β peptide could be quantified as several hundred amol/mL. To our knowledge, this is the lowest detection level of endogenous plasma peptide quantified by SRM/MRM.

Single-Nucleotide Polymorphism Array-Based Karyotyping of Acute Promyelocytic Leukemia

PubMed Central

Gómez-Seguí, Inés; Sánchez-Izquierdo, Dolors; Barragán, Eva; Such, Esperanza; Luna, Irene; López-Pavía, María; Ibáñez, Mariam; Villamón, Eva; Alonso, Carmen; Martín, Iván; Llop, Marta; Dolz, Sandra; Fuster, Óscar; Montesinos, Pau; Cañigral, Carolina; Boluda, Blanca; Salazar, Claudia

2014-01-01

Acute promyelocytic leukemia (APL) is characterized by the t(15;17)(q22;q21), but additional chromosomal abnormalities (ACA) and other rearrangements can contribute in the development of the whole leukemic phenotype. We hypothesized that some ACA not detected by conventional techniques may be informative of the onset of APL. We performed the high-resolution SNP array (SNP-A) 6.0 (Affymetrix) in 48 patients diagnosed with APL on matched diagnosis and remission sample. Forty-six abnormalities were found as an acquired event in 23 patients (48%): 22 duplications, 23 deletions and 1 Copy-Neutral Loss of Heterozygocity (CN-LOH), being a duplication of 8(q24) (23%) and a deletion of 7(q33-qter) (6%) the most frequent copy-number abnormalities (CNA). Four patients (8%) showed CNAs adjacent to the breakpoints of the translocation. We compared our results with other APL series and found that, except for dup(8q24) and del(7q33-qter), ACA were infrequent (≤3%) but most of them recurrent (70%). Interestingly, having CNA or FLT3 mutation were mutually exclusive events. Neither the number of CNA, nor any specific CNA was associated significantly with prognosis. This study has delineated recurrent abnormalities in addition to t(15;17) that may act as secondary events and could explain leukemogenesis in up to 40% of APL cases with no ACA by conventional cytogenetics. PMID:24959826

Single-nucleotide polymorphism array-based karyotyping of acute promyelocytic leukemia.

PubMed

Gómez-Seguí, Inés; Sánchez-Izquierdo, Dolors; Barragán, Eva; Such, Esperanza; Luna, Irene; López-Pavía, María; Ibáñez, Mariam; Villamón, Eva; Alonso, Carmen; Martín, Iván; Llop, Marta; Dolz, Sandra; Fuster, Oscar; Montesinos, Pau; Cañigral, Carolina; Boluda, Blanca; Salazar, Claudia; Cervera, Jose; Sanz, Miguel A

2014-01-01

Acute promyelocytic leukemia (APL) is characterized by the t(15;17)(q22;q21), but additional chromosomal abnormalities (ACA) and other rearrangements can contribute in the development of the whole leukemic phenotype. We hypothesized that some ACA not detected by conventional techniques may be informative of the onset of APL. We performed the high-resolution SNP array (SNP-A) 6.0 (Affymetrix) in 48 patients diagnosed with APL on matched diagnosis and remission sample. Forty-six abnormalities were found as an acquired event in 23 patients (48%): 22 duplications, 23 deletions and 1 Copy-Neutral Loss of Heterozygocity (CN-LOH), being a duplication of 8(q24) (23%) and a deletion of 7(q33-qter) (6%) the most frequent copy-number abnormalities (CNA). Four patients (8%) showed CNAs adjacent to the breakpoints of the translocation. We compared our results with other APL series and found that, except for dup(8q24) and del(7q33-qter), ACA were infrequent (≤3%) but most of them recurrent (70%). Interestingly, having CNA or FLT3 mutation were mutually exclusive events. Neither the number of CNA, nor any specific CNA was associated significantly with prognosis. This study has delineated recurrent abnormalities in addition to t(15;17) that may act as secondary events and could explain leukemogenesis in up to 40% of APL cases with no ACA by conventional cytogenetics.

Primary prophylaxis to prevent obstetric complications in asymptomatic women with antiphospholipid antibodies: a systematic review.

PubMed

Amengual, O; Fujita, D; Ota, E; Carmona, L; Oku, K; Sugiura-Ogasawara, M; Murashima, A; Atsumi, T

2015-10-01

Obstetric complications are common in patients with antiphospholipid syndrome. However, the impact of antiphosholipid antibodies (aPL) in the pregnancy outcomes of asymptomatic aPL carriers is uncertain. The aim of this systematic review is to assess whether primary prophylaxis is beneficial to prevent obstetric complications during pregnancy in asymptomatic women positive for aPL who have no history of recurrent pregnancy loss or intrauterine fetal death. Studies evaluating the effect of prophylactic treatment versus no treatment in asymptomatic pregnant aPL carriers were identified in an electronic database search. Design, population and outcome homogeneity of studies was assessed and meta-analysis was performed. The pooled Mantel-Haenszel relative risk of specific pregnancy outcomes was obtained using random effects models. Heterogeneity was measured with the I(2) statistic. All analyses were conducted using Review Manager 5.3. Data from five studies involving 154 pregnancies were included and three studies were meta-analysed. The risk ratio and 95% confidence interval (CI) of live birth rates, preterm birth, low birth weight and overall pregnancy complications in treated and untreated pregnancies were 1.14 (0.18-7.31); 1.71 (0.32-8.98); 0.98 (0.07-13.54) and 2.15 (0.63-7.33),respectively. Results from the meta-analysis revealed that prophylactic treatment with aspirin is not superior to placebo to prevent pregnancy complications in asymptomatic aPL carriers. This systematic review did not find evidence of the superiority of prophylactic treatment with aspirin compared to placebo or usual care to prevent unfavourable obstetric outcomes in otherwise healthy women with aPL during the first pregnancy. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

The expression of the Alzheimer’s Amyloid Precursor Protein-like gene is regulated by developmental timing microRNAs and their targets in Caenorhabditis elegans

PubMed Central

Niwa, Ryusuke; Zhou, Feng; Li, Chris; Slack, Frank J.

2008-01-01

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of dense plaques in the brain, resulting in progressive dementia. A major plaque component is the β-amyloid peptide, which is a cleavage product of the amyloid precursor protein (APP). Studies of dominant inheritable familial AD support the hypothesis that APP is critical for AD development. On the other hand, the pathogenesis of amyloid plaque deposition in AD is thought to be the result of age-related changes with unknown mechanisms. Here we show that the Caenorhabditis elegans homolog of APP, APP-like-1 (apl-1), functions with and is under the control of molecules regulating developmental progression. In C. elegans, the timing of cell fate determination is controlled by the heterochronic genes, including let-7 microRNAs. C. elegans apl-1 shows significant genetic interactions with let-7 family microRNAs and let-7-targeted heterochronic genes, hbl-1, lin-41 and lin-42. apl-1 expression is upregulated during the last larval stage in hypodermal seam cells which is transcriptionally regulated by hbl-1, lin-41 and lin-42. Moreover, the levels of the apl-1 transcription are modulated by the activity of let-7 family microRNAs. Our works places apl-1 in a developmental timing pathway and may provide new insights into the time-dependent progression of AD. PMID:18262516

Epidemiology of acute promyelocytic leukemia.

PubMed

Mele, A; Stazi, M A; Pulsoni, A; Visani, G; Monarca, B; Castelli, G; Rocchi, L; Avvisati, G; Mandelli, F

1995-01-01

The estimated incidence of acute promyelocytic leukemia (APL) is approximately 6 cases per 10 million people per year with no apparent differences between sexes. The age of APL cases is younger than that of other acute myeloid leukemias (AML). Spatial and temporal clusters of APL have been reported. These observations suggest a possible selective role for environmental and/or occupational factors in APL development. A multicenter case-control study was carried out on risk factors for acute leukemias and preleukemias. In this report data related to APL are selectively analyzed from the larger study to identify specific risk factors. The case-control study on 38 cases of APL showed a strong association with shoemaking (odds ration 6.3, 95% confidence interval 1.3-31.1). A moderate leukemogenic effect from living in houses built with tuff, a polous building material containing gamma-emitting radionuclides and having a high radon concentration, and from using hair dyes was also suggested. These data, together with the reported spatial and temporal clustering of APL, support the hypothesis of specific environmental and/or occupational risk factors for APL among other AML subtypes and indicate the need for additional ad hoc multicenter studies.

Pregnancy complications of the antiphospholipid syndrome.

PubMed

Tincani, A; Balestrieri, G; Danieli, E; Faden, D; Lojacono, A; Acaia, B; Trespidi, L; Ventura, D; Meroni, P L

2003-02-01

Starting from their first description, antiphospholipid antibodies (aPL) were associated with repeated miscarriages and fetal losses. Other complications of pregnancy like preterm birth,with pre-eclampsia or severe placental insufficiency were also frequently reported and are included in the current classification criteria of the antiphospholipid syndrome (APS). The titre, the isotype of the antibodies or their antigen specificity may be important in the risk level determination. Some of the difference in the reported results can be explained by the poor standardization achieved in aPL testing or by the not univocal classification of pregnancy complications. The pathogenesis of pregnancy failures is linked to the thrombophilic effect of aPL but also to different mechanisms including a direct effect of antibodies on the throphoblast differentiation and invasion. The study of experimental animal models provided sound evidence of the pathogenic role of aPL both in lupus prone and naive mice. The definition of APS as a condition linked to high obstetric risk and the application of an effective therapy have completely changed the prognosis of pregnancy in these patients. In fact, despite the high number of complications and preterm delivery, today a successful outcome can be achieved in the large majority of the cases.

Antibodies to Phosphatidylserine/Prothrombin Complex in Antiphospholipid Syndrome: Analytical and Clinical Perspectives.

PubMed

Peterson, Lisa K; Willis, Rohan; Harris, E Nigel; Branch, Ware D; Tebo, Anne E

2016-01-01

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy-related morbidity accompanied by persistently positive antiphospholipid antibodies (aPL). Current laboratory criteria for APS classification recommend testing for lupus anticoagulant as well as IgG and IgM anticardiolipin, and beta-2 glycoprotein I (anti-β2GPI) antibodies. However, there appears to be a subset of patients with classical APS manifestations who test negative for the recommended criteria aPL tests. While acknowledging that such patients may have clinical features that are not of an autoimmune etiology, experts also speculate that these "seronegative" patients may test negative for relevant autoantibodies as a result of a lack of harmonization and/or standardization. Alternatively, they may have aPL that target other antigens involved in the pathogenesis of APS. In the latter, autoantibodies that recognize a phosphatidylserine/prothrombin (PS/PT) complex have been reported to be associated with APS and may have diagnostic relevance. This review highlights analytical and clinical attributes associated with PS/PT antibodies, taking into consideration the performance characteristics of criteria aPL tests in APS with specific recommendations for harmonization and standardization efforts. © 2016 Elsevier Inc. All rights reserved.

Multiple variations of the tendons of the anatomical snuffbox.

PubMed

Thwin, San San; Fazlin, Fazlin; Than, Myo

2014-01-01

Multiple tendons of the abductor pollicis longus (APL) in the anatomical snuffbox of the wrist can lead to the development of de Quervain's syndrome, which is caused by stenosing tenosynovitis. A cadaveric study was performed to establish the variations present in the tendons of the anatomical snuffbox in a Malaysian population, in the hope that this knowledge would aid clinical investigation and surgical treatment of de Quervain's tenosynovitis. Routine dissection of ten upper limbs was performed to determine the variations in the tendons of the anatomical snuffbox of the wrist. In all the dissected upper limbs, the APL tendon of the first extensor compartment was found to have several (3-14) tendon slips. The insertion of the APL tendon slips in all upper limbs were at the base of the first metacarpal bone, trapezium and fascia of the opponens pollicis muscle; however, in seven specimens, they were also found to be attached to the fleshy belly of the abductor pollicis brevis muscle. In two specimens, double tendons of the extensor pollicis longus located in the third extensor compartment were inserted into the capsule of the proximal interphalangeal joints before being joined to the extensor expansion. In two other specimens, the first extensor compartment had two osseofibrous tunnels divided by a septum that separated the APL tendon from the extensor pollicis brevis tendon. Multiple variations were found in the anatomical snuffbox region of the dissected upper limbs. Knowledge of these variations would be useful in interventional radiology and orthopaedic surgery.

Anti-phospholipid Antibodies and Smoking: An Overview.

PubMed

Binder, Steven R; Litwin, Christine M

2017-08-01

Antiphospholipid syndrome is characterized by the presence of antiphospholipid antibodies, specifically lupus anticoagulant, anticardiolipin antibodies, and anti-β2 glycoprotein-I antibodies. Antiphospholipid syndrome can occur on its own or in association with other autoimmune diseases, most commonly systemic lupus erythematosus (SLE). A connection between cigarette smoking and anti-phospholipid antibodies (aPL) was first reported in the late1980s. Systemic lupus erythematosus patients with aPL are more likely to be smokers than those without aPL. These patients have a particularly high frequency of vascular events. Recently, a potential link between periodontitis, tobacco, and aPL has been proposed. Research has also suggested that periodontitis and Porphyromonas gingivalis infection are associated with citrullination through the action of peptidylarginine deiminase. A strong correlation between smoking and the presence of citrillunated autoantibodies, which are characteristic of rheumatoid arthritis, has also been observed. While many studies have investigated possible links between infection and aPL in patients with autoimmune diseases, the association of smoking with aPL has not been systematically examined. The fact that both aPL and tobacco are risk factors for thrombosis has complicated efforts to evaluate these factors separately. Also, there has been great variability in measurement techniques, and laboratories lack routine methods for differentiating transient and persistent aPL; both of these factors can make interpretation of autoantibody results quite challenging. This review summarizes the clinical evidence supporting a posited link between aPL and smoking, both in patients with a systemic autoimmune disease and in patients with other medical conditions.

Apelin13/APJ promotes proliferation of colon carcinoma by activating Notch3 signaling pathway.

PubMed

Chen, Tong; Liu, Ning; Xu, Guang-Meng; Liu, Tong-Jun; Liu, Ying; Zhou, Yan; Huo, Si-Bo; Zhang, Kai

2017-11-24

The link between Apelin (APL)/APL receptor (APJ) and Jagged (JAG)/Notch signaling pathways in colorectal cancer (CRC) has been poorly investigated. APL/APJ system, a potent angiogenic factor, is up-regulated in a variety of cancers. It contributes to tumor angiogenesis, and correlates with progression of malignancy. JAG/Notch signaling also contributes to progression, proliferation and metastasis of multiple cancers, including CRC. Here we tested the hypothesis that APL/APJ system promotes CRC proliferation by up-regulating Notch3, thus allowing further binding of JAG1 to Notch3. We used a variety of methods including Western blot, RT-qPCR, gene silencing, ELISA, immunofluorescence staining, to investigate the interaction between APL/APJ system and Notch3 signaling pathway in both surgically-resected specimens and CRC cell line LS180. We show that the expression of APL13, APJ, and Notch3 is elevated in CRC. We further demonstrate that APL13 can be secreted into culture media of LS180 cells, suggesting the existence of autocrine loop in CRC. Moreover, we found that APL13 stimulated expression of Notch3. Finally, we found that inhibition of either APJ or Notch3 prevents proliferation of LS180 cells. Our results suggest that APL13/APJ and JAG1/Notch3 signaling pathways are linked in CRC. These findings provide a new direction to the efforts targeting effective therapeutic and management approaches in the treatment of CRC.

Cerebral changes in SLE with or without antiphospholipid syndrome. a case-control MRI study.

PubMed

Valdés-Ferrer, Sergio I; Vega, Felipe; Cantú-Brito, Carlos; Ceballos-Ceballos, Joel; Estañol, Bruno; García-Ramos, Gullermo; Cabral, Antonio R

2008-01-01

To determine and characterize the prevalence of cerebral changes on MRI in patients with antiphospholipid syndrome (APLS) within systemic lupus erythematosus (SLE). Seventy-one patients with SLE were prospectively studied with brain MRI: 32 with definite APLS and 39 without. Atrophy, ventricular enlargement, leukoaraiosis, interuncal distance, Evans' index, infarcts, and white matter hyperintensities (WMH) were analyzed. Demographic data, treatment, and SLE activity were analyzed. Groups were similar in age (32.4 vs. 32.8 years old; P= non-significant [NS]), and gender. Duration of disease was longer in patients with APLS (87.3 vs. 55.4 months; P= .064). Cortical atrophy was common in both groups (68.7% vs. 89.7%; P= NS). Leukoaraiosis was present in only 3 patients (9.4%; P= .08), all in the APLS group. WMH were found in more than 40% of the patients from both groups. Infarcts (21.9% vs. 2.6%; P= .019) and infarcts plus WHM (12.5% vs. 0; P= .037) were more common in patients with APLS. Although a higher prevalence of neurological involvement in SLE has been reported in APLS patients, we found gross brain changes to be similar between groups. Strokes and leukoaraiosis were more common in the APLS group, consistent with the idea of an APLS-induced prothrombotic state.

APL: a corporate strategy.

PubMed

Fox, J; Nyatanga, L; Ringer, C; Greaves, J

1992-06-01

This paper is based on, and summarises, papers read at the second annual international conference of Nurse Education Tomorrow held at the University of Durham (UK) September 1991. To this end this paper will offer: Some Accreditation of Prior Learning (APL) definition and process as reflected in the literature available. A distinction will be made between APL and Accreditation of Prior Experiential Learning (APEL) although the procedures and processes for assessing them will be shown to be the same. A brief outline of corporate strategy, as it applies to APL, will be given to form the basis for logical demonstration of how Derbyshire Institute of Health and Community Studies has employed such a corporate strategy. Insights developed and gained from APL research currently being undertaken through the college of nursing and midwifery will be used to inform the development and nature of corporate strategy. A flowchart of the operationalisation of the corporate strategy is offered as an integrative summary of how all the APL ideas have had a positive cumulative effect. The paper finishes by highlighting the possible strengths and limitations of APL corporate strategy.

Antiphospholipid antibody profiles in lupus nephritis with glomerular microthrombosis: a prospective study of 124 cases.

PubMed

Zheng, Hui; Chen, Yi; Ao, Wen; Shen, Yan; Chen, Xiao-wei; Dai, Min; Wang, Xiao-dong; Yan, Yu-cheng; Yang, Cheng-de

2009-01-01

Glomerular microthrombosis (GMT) is a common vascular change in patients with lupus nephritis (LN). The mechanism underlying GMT is largely unknown. Although several studies have reported the association of antiphospholipid antibodies (aPL) with GMT, the relation between GMT and aPL remains controversial. Previous studies have demonstrated that some aPL could bind to several hemostatic and fibrinolytic proteases that share homologous enzymatic domains. Of the protease-reactive aPL, some can inhibit the anticoagulant activity of activated protein C and the fibrinolytic function of plasmin, and hinder the antithrombin inactivation of thrombin. The purpose of this study was to investigate the prevalence of GMT in LN patients and examine the relation between the aPL profiles (including some protease-reactive aPL) and GMT. Renal biopsy specimens were examined for the presence of glomerular microthrombi. Plasma samples from 25 LN patients with GMT (LN-GMT group) and 99 LN patients without GMT (LN-non-GMT group) were tested for lupus anticoagulant and antibodies against cardiolipin, beta2 glycoprotein I, plasmin, thrombin, tissue plasminogen activator, and annexin II. The prevalence of GMT in LN patients was 20.2%. Compared with the LN-non-GMT group, the LN-GMT group had an elevated systemic lupus erythematosus disease activity index; elevated renal tissue injury activity and chronicity indices; elevated serum creatinine, blood urea nitrogen, and proteinuria levels; a lower serum C3 level and much intense glomerular C3, C1q staining; and a higher frequency of hypertension (P < 0.05 for all). Additionally, the detection rate of lupus anticoagulant, immunoglobulin G (IgG) anti-beta2 glycoprotein I and anti-thrombin antibodies were higher in the LN-GMT group than in the LN-non-GMT group (P < 0.05 for all). No statistical differences were found in the detection rates of IgG anti-cardiolipin, plasmin, tissue plasminogen activator, or annexin II antibodies (P > 0.05 for all). No detectable difference in IgM autoantibodies to the above antigens was observed between the two groups. GMT occurs in approximately 20.2% of LN patients. Patients with GMT have severer renal tissue injuries and poorer renal functions than patients without GMT. The lupus anticoagulant and antibodies against beta2 glycoprotein I and thrombin may play a role in GMT.

Antiphospholipid antibody profiles in lupus nephritis with glomerular microthrombosis: a prospective study of 124 cases

PubMed Central

Zheng, Hui; Chen, Yi; Ao, Wen; Shen, Yan; Chen, Xiao-wei; Dai, Min; Wang, Xiao-dong; Yan, Yu-cheng; Yang, Cheng-de

2009-01-01

Introduction Glomerular microthrombosis (GMT) is a common vascular change in patients with lupus nephritis (LN). The mechanism underlying GMT is largely unknown. Although several studies have reported the association of antiphospholipid antibodies (aPL) with GMT, the relation between GMT and aPL remains controversial. Previous studies have demonstrated that some aPL could bind to several hemostatic and fibrinolytic proteases that share homologous enzymatic domains. Of the protease-reactive aPL, some can inhibit the anticoagulant activity of activated protein C and the fibrinolytic function of plasmin, and hinder the antithrombin inactivation of thrombin. The purpose of this study was to investigate the prevalence of GMT in LN patients and examine the relation between the aPL profiles (including some protease-reactive aPL) and GMT. Methods Renal biopsy specimens were examined for the presence of glomerular microthrombi. Plasma samples from 25 LN patients with GMT (LN-GMT group) and 99 LN patients without GMT (LN-non-GMT group) were tested for lupus anticoagulant and antibodies against cardiolipin, β2 glycoprotein I, plasmin, thrombin, tissue plasminogen activator, and annexin II. Results The prevalence of GMT in LN patients was 20.2%. Compared with the LN-non-GMT group, the LN-GMT group had an elevated systemic lupus erythematosus disease activity index; elevated renal tissue injury activity and chronicity indices; elevated serum creatinine, blood urea nitrogen, and proteinuria levels; a lower serum C3 level and much intense glomerular C3, C1q staining; and a higher frequency of hypertension (P < 0.05 for all). Additionally, the detection rate of lupus anticoagulant, immunoglobulin G (IgG) anti-β2 glycoprotein I and anti-thrombin antibodies were higher in the LN-GMT group than in the LN-non-GMT group (P < 0.05 for all). No statistical differences were found in the detection rates of IgG anti-cardiolipin, plasmin, tissue plasminogen activator, or annexin II antibodies (P > 0.05 for all). No detectable difference in IgM autoantibodies to the above antigens was observed between the two groups. Conclusions GMT occurs in approximately 20.2% of LN patients. Patients with GMT have severer renal tissue injuries and poorer renal functions than patients without GMT. The lupus anticoagulant and antibodies against β2 glycoprotein I and thrombin may play a role in GMT. PMID:19545416

Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia.

PubMed

Wang, Lan; Zhou, Guang-Biao; Liu, Ping; Song, Jun-Hong; Liang, Yang; Yan, Xiao-Jing; Xu, Fang; Wang, Bing-Shun; Mao, Jian-Hua; Shen, Zhi-Xiang; Chen, Sai-Juan; Chen, Zhu

2008-03-25

To enhance therapeutic efficacy and reduce adverse effects, practitioners of traditional Chinese medicine (TCM) prescribe a combination of plant species/minerals, called formulae, based on clinical experience. Nearly 100,000 formulae have been recorded, but the working mechanisms of most remain unknown. In trying to address the possible beneficial effects of formulae with current biomedical approaches, we use Realgar-Indigo naturalis formula (RIF), which has been proven to be very effective in treating human acute promyelocytic leukemia (APL) as a model. The main components of RIF are realgar, Indigo naturalis, and Salvia miltiorrhiza, with tetraarsenic tetrasulfide (A), indirubin (I), and tanshinone IIA (T) as major active ingredients, respectively. Here, we report that the ATI combination yields synergy in the treatment of a murine APL model in vivo and in the induction of APL cell differentiation in vitro. ATI causes intensified ubiquitination/degradation of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARalpha) oncoprotein, stronger reprogramming of myeloid differentiation regulators, and enhanced G(1)/G(0) arrest in APL cells through hitting multiple targets compared with the effects of mono- or biagents. Furthermore, ATI intensifies the expression of Aquaglyceroporin 9 and facilitates the transportation of A into APL cells, which in turn enhances A-mediated PML-RARalpha degradation and therapeutic efficacy. Our data also indicate A as the principal component of the formula, whereas T and I serve as adjuvant ingredients. We therefore suggest that dissecting the mode of action of clinically effective formulae at the molecular, cellular, and organism levels may be a good strategy in exploring the value of traditional medicine.

Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway

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

Huai, Lei; Wang, Cuicui; Zhang, Cuiping

2012-06-08

Highlights: Black-Right-Pointing-Pointer Metformin induces differentiation in NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces activation of the MEK/ERK signaling pathway in APL cells. Black-Right-Pointing-Pointer Metformin synergizes with ATRA to trigger maturation of NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces the relocalization and degradation of the PML-RAR{alpha} fusion protein. Black-Right-Pointing-Pointer The study may be applicable for new differentiation therapy in cancer treatment. -- Abstract: Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acutemore » promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RAR{alpha} and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.« less

The influence of speed abilities and technical skills in early adolescence on adult success in soccer: A long-term prospective analysis using ANOVA and SEM approaches

PubMed Central

2017-01-01

Several talent development programs in youth soccer have implemented motor diagnostics measuring performance factors. However, the predictive value of such tests for adult success is a controversial topic in talent research. This prospective cohort study evaluated the long-term predictive value of 1) motor tests and 2) players’ speed abilities (SA) and technical skills (TS) in early adolescence. The sample consisted of 14,178 U12 players from the German talent development program. Five tests (sprint, agility, dribbling, ball control, shooting) were conducted and players’ height, weight as well as relative age were assessed at nationwide diagnostics between 2004 and 2006. In the 2014/15 season, the players were then categorized as professional (n = 89), semi-professional (n = 913), or non-professional players (n = 13,176), indicating their adult performance level (APL). The motor tests’ prognostic relevance was determined using ANOVAs. Players’ future success was predicted by a logistic regression threshold model. This structural equation model comprised a measurement model with the motor tests and two correlated latent factors, SA and TS, with simultaneous consideration for the manifest covariates height, weight and relative age. Each motor predictor and anthropometric characteristic discriminated significantly between the APL (p < .001; η2 ≤ .02). The threshold model significantly predicted the APL (R2 = 24.8%), and in early adolescence the factor TS (p < .001) seems to have a stronger effect on adult performance than SA (p < .05). Both approaches (ANOVA, SEM) verified the diagnostics’ predictive validity over a long-term period (≈ 9 years). However, because of the limited effect sizes, the motor tests’ prognostic relevance remains ambiguous. A challenge for future research lies in the integration of different (e.g., person-oriented or multilevel) multivariate approaches that expand beyond the “traditional” topic of single tests’ predictive validity and toward more theoretically founded issues. PMID:28806410

[Reccurent stroke revealing catastrophic antiphospholipid syndrome with hepatitis C viral infection].

PubMed

Rafai, M A; Fadel, H; Gam, I; Hakim, K; El Moutawakkil, B; Kissani, N; Slassi, I

2006-11-01

Very little cases of antiphospholipid syndrome (APLS) have been described among patients having chronic hepatitis C virus infection (HCV). We report the observation of a 43-year-old woman who presented APLS diagnosed following recurrent strokes. Etiological investigations concluded on an association of APLS with HCV infection. Besides being exceptional, this association raises certain etiopathogenic problems. Indeed while antiphospholipid antibodies (aPL) are frequently noted during chronic hepatitis C, they rarely generate thromboembolic complications.

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

Orfali, Nina; Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.; McKenna, Sharon L.

Retinoids are a family of signaling molecules derived from vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL.more » Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies. - Highlights: • Normal and aberrant retinoid signaling in hematopoiesis and leukemia is reviewed. • We suggest a novel role for RARα in the development of X-RARα gene fusions in APL. • ATRA therapy in APL activates transcription and promotes onco-protein degradation. • Autophagy may be involved in both onco-protein degradation and differentiation. • Pharmacologic autophagy induction may potentiate ATRA's therapeutic effects.« less

[Cardiac abnormalities in patients with systemic lupus erythematosus: the role of antiphospholipid antibodies].

PubMed

Monti, Manuel; Borgognoni, Francesco; Pastacci, Loredana; Vincentelli, Giovanni Maria

2016-12-01

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that has protean manifestations and follows a relapsing and remitting course. More than 90% of cases of SLE occur in women, frequently starting at childbearing age. It is characterized by the presence of autoantibodies potentially directed toward every organ or apparatus. Cardiac alterations are frequent in patients affected by SLE and the simultaneous presence of antiphospholipid antibodies (aPL), able to cause arterial thrombosis in any vascular district, is considered a possible risk factor for cardiac damage in SLE patients. The aim of this study is to correlate the main cardiac disorders, estimable through transthoracic echocardiography, in SLE patients as well as the typical autoantibody pattern of the disease. Our study included 76 patients: 38 SLE and 38 controls patients. Control patients have been properly selected to be comparable in gender, age and risks factors for cardiovascular disease. We performed autoantibody panel to assess the prevalence of various autoantibodies during SLE development (antinuclear antibody [ANA], double-stranded DNA [dsDNA], extractable nuclear antigen antibodies [ENA], aPL). In the study, the determination of the IgG and IgM isotypes for aPL (cardiolipin, phosphatidylinositol [aPI], phosphatidylserine, phosphatidic acid [aPA], and anti-β2-glycoprotein I antibodies) were checked. Echocardiography was performed in all patients. In patients affected by SLE, 94.7% was positive to ANA (relative risk 20; 95% confidence interval 4.9-340; p<0.0001) whereas 60.5% was positive for aPL. In patients with SLE, valvular alterations were observed, with a statistically significant correlation between mitral and aortic insufficiency (p=0.01 and p=0.02, respectively). Among aPL-positive patients, 68% (17/25) exhibited at least one hemodynamically significant echocardiographic alteration, vss 3/13 (23%) of patients with negative aPL, with a statistically significant correlation (relative risk 2; 95% confidence interval 1.0-29.8; p=0.01). Among positive-aPL patients, a statistically significant correlation was also observed between mitral insufficiency and aPI-IgG positivity (p=0.01) and, regarding non-valvular alterations, between left atrial enlargement and aPI-IgG positivity (p=0.01) and between left ventricular hypertrophy and aPA-IgG positivity (p=0.03). The present study confirms that SLE is an important risk factor for the presence of cardiac alterations, especially for valvular damage. Moreover, the presence of aPL antibodies in patients with SLE is significantly associated with an increased risk of heart disease, and some specific cardiac alterations are correlated with the positivity of some subclasses of aPL.

Solid cancer, antiphospholipid antibodies, and venous thromboembolism.

PubMed

Font, Carme; Vidal, Laura; Espinosa, Gerard; Tàssies, Dolors; Monteagudo, Joan; Farrús, Blanca; Visa, Laura; Cervera, Ricard; Gascon, Pere; Reverter, Joan C

2011-02-01

The pathogenic role of antiphospholipid antibodies (aPL) in the development of venous thromboembolism (VTE) in patients with malignancies has not been established. From May 2006 to April 2008, 258 consecutive patients with solid-organ malignancies who developed VTE (VTE+) were recruited. A group of 142 patients matched for age, sex and tumor type cancer patients without VTE (VTE-) and an age-and-sex matched group of 258 healthy subjects were also included. A second blood sample was taken in positive aPL patients at least 12 weeks later. Twenty-one (8.1%) VTE+ patients, 2 (1.4%) VTE- patients (p=0.006) and 2 (0.8%) healthy subjects (p<0.001) were positive for aPL. Persistent aPL positivity was observed in only 4 out of 15 available VTE+ patients. No differences in demographic characteristics, clinical pattern and outcome were observed in VTE+ patients according to aPL status. The low prevalence and transience of aPL positivity in patients with solid-organ malignancies with VTE argues against a pathogenic role in the development of thrombosis in this setting. The published evidence of the relationship between cancer, aPL, and thrombosis is reviewed. Copyright © 2010 Elsevier B.V. All rights reserved.

Multiple variations of the tendons of the anatomical snuffbox

PubMed Central

Thwin, San San; Zaini, Fazlin; Than, Myo

2014-01-01

INTRODUCTION Multiple tendons of the abductor pollicis longus (APL) in the anatomical snuffbox of the wrist can lead to the development of de Quervain's syndrome, which is caused by stenosing tenosynovitis. A cadaveric study was performed to establish the variations present in the tendons of the anatomical snuffbox in a Malaysian population, in the hope that this knowledge would aid clinical investigation and surgical treatment of de Quervain's tenosynovitis. METHODS Routine dissection of ten upper limbs was performed to determine the variations in the tendons of the anatomical snuffbox of the wrist. RESULTS In all the dissected upper limbs, the APL tendon of the first extensor compartment was found to have several (3–14) tendon slips. The insertion of the APL tendon slips in all upper limbs were at the base of the first metacarpal bone, trapezium and fascia of the opponens pollicis muscle; however, in seven specimens, they were also found to be attached to the fleshy belly of the abductor pollicis brevis muscle. In two specimens, double tendons of the extensor pollicis longus located in the third extensor compartment were inserted into the capsule of the proximal interphalangeal joints before being joined to the extensor expansion. In two other specimens, the first extensor compartment had two osseofibrous tunnels divided by a septum that separated the APL tendon from the extensor pollicis brevis tendon. CONCLUSION Multiple variations were found in the anatomical snuffbox region of the dissected upper limbs. Knowledge of these variations would be useful in interventional radiology and orthopaedic surgery. PMID:24452976

Acute promyelocytic leukemia in children and adolescents.

PubMed

Stein, Eytan M; Tallman, Martin S

2014-01-01

Acute promyelocytic leukemia (APL) is a rare subtype of AML characterized by a reciprocal balanced translocation between chromosomes 15 and 17 that fuses the PML gene with the RARα gene and leads to the leukemic phenotype. Although best described in large clinical trials of adults, APL, like other forms of AML, also occurs in children. The positive outcome of children with APL mirrors the dramatic increase in survival seen in adults since the introduction of all-trans retinoic acid (ATRA). In this paper, we review the diagnosis of APL in children as well as large, retrospective, clinical trial data collected on pediatric APL. We also raise management issues and toxicities that are unique to children. © 2014 S. Karger AG, Basel.

Estimation and Mitigation of Unmodeled Errors for a Pseudolite Based Reference System

DTIC Science & Technology

2005-03-01

42700− hs)× 10−6 5Ts∆hu [( 1− ∆hAPL 42700− hs )5 − ( 1− ∆hAPL + ∆hu 42700− hs )5] Ru + Ns × (13000− hs)× 10−6 5∆hu [( 1− ∆hAPL 13000− hs )5 − ( 1− ∆hAPL...hu 13000− hs )5] Ru (1.1) where Ns = 2.277(10 −6) RH T 2s ( 10 7.4475(Ts−273K) Ts−38.3K ) (1.2) and τAPL,u = tropospheric delay for mobile receiver...humidity (percent) Ns = surface refractivity 1-8 Bouska and Raquet [4] discuss the effects of tropospheric reduction efforts re- lating to DGPS and

[PML-RARα and p21 are key factors for maintaining acute promyelocytic leukemia stem cells survival].

PubMed

Ding, Fei; Li, Jun-Min

2011-10-01

Tumor stem/progenitor cells are the cells with the characteristics of self-renewal, differentiating to all the other cell populations within tumor, which are also regarded as the source of tumor relapse, drug-resistance and metastasis. As a subtype of acute myeloid leukemia, acute promyelocytic leukemia (APL) represents the target of therapy due to the good response of the oncogenic protein PML-RARα to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). This review summarizes the latest research results of APL as follows: (1) there probably are two APL stem/progenitor cell populations within APL, and self-renewal and survival of APL stem/progenitor cells highly depend on PML-RARα expression, cell cycle inhibitor p21, self-renewal associated molecules and chemokines; and (2) ATRA and ATO eradicate APL stem/progenitor cells mainly by PML-RARα degradation, FOXO3A activation and the inhibition of self-renewal-associated signaling pathway of sonic hedgehog. These findings are helpful to improve other tumor therapy.

Clearance of PML/RARA-bound promoters suffice to initiate APL differentiation.

PubMed

Vitaliano-Prunier, Adeline; Halftermeyer, Juliane; Ablain, Julien; de Reynies, Aurélien; Peres, Laurent; Le Bras, Morgane; Metzger, Daniel; de Thé, Hugues

2014-12-11

PML/RARA, a potent transcriptional inhibitor of nuclear receptor signaling, represses myeloid differentiation genes and drives acute promyelocytic leukemia (APL). Association of the retinoid X receptor-α (RXRA) coreceptor to PML/RARA is required for transformation, with RXRA promoting its efficient DNA binding. APL is exquisitely sensitive to retinoic acid (RA) and arsenic trioxide (arsenic), which both trigger cell differentiation in vivo. Whereas RA elicits transcriptional activation of PML/RARA targets, how arsenic triggers differentiation remains unclear. Here we demonstrate that extinction of PML/RARA triggers terminal differentiation in vivo. Similarly, ablation of retinoid X receptors loosens PML/RARA DNA binding, inducing terminal differentiation of APL cells ex vivo or in vivo. RXRA sumoylation directly contributes to PML/RARA-dependent transformation ex vivo, presumably by enhancing transcriptional repression. Thus, APL differentiation is a default program triggered by clearance of PML/RARA-bound promoters, rather than obligatory active transcriptional activation, explaining how arsenic elicits APL maturation through PML/RARA degradation. © 2014 by The American Society of Hematology.

Arsenic trioxide promoting ETosis in acute promyelocytic leukemia through mTOR-regulated autophagy.

PubMed

Li, Tao; Ma, Ruishuang; Zhang, Yan; Mo, Hongdan; Yang, Xiaoyan; Hu, Shaoshan; Wang, Lixiu; Novakovic, Valerie A; Chen, He; Kou, Junjie; Bi, Yayan; Yu, Bo; Fang, Shaohong; Wang, Jinghua; Zhou, Jin; Shi, Jialan

2018-01-23

Despite the high efficacy and safety of arsenic trioxide (ATO) in treating acute promyelocytic leukemia (APL) and eradicating APL leukemia-initiating cells (LICs), the mechanism underlying its selective cytotoxicity remains elusive. We have recently demonstrated that APL cells undergo a novel cell death program, termed ETosis, through autophagy. However, the role of ETosis in ATO-induced APL LIC eradication remains unclear. For this study, we evaluated the effects of ATO on ETosis and the contributions of drug-induced ETosis to APL LIC eradication. In NB4 cells, ATO primarily increased ETosis at moderate concentrations (0.5-0.75 μM) and stimulated apoptosis at higher doses (1.0-2.0 μM). Furthermore, ATO induced ETosis through mammalian target of rapamycin (mTOR)-dependent autophagy, which was partially regulated by reactive oxygen species. Additionally, rapamycin-enhanced ATO-induced ETosis in NB4 cells and APL cells from newly diagnosed and relapsed patients. In contrast, rapamycin had no effect on apoptosis in these cells. We also noted that PML/RARA oncoprotein was effectively cleared with this combination. Intriguingly, activation of autophagy with rapamycin-enhanced APL LIC eradication clearance by ATO in vitro and in a xenograft APL model, while inhibition of autophagy spared clonogenic cells. Our current results show that ATO exerts antileukemic effects at least partially through ETosis and targets LICs primarily through ETosis. Addition of drugs that target the ETotic pathway could be a promising therapeutic strategy to further eradicate LICs and reduce relapse.

Promyelocytic extracellular chromatin exacerbates coagulation and fibrinolysis in acute promyelocytic leukemia

PubMed Central

Cao, Muhua; Li, Tao; He, Zhangxiu; Wang, Lixiu; Yang, Xiaoyan; Kou, Yan; Zou, Lili; Dong, Xue; Novakovic, Valerie A.; Bi, Yayan; Kou, Junjie; Yu, Bo; Fang, Shaohong; Wang, Jinghua; Zhou, Jin

2017-01-01

Despite routine treatment of unselected acute promyelocytic leukemia (APL) with all-trans-retinoic acid (ATRA), early death because of hemorrhage remains unacceptably common, and the mechanism underlying this complication remains elusive. We have recently demonstrated that APL cells undergo a novel cell death program, termed ETosis, which involves release of extracellular chromatin. However, the role of promyelocytic extracellular chromatin in APL-associated coagulation remains unclear. Our objectives were to identify the novel role of ATRA-promoted extracellular chromatin in inducing a hypercoagulable and hyperfibrinolytic state in APL and to evaluate its interaction with fibrin and endothelial cells (ECs). Results from a series of coagulation assays have shown that promyelocytic extracellular chromatin increases thrombin and plasmin generation, causes a shortening of plasma clotting time of APL cells, and increases fibrin formation. DNase I but not anti-tissue factor antibody could inhibit these effects. Immunofluorescence staining showed that promyelocytic extracellular chromatin and phosphatidylserine on APL cells provide platforms for fibrin deposition and render clots more resistant to fibrinolysis. Additionally, coincubation assays revealed that promyelocytic extracellular chromatin is cytotoxic to ECs, converting them to a procoagulant phenotype. This cytotoxity was blocked by DNase I by 20% or activated protein C by 31%. Our current results thus delineate the pathogenic role of promyelocytic extracellular chromatin in APL coagulopathy. Furthermore, the remaining coagulation disturbance in high-risk APL patients after ATRA administration may be treatable by intrinsic pathway inhibition via accelerating extracellular chromatin degradation. PMID:28053193

An innovative on-board processor for lightsats

NASA Technical Reports Server (NTRS)

Henshaw, R. M.; Ballard, B. W.; Hayes, J. R.; Lohr, D. A.

1990-01-01

The Applied Physics Laboratory (APL) has developed a flightworthy custom microprocessor that increases capability and reduces development costs of lightsat science instruments. This device, called the FRISC (FORTH Reduced Instruction Set Computer), directly executes the high-level language called FORTH, which is ideally suited to the multitasking control and data processing environment of a spaceborne instrument processor. The FRISC will be flown as the onboard processor in the Magnetic Field Experiment on the Freja satllite. APL has achieved a significant increase in onboard processing capability with no increase in cost when compared to the magnetometer instrument on Freja's predecessor, the Viking satellite.

Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia

PubMed Central

Wang, Lan; Zhou, Guang-Biao; Liu, Ping; Song, Jun-Hong; Liang, Yang; Yan, Xiao-Jing; Xu, Fang; Wang, Bing-Shun; Mao, Jian-Hua; Shen, Zhi-Xiang; Chen, Sai-Juan; Chen, Zhu

2008-01-01

To enhance therapeutic efficacy and reduce adverse effects, practitioners of traditional Chinese medicine (TCM) prescribe a combination of plant species/minerals, called formulae, based on clinical experience. Nearly 100,000 formulae have been recorded, but the working mechanisms of most remain unknown. In trying to address the possible beneficial effects of formulae with current biomedical approaches, we use Realgar-Indigo naturalis formula (RIF), which has been proven to be very effective in treating human acute promyelocytic leukemia (APL) as a model. The main components of RIF are realgar, Indigo naturalis, and Salvia miltiorrhiza, with tetraarsenic tetrasulfide (A), indirubin (I), and tanshinone IIA (T) as major active ingredients, respectively. Here, we report that the ATI combination yields synergy in the treatment of a murine APL model in vivo and in the induction of APL cell differentiation in vitro. ATI causes intensified ubiquitination/degradation of promyelocytic leukemia (PML)-retinoic acid receptor α (RARα) oncoprotein, stronger reprogramming of myeloid differentiation regulators, and enhanced G1/G0 arrest in APL cells through hitting multiple targets compared with the effects of mono- or biagents. Furthermore, ATI intensifies the expression of Aquaglyceroporin 9 and facilitates the transportation of A into APL cells, which in turn enhances A-mediated PML-RARα degradation and therapeutic efficacy. Our data also indicate A as the principal component of the formula, whereas T and I serve as adjuvant ingredients. We therefore suggest that dissecting the mode of action of clinically effective formulae at the molecular, cellular, and organism levels may be a good strategy in exploring the value of traditional medicine. PMID:18344322

CD8+ recent thymic emigrants exhibit increased responses to low affinity ligands and improved access to peripheral sites of inflammation

PubMed Central

Berkley, Amy M.; Fink, Pamela J.

2014-01-01

To explore the TCR sensitivity of recent thymic emigrants (RTEs), we triggered T cells with altered peptide ligands (APLs). Upon peptide stimulation in vitro, RTEs exhibited increased TCR signal transduction, and following infection in vivo with APL-expressing bacteria, CD8 RTEs expanded to a greater extent in response to low affinity antigens than their mature T cell counterparts. RTEs skewed to short-lived effector cells in response to all APLs but were also characterized by diminished cytokine production. RTEs responding to infection expressed increased levels of VLA-4, with consequent improved entry into inflamed tissue and pathogen clearance. These positive outcomes were offset by the capacity of RTEs to elicit autoimmunity. Overall, salient features of CD8 RTE biology should inform strategies to improve neonatal vaccination and therapies for cancer and HIV, as RTEs make up a large proportion of the T cells in lymphodepleted environments. PMID:25172492

Cutting edge: CD8+ recent thymic emigrants exhibit increased responses to low-affinity ligands and improved access to peripheral sites of inflammation.

PubMed

Berkley, Amy M; Fink, Pamela J

2014-10-01

To explore the TCR sensitivity of recent thymic emigrants (RTEs), we triggered T cells with altered peptide ligands (APLs). Upon peptide stimulation in vitro, RTEs exhibited increased TCR signal transduction, and following infection in vivo with APL-expressing bacteria, CD8 RTEs expanded to a greater extent in response to low-affinity Ags than did their mature T cell counterparts. RTEs skewed to short-lived effector cells in response to all APLs but also were characterized by diminished cytokine production. RTEs responding to infection expressed increased levels of VLA-4, with consequent improved entry into inflamed tissue and pathogen clearance. These positive outcomes were offset by the capacity of RTEs to elicit autoimmunity. Overall, salient features of CD8 RTE biology should inform strategies to improve neonatal vaccination and therapies for cancer and HIV, because RTEs make up a large proportion of the T cells in lymphodepleted environments. Copyright © 2014 by The American Association of Immunologists, Inc.

Programming Errors in APL.

ERIC Educational Resources Information Center

Kearsley, Greg P.

This paper discusses and provides some preliminary data on errors in APL programming. Data were obtained by analyzing listings of 148 complete and partial APL sessions collected from student terminal rooms at the University of Alberta. Frequencies of errors for the various error messages are tabulated. The data, however, are limited because they…

Alabama Public Library Service Annual Report, 1990.

ERIC Educational Resources Information Center

Alabama Public Library Service, Montgomery.

This annual report highlights the accomplishments of the Alabama Public Library Service (APLS) during 1990. Introductory materials include a map of Alabama's Congressional districts, photographs of the executive board of APLS, and comments from the chairman of the executive board and from APLS' director. Accomplishments are reported under the…

PML-RARα stabilized by zinc in human acute promyelocytic leukemia NB4 cells.

PubMed

Zhu, Bo; Wang, Jia-Yu; Zhou, Jun-Jie; Zhou, Feng; Cheng, Wei; Liu, Ying-Ting; Wang, Jie; Chen, Xiao; Chen, Dian-Hua; Luo, Lan; Hua, Zi-Chun

2017-10-01

Acute promyelocytic leukemia (APL) is characterized and driven by the promyelocytic leukemia protein-retinoic acid receptor alpha (PML-RARα) fusion gene. Previous studies have highlighted the importance of PML-RARα degradation in the treatment against APL. Considering the presence of two zinc fingers in the PML-RARα fusion protein, we explored the function of zinc homeostasis in maintaining PML-RARα stability. We demonstrated for the first time that zinc depletion by its chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) triggered PML-RARα degradation in NB4 APL cells via the proteasome pathway rather than the autophagy-lysosomal pathway. In contrast, autophagy protected TPEN-mediated PML-RARα degradation in NB4 APL cells. We further demonstrated that crosstalk between zinc homeostasis and nitric oxide pathway played a key role in maintaining PML-RARα stability in NB4 APL cells. These results demonstrate that zinc homeostasis is vital for maintaining PML-RARα stability, and zinc depletion by TPEN may be useful as a potential strategy to trigger PML-RARα degradation in APL cells. We also found that TPEN triggered apoptosis of NB4 APL cells in a time-dependent manner. The relationship between PML-RARα degradation and apoptosis triggered by TPEN deserves further study. Copyright © 2017 Elsevier Inc. All rights reserved.

HLA-DRB1*04/*13 alleles are associated with vascular disease and antiphospholipid antibodies in systemic lupus erythematosus.

PubMed

Lundström, Emeli; Gustafsson, Johanna T; Jönsen, Andreas; Leonard, Dag; Zickert, Agneta; Elvin, Kerstin; Sturfelt, Gunnar; Nordmark, Gunnel; Bengtsson, Anders A; Sundin, Ulf; Källberg, Henrik; Sandling, Johanna K; Syvänen, Ann-Christine; Klareskog, Lars; Gunnarsson, Iva; Rönnblom, Lars; Padyukov, Leonid; Svenungsson, Elisabet

2013-06-01

Vascular disease is common in systemic lupus erythematosus (SLE) and patients with antiphospholipid antibodies (aPL) are at high risk to develop arterial and venous thrombosis. Since HLA class II genotypes have been linked to the presence of pro-thrombotic aPL, we investigated the relationship between HLA-DRB1 alleles, aPL and vascular events in SLE patients. 665 SLE patients of Caucasian origin and 1403 controls were included. Previous manifestations of ischaemic heart disease, ischaemic cerebrovascular disease (ICVD) and venous thromboembolism (together referred to as any vascular events (AVE)) were tabulated. aPL were measured with ELISA. Two-digit HLA-DRB1 typing was performed by sequence-specific primer-PCR. HLA-DRB1*04 was more frequent among SLE patients with ICVD compared to unaffected patients. This association remained after adjustment for known traditional cardiovascular risk factors. HLA-DRB1*13 was associated with AVE. All measured specificities of aPL-cardiolipin IgG and IgM, β2-glycoprotein-1 IgG, prothrombin (PT) IgG and a positive lupus anticoagulant test were associated with HLA-DRB1*04-while HLA-DRB1*13 was associated with IgG antibodies (β2-glycoprotein-1, cardiolipin and PT). In patients with the combined risk alleles, HLA-DRB1*04/*13, there was a significant additive interaction for the outcomes AVE and ICVD. The HLA-DRB1*04 and HLA-DRB1*13 alleles are associated with vascular events and an aPL positive immune-phenotype in SLE. Results demonstrate that a subset of SLE patients is genetically disposed to vascular vulnerability.

HPLC-HG-AFS determination of arsenic species in acute promyelocytic leukemia (APL) plasma and blood cells.

PubMed

Guo, Meihua; Wang, Wenjing; Hai, Xin; Zhou, Jin

2017-10-25

Arsenic trioxide (ATO) has been successfully used in the treatment of acute promyelocytic leukemia (APL). To clarify the arsenic species in APL patients, high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) and HG-AFS methods were developed and validated to quantify the plasma concentrations of inorganic arsenic (As(III) and As(V)) and methylated metabolites (MMA and DMA), and the total amounts of arsenic in blood cells and plasma. Blood cells and plasma were digested with mixtures of HNO 3 H 2 O 2 and analyzed by HG-AFS. For arsenic speciation, plasma samples were prepared with perchloric acid to precipitate protein. The supernatant was separated on an anion-exchange column within 6min with isocratic elution using 13mM CH 3 COONa, 3mM NaH 2 PO 4 , 4mM KNO 3 and 0.2mM EDTA-2Na. The methods provided linearity range of 0.2-20ng/mL for total arsenic and 2.0-50ng/mL for four arsenic species. The developed methods for total arsenic and arsenic species determination were precise and accurate. The spiked recoveries ranged from 81.2%-108.6% and the coefficients of variation for intra- and inter-batch precision were less than 9.3% and 12.5%, respectively. The developed methods were applied successfully for the assay of total arsenic and arsenic species in 5 APL patients. The HPLC-HG-AFS may be a good alternative for arsenic species determination in APL patients with its simplicity and low-cost in comparison with HPLC-ICP-MS. Copyright © 2017 Elsevier B.V. All rights reserved.

Assessment of late cardiomyopathy by magnetic resonance imaging in patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and idarubicin.

PubMed

Rodríguez-Veiga, Rebeca; Igual, Begoña; Montesinos, Pau; Tormo, Mar; Sayas, Mª José; Linares, Mariano; Fernández, José María; Salvador, Antonio; Maceira-González, Alicia; Estornell, Jordi; Calabuig, Marisa; Pedreño, María; Roig, Mónica; Sanz, Jaime; Sanz, Guillermo; Carretero, Carlos; Boluda, Blanca; Martínez-Cuadrón, David; Sanz, Miguel Ángel

2017-07-01

Late cardiomyopathy CMP is regarded as a potential severe long-term complication after anthracycline-based regimens for acute promyelocitic leukaemia (APL). We assess by MRI the incidence and severity of clinical and subclinical long-term CMP in a cohort of adult APL patients in first complete remission with PETHEMA trials. Adult patients diagnosed with APL in first complete remission lasting ≥2 years underwent anamnesis and physical examination and were asked to perform a cardiac MRI. Clinical CMP was defined as radiographic and physical signs of heart failure accompanied by symptoms or by left ventricle ejection fraction (LVEF) <45% by MRI with or without symptoms. Subclinical CMP was defined as the following MRI abnormalities: LVEF 45-50% or late gadolinium enhancement or two or more of LVEF ≤55%, left ventricle end-diastolic volume index ≥98 ml/m 2 , left ventricle end-systolic volume index ≥38 ml/m 2 , right ventricle end-diastolic volume index ≥106 ml/m 2 and regional wall motion abnormalities. Of the 82 patients enrolled in the study, median cumulative dose of anthracyclines (doxorubicin equivalence) was 650 mg/m 2 , and median time from APL diagnosis to the study was 87 months (range, 24-195). Seven out of 57 patients with available MRI (12%) had subclinical CMP (all of them showed late gadolinium enhancement in MRI), and none had clinical CMP. Among the 25 patients without MRI, none had CMP by chest X-ray and physical assessment. In summary, we found 12% of subclinical and no clinical late CMP assessed by MRI in APL patients treated with PETHEMA protocols. Due to the low number of patients, we must interpret our results cautiously.

14th International Congress on Antiphospholipid Antibodies Task Force report on obstetric antiphospholipid syndrome.

PubMed

de Jesus, Guilherme R; Agmon-Levin, Nancy; Andrade, Carlos A; Andreoli, Laura; Chighizola, Cecilia B; Porter, T Flint; Salmon, Jane; Silver, Robert M; Tincani, Angela; Branch, D Ware

2014-08-01

Pregnancy morbidity is one of the clinical manifestations used for classification criteria of antiphospholipid syndrome (APS). During the 14th International Congress on Antiphospholipid Antibodies (aPL), a Task Force with internationally-known experts was created to carry out a critical appraisal of the literature available regarding the association of aPL with obstetric manifestations present in actual classification criteria (recurrent early miscarriage, fetal death, preeclampsia and placental insufficiency) and the quality of the evidence that treatment(s) provide benefit in terms of avoiding recurrent adverse obstetric outcomes. The association of infertility with aPL and the effectiveness of the treatment of patients with infertility and positive aPL was also investigated. This report presents current knowledge and limitations of published studies regarding pregnancy morbidity, infertility and aPL, identifying areas that need better investigative efforts and proposing how critical flaws could be avoided in future studies, as suggested by participants of the Task Force. Except for fetal death, there are limitations in the quality of the data supporting the association of aPL with obstetric complications included in the current APS classification criteria. Recommended treatments for all pregnancy morbidity associated to APS also lack well-designed studies to confirm its efficacy. APL does not seem to be associated with infertility and treatment does not improve the outcomes in infertile patients with aPL. In another section of the Task Force, Dr. Jane Salmon reviewed complement-mediated inflammation in reproductive failure in APS, considering new therapeutic targets to obstetric APS (Ob APS). Copyright © 2014 Elsevier B.V. All rights reserved.

Zebrafish on a chip: a novel platform for real-time monitoring of drug-induced developmental toxicity.

PubMed

Li, Yinbao; Yang, Fan; Chen, Zuanguang; Shi, Lijuan; Zhang, Beibei; Pan, Jianbin; Li, Xinchun; Sun, Duanping; Yang, Hongzhi

2014-01-01

Pharmaceutical safety testing requires a cheap, fast and highly efficient platform for real-time evaluation of drug toxicity and secondary effects. In this study, we have developed a microfluidic system for phenotype-based evaluation of toxic and teratogenic effects of drugs using zebrafish (Danio rerio) embryos and larvae as the model organism. The microfluidic chip is composed of two independent functional units, enabling the assessment of zebrafish embryos and larvae. Each unit consists of a fluidic concentration gradient generator and a row of seven culture chambers to accommodate zebrafish. To test the accuracy of this new chip platform, we examined the toxicity and teratogenicity of an anti-asthmatic agent-aminophylline (Apl) on 210 embryos and 210 larvae (10 individuals per chamber). The effect of Apl on zebrafish embryonic development was quantitatively assessed by recording a series of physiological indicators such as heart rate, survival rate, body length and hatch rate. Most importantly, a new index called clonic convulsion rate, combined with mortality was used to evaluate the toxicities of Apl on zebrafish larvae. We found that Apl can induce deformity and cardiovascular toxicity in both zebrafish embryos and larvae. This microdevice is a multiplexed testing apparatus that allows for the examination of indexes beyond toxicity and teratogenicity at the sub-organ and cellular levels and provides a potentially cost-effective and rapid pharmaceutical safety assessment tool.

C/EBPβ contributes to transcriptional activation of long non-coding RNA NEAT1 during APL cell differentiation.

PubMed

Wang, Yewei; Fu, Lei; Sun, Ailian; Tang, Doudou; Xu, Yunxiao; Li, Zheyuan; Chen, Mingjie; Zhang, Guangsen

2018-05-05

Emerging evidences have shown that long non-coding RNAs (lncRNAs) play critical roles in cancer development and cancer therapy. LncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) is indispensable during acute promyelocytic leukemia (APL) cell differentiation induced by all-trans retinoic acid (ATRA). However, the precise mechanism of NEAT1 upregulation has not been fully understood. In this study, we performed chromatin immunoprecipitation and luciferase reporter assays to demonstrate that C/EBP family transcription factor C/EBPβ bind to and transactivate the promoter of lncRNA NEAT1 through the C/EBPβ binding sites both around -54 bp and -1453 bp upstream of the transcription start site. Moreover, the expression of C/EBPβ was increased after ATRA treatment, and the binding of C/EBPβ in the NEAT1 promoter was also dramatically increased. Finally, knockdown of C/EBPβ significantly reduced the ATRA-induced upregulation of NEAT1. In conclusion, C/EBPβ directly activates the expression of NEAT1 through binding to the promoter of NEAT1. Knockdown of C/EBPβ impairs ATRA-induced transcriptional activation of NEAT1. Our data indicate that C/EBPβ contributes to ATRA-induced activation of NEAT1 during APL cell differentiation. Our results enrich our knowledge on the regulation of lncRNAs and the regulatory role of C/EBPβ in APL cell differentiation. Copyright © 2017. Published by Elsevier Inc.

PML–RARA-RXR Oligomers Mediate Retinoid and Rexinoid/cAMP Cross-Talk in Acute Promyelocytic Leukemia Cell Differentiation

PubMed Central

Kamashev, Dmitrii; Vitoux, Dominique; de Thé, Hugues

2004-01-01

PML–RARA was proposed to initiate acute promyelocytic leukemia (APL) through PML–RARA homodimer–triggered repression. Here, we examined the nature of the PML–RARA protein complex and of its DNA targets in APL cells. Using a selection/amplification approach, we demonstrate that PML–RARA targets consist of two AGGTCA elements in an astonishing variety of orientations and spacings, pointing to highly relaxed structural constrains for DNA binding and identifying a major gain of function of this oncogene. PML–RARA-specific response elements were identified, which all conveyed a major transcriptional response to RA only in APL cells. In these cells, we demonstrate that PML–RARA oligomers are complexed to RXR. Directly probing PML–RARA function in APL cells, we found that the differentiation enhancer cyclic AMP (cAMP) boosted transcriptional activation by RA. cAMP also reversed the normal silencing (subordination) of the transactivating function of RXR when bound to RARA or PML–RARA, demonstrating that the alternate rexinoid/cAMP-triggered APL differentiation pathway also activates PML–RARA targets. Finally, cAMP restored both RA-triggered differentiation and PML–RARA transcriptional activation in mutant RA-resistant APL cells. Collectively, our findings directly demonstrate that APL cell differentiation parallels transcriptional activation through PML–RARA-RXR oligomers and that those are functionally targeted by cAMP, identifying this agent as another oncogene-targeted therapy. PMID:15096541

Supporting Teaching and Learning Using Authentic Scientific Texts: A Rejoinder to Danielle J. Ford

ERIC Educational Resources Information Center

Yarden, Anat; Falk, Hedda; Federico-Agraso, Marta; Jimenez-Aleixandre, Maria Pilar; Norris, Stephen P.; Phillips, Linda M.

2009-01-01

In her commentary Danielle J. Ford mainly focused on three issues that highlight the promises and challenges for the use of Adapted Primary Literature (APL) in science curricula: the possible contribution of APL to authentic experiences in secondary schools, implementation issues of APL including the support required for the teachers, and the…

How I treat children and adolescents with acute promyelocytic leukaemia.

PubMed

Abla, Oussama; Ribeiro, Raul C

2014-01-01

Acute promyelocytic leukaemia (APL) is a rare subtype of acute myeloid leukaemia. The outcome of paediatric APL has improved substantially over the past 20 years; cure rates above 80% are expected when all-trans retinoic acid (ATRA) is given with anthracycline-based regimens. The presenting features of paediatric APL may include severe bleeding and thrombotic complications, which contribute to the high early death rate. The incidence of leucocytosis and the microgranular subtype is greater in paediatric than adult APL, and children experience greater ATRA-related toxicity. It is crucial to begin ATRA therapy and intensive platelet and fibrinogen replacement on first suspicion of APL. Recent risk-adapted therapeutic trials have shown that patients at greater risk of relapse benefit from the introduction of high-dose cytarabine during consolidation. Combination therapy with ATRA and arsenic trioxide provides very effective frontline treatment and may reduce the need for subsequent anthracycline therapy. © 2013 John Wiley & Sons Ltd.

How I Treat Children and Adolescents with Acute Promyelocytic Leukaemia

PubMed Central

Abla, Oussama; Ribeiro, Raul C.

2016-01-01

Summary Acute promyelocytic leukaemia (APL) is a rare subtype of acute myeloid leukaemia. The outcome of paediatric APL has improved substantially over the past 20 years; cure rates above 80% are expected when all-trans retinoic acid (ATRA) is given with anthracycline-based regimens. The presenting features of paediatric APL may include severe bleeding and thrombotic complications, which contribute to the high early death rate. The incidence of leucocytosis and the microgranular subtype is greater in paediatric than adult APL, and children experience greater ATRA-related toxicity. It is crucial to begin ATRA therapy and intensive platelet and fibrinogen replacement on first suspicion of APL. Recent risk-adapted therapeutic trials have shown that patients at greater risk of relapse benefit from the introduction of high-dose cytarabine during consolidation. Combination therapy with ATRA and arsenic trioxide provides very effective frontline treatment and may reduce the need for subsequent anthracycline therapy. PMID:24117210

Detoxification of acidic biorefinery waste liquor for production of high value amino acid.

PubMed

Christopher, Meera; Anusree, Murali; Mathew, Anil K; Nampoothiri, K Madhavan; Sukumaran, Rajeev Kumar; Pandey, Ashok

2016-08-01

The current study evaluates the detoxification of acid pretreatment liquor (APL) using adsorbent (ADS 400 & ADS 800) or ion-exchange (A-27MP & A-72MP) resins and its potential for amino acid production. The APL is generated as a by-product from the pretreatment of lignocellulosic biomass and is rich monomeric sugars as well as sugar degradation products (fermentation inhibitors) such as furfural and hydroxymethyl furfural (HMF). Of the four resins compared, ADS 800 removed approximately 85% and 60% of furfural and HMF, respectively. ADS 800 could be reused for up to six cycles after regeneration without losing its adsorption properties. The study was further extended by assessing the fermentability of detoxified APL for l-lysine production using wild and mutant strains of Corynebacterium glutamicum. The detoxified APL was superior to APL for l-lysine production. Copyright © 2016 Elsevier Ltd. All rights reserved.

Curing APL through PML/RARA degradation by As2O3.

PubMed

Lallemand-Breitenbach, Valerie; Zhu, Jun; Chen, Zhu; de Thé, Hugues

2012-01-01

Acute promyelocytic leukemia (APL) is a hematological malignancy driven by the PML/RARA oncogene. The prognosis for patients with APL was revolutionized by two treatments: retinoic acid (RA) and As(2)O(3) (arsenic trioxide). These were both shown a posteriori to target PML/RARA, explaining their exquisite specificity for APL. Arsenic, as a single agent, cures up to 70% of patients, whereas APL patients treated with the combination of RA and As(2)O(3) reach a stunning 90% cure rate. Recent physiopathological models highlight the key role of RA- and As(2)O(3)-triggered PML/RARA degradation, and the molecular mechanisms underlying As(2)O(3)-induced PML/RARA degradation have been recently clarified. As discussed below, arsenic binding, oxidation, sumoylation on PML nuclear bodies, and RNF4-mediated ubiquitination all contribute to the As(2)O(3)-triggered catabolism of PML/RARA. Copyright © 2011 Elsevier Ltd. All rights reserved.

Retinoic acid signaling in cancer: The parable of acute promyelocytic leukemia.

PubMed

Ablain, Julien; de Thé, Hugues

2014-11-15

Inevitably fatal some 40 years, acute promyelocytic leukemia (APL) can now be cured in more than 95% of cases. This clinical success story is tightly linked to tremendous progress in our understanding of retinoic acid (RA) signaling. The discovery of retinoic acid receptor alpha (RARA) was followed by the cloning of the chromosomal translocations driving APL, all of which involve RARA. Since then, new findings on the biology of nuclear receptors have progressively enlightened the basis for the clinical efficacy of RA in APL. Reciprocally, the disease offered a range of angles to approach the cellular and molecular mechanisms of RA action. This virtuous circle contributed to make APL one of the best-understood cancers from both clinical and biological standpoints. Yet, some important questions remain unanswered including how lessons learnt from RA-triggered APL cure can help design new therapies for other malignancies. © 2014 UICC.

Revisiting the Phadia/EliA cut-off values for anticardiolipin and anti-β2-glycoprotein I antibodies: a systematic evaluation according to the guidelines.

PubMed

Bor, M V; Jacobsen, I-L Søtang; Gram, J B; Sidelmann, J J

2018-01-01

Background Phadia/EliA fluorescence enzyme immunoassays are widely used automated assays for anticardiolipin (aCL) and anti-β2-glycoprotein I (aβ2GPI) antibodies. To date, cut-off values for these assays have not been evaluated systematically and the evidence behind manufacturer's recommended cut-off values is not clear. Objective To determine Phadia/EliA cut-off values for antiphospholipid antibodies (aPL) according to the procedures suggested by guidelines. Methods A total of 266 blood donors (135 females and 131 males) were included. The pre-handling and analysis of the samples were performed according to the International Society on Thrombosis and Hemostasis (ISTH) guideline for solid phase aPL assays. Cut-off values and corresponding 90% confidence intervals (CI) for each antibody were established and outliers were handled according to the Clinical and Laboratory Standards Institute (CLSI) guideline for reference intervals. Samples from 377 consecutive patients, referred to our thrombophilia center with evidence of thrombosis or pregnancy morbidity were included for aPL testing. Results The in-house 99th (97.5th) percentile cut-off values were 11 (8.7), 12 (6.9) 8.5 (5.0) AU/mL for aβ2GPI IgG, IgM and IgA, and 21 (13) GPL-U/mL and 41 (25) MPL-U/mL for aCL IgG and IgM, respectively. The prevalence of positive results (%) defined by these cut-off values in patients with evidence of thrombosis or pregnancy morbidity was 9.5 (12.2), 1.6 (2.9), and 7.0 (9.9), and 0.8 (3.8) for aβ2GPI IgG, IgM, and aCL IgG and IgM respectively. The use of in-house 99th percentile cut-off values compared to the manufacturer suggested cut-off values resulted in 1 and 39 fewer samples for aβ2GPI and aCL to be classified as positive for aPL, respectively. Conclusions We present Phadia/EliA cut-off values with 90% CI for aPL determined systematically according to the ISTH and CLSI guidelines. These values are different from values previously determined, suggesting variation of aPLs in different populations. Our findings indicate the need for each laboratory to determine/validate assay specific cut-off values for aPL.

Acute promyelocytic leukemia, arsenic, and PML bodies

PubMed Central

Le Bras, Morgane; Lallemand-Breitenbach, Valérie

2012-01-01

Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose product, the PML/retinoic acid (RA) receptor α (RARA) fusion protein, affects both nuclear receptor signaling and PML body assembly. Dissection of APL pathogenesis has led to the rediscovery of PML bodies and revealed their role in cell senescence, disease pathogenesis, and responsiveness to treatment. APL is remarkable because of the fortuitous identification of two clinically effective therapies, RA and arsenic, both of which degrade PML/RARA oncoprotein and, together, cure APL. Analysis of arsenic-induced PML or PML/RARA degradation has implicated oxidative stress in the biogenesis of nuclear bodies and SUMO in their degradation. PMID:22778276

The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies.

PubMed

de Thé, Hugues; Le Bras, Morgane; Lallemand-Breitenbach, Valérie

2012-07-09

Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose product, the PML/retinoic acid (RA) receptor α (RARA) fusion protein, affects both nuclear receptor signaling and PML body assembly. Dissection of APL pathogenesis has led to the rediscovery of PML bodies and revealed their role in cell senescence, disease pathogenesis, and responsiveness to treatment. APL is remarkable because of the fortuitous identification of two clinically effective therapies, RA and arsenic, both of which degrade PML/RARA oncoprotein and, together, cure APL. Analysis of arsenic-induced PML or PML/RARA degradation has implicated oxidative stress in the biogenesis of nuclear bodies and SUMO in their degradation.

ZBTB16-RARα variant of acute promyelocytic leukemia with tuberculosis: a case report and review of literature.

PubMed

Palta, Anshu; Dhiman, Pratibha; Cruz, Sanjay D

2012-09-01

A 23-year-old male presented with pulmonary tuberculosis and swelling of both lower limbs. He was put on antitubercular treatment. Hemogram showed mild anemia and Pseudo Pelger-huet cells. The bone marrow (BM) examination showed 52% promyelocytes with regular round to oval nuclei, few granules and were positive for CD13 and CD33, and negative for HLA-DR. Cytogenetic analysis of the BM aspirate revealed an apparently balanced t(11;17)(q23;q21). Final diagnosis rendered was acute promyelocytic leukemia (APL) with t(11;17)(q23;q21); ZBTB16/RARA. APL is a distinct subtype of acute myeloid leukemia. The variant APL with t(11;17)(q23;q21) cases that are associated with the ZBTB16/RARA fusion gene have been reported as being resistant to all-trans-retinoic acid (ATRA). Therefore, differential diagnosis of variant APL with t(11;17)(q23;q12) from classical APL with t(15;17)(q22;q12); PML-RARA is very important. Here we have discussed the importance of distinct morphology of variant APL and also significance of rare presentation with tuberculosis.

Some practical approaches to a course on paraconsistent logic for engineers

NASA Astrophysics Data System (ADS)

Lambert-Torres, Germano; de Moraes, Carlos Henrique Valerio; Coutinho, Maurilio Pereira; Martins, Helga Gonzaga; Borges da Silva, Luiz Eduardo

2017-11-01

This paper describes a non-classical logic course primarily indicated for graduate students in electrical engineering and energy engineering. The content of this course is based on the vision that it is not enough for a student to indefinitely accumulate knowledge; it is necessary to explore all the occasions to update, deepen, and enrich that knowledge, adapting it to a complex world. Therefore, this course is not tied to theoretical formalities and tries at each moment to provide a practical view of the non-classical logic. In the real world, the inconsistencies are important and cannot be ignored because contradictory information brings relevant facts, sometimes modifying the entire result of the analysis. As consequence, the non-classical logics, such as annotated paraconsistent logic - APL, are efficiently framed in the approach of complex situations of the real world. In APL, the concepts of unknown, partial, ambiguous, and inconsistent knowledge are referred not to trivialise any system in analysis. This course presents theoretical and applicable aspects of APL, which are successfully used in decision-making structures. The course is divided into modules: Basic, 2vAPL, 3vAPL, 4vAPL, and Final Project.

A Study on Corrosion Inhibitor for Mild Steel in Ethanol Fuel Blend

PubMed Central

Vu, Nguyen Si Hoai; Hien, Pham Van; Man, Tran Van; Hanh Thu, Vu Thi; Tri, Mai Dinh

2017-01-01

The main aim of this study is to investigate Aganonerion polymorphum leaf-ethyl acetate extract (APL-EAE) and its inhibiting effect for steel in ethanol fuel blend. The immersion test, electrochemical and surface analysis techniques were successfully carried out in this research. Scanning electron microscope images indicated that the ethanol fuel blend induced pitting corrosion of steel. Remarkably, the surface of the sample containing 1000 ppm APL-EAE is smoother than the others submerged in different conditions. The electrochemical impedance spectroscopy result shows that APL-EAE has formed a good protective layer, preventing corrosive factors from hitting the steel surface. The potentiodynamic polarization data argue that the corrosion inhibition efficiency was strengthened with the increase of APL-EAE concentration. The Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy demonstrated less intensity of Fe peaks, higher intensity of C1s peak and the appearance of organic peaks (N1s, P2p, O1s) from specimens with and without APL-EAE addition. Therefore, the results suggest the formation of the protective film on steel surface and affirm that APL-EAE has served as an effective corrosion inhibitor for steel in ethanol fuel blend. PMID:29301224

Identification of a novel fusion gene, IRF2BP2-RARA, in acute promyelocytic leukemia.

PubMed

Yin, C Cameron; Jain, Nitin; Mehrotra, Meenakshi; Zhagn, Jianhua; Protopopov, Alexei; Zuo, Zhuang; Pemmaraju, Naveen; DiNardo, Courtney; Hirsch-Ginsberg, Cheryl; Wang, Sa A; Medeiros, L Jeffrey; Chin, Lynda; Patel, Keyur P; Ravandi, Farhad; Futreal, Andrew; Bueso-Ramos, Carlos E

2015-01-01

Acute promyelocytic leukemia (APL) is characterized by the fusion of retinoic acid receptor alpha (RARA) with promyelocytic leukemia (PML) or, rarely, other gene partners. This report presents a patient with APL with a novel fusion between RARA and the interferon regulatory factor 2 binding protein 2 (IRF2BP2) genes. A bone marrow examination in a 19-year-old woman who presented with ecchymoses and epistaxis showed morphologic and immunophenotypic features consistent with APL. PML oncogenic domain antibody was positive. Results of fluorescence in situ hybridization, conventional cytogenetics, reverse transcription-polymerase chain reaction (RT-PCR), and oligonucleotide microarray for PML-RARA and common APL variant translocations were negative. Next-generation RNA-sequencing analysis followed by RT-PCR and direct sequencing revealed distinct breakpoints within IRF2BP2 exon 2 and RARA intron 2. The patient received all-trans retinoic acid, arsenic, and gemtuzumab ozogamicin, and achieved complete remission. However, the disease relapsed 10 months later, 2 months after consolidation therapy. This is the first report showing involvement of IRF2BP2 in APL, and it expands the list of novel RARA partners identified in APL. Copyright © 2015 by the National Comprehensive Cancer Network.

A Study on Corrosion Inhibitor for Mild Steel in Ethanol Fuel Blend.

PubMed

Vu, Nguyen Si Hoai; Hien, Pham Van; Man, Tran Van; Hanh Thu, Vu Thi; Tri, Mai Dinh; Nam, Nguyen Dang

2017-12-31

The main aim of this study is to investigate Aganonerion polymorphum leaf-ethyl acetate extract (APL-EAE) and its inhibiting effect for steel in ethanol fuel blend. The immersion test, electrochemical and surface analysis techniques were successfully carried out in this research. Scanning electron microscope images indicated that the ethanol fuel blend induced pitting corrosion of steel. Remarkably, the surface of the sample containing 1000 ppm APL-EAE is smoother than the others submerged in different conditions. The electrochemical impedance spectroscopy result shows that APL-EAE has formed a good protective layer, preventing corrosive factors from hitting the steel surface. The potentiodynamic polarization data argue that the corrosion inhibition efficiency was strengthened with the increase of APL-EAE concentration. The Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy demonstrated less intensity of Fe peaks, higher intensity of C 1s peak and the appearance of organic peaks (N 1s , P 2p , O 1s ) from specimens with and without APL-EAE addition. Therefore, the results suggest the formation of the protective film on steel surface and affirm that APL-EAE has served as an effective corrosion inhibitor for steel in ethanol fuel blend.

Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation.

PubMed

Nasr, Rihab; Guillemin, Marie-Claude; Ferhi, Omar; Soilihi, Hassan; Peres, Laurent; Berthier, Caroline; Rousselot, Philippe; Robledo-Sarmiento, Macarena; Lallemand-Breitenbach, Valérie; Gourmel, Bernard; Vitoux, Dominique; Pandolfi, Pier Paolo; Rochette-Egly, Cécile; Zhu, Jun; de Thé, Hugues

2008-12-01

Retinoic acid and arsenic trioxide target the protein stability and transcriptional repression activity of the fusion oncoprotein PML-RARA, resulting in regression of acute promyelocytic leukemia (APL). Phenotypically, retinoic acid induces differentiation of APL cells. Here we show that retinoic acid also triggers growth arrest of leukemia-initiating cells (LICs) ex vivo and their clearance in PML-RARA mouse APL in vivo. Retinoic acid treatment of mouse APLs expressing the fusion protein PLZF-RARA triggers full differentiation, but not LIC loss or disease remission, establishing that differentiation and LIC loss can be uncoupled. Although retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation. A cyclic AMP (cAMP)-dependent phosphorylation site in PML-RARA is crucial for retinoic acid-induced PML-RARA degradation and LIC clearance. Moreover, activation of cAMP signaling enhances LIC loss by retinoic acid, identifying cAMP as another potential APL therapy. Thus, whereas transcriptional activation of PML-RARA is likely to control differentiation, its catabolism triggers LIC eradication and long-term remission of mouse APL. Therapy-triggered degradation of oncoproteins could be a general strategy to eradicate cancer stem cells.

Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure.

PubMed

Ablain, Julien; Rice, Kim; Soilihi, Hassane; de Reynies, Aurélien; Minucci, Saverio; de Thé, Hugues

2014-02-01

Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)-retinoic acid receptor-α (PML-RARA) fusion protein, which interferes with nuclear receptor signaling and PML nuclear body (NB) assembly. APL is the only malignancy definitively cured by targeted therapies: retinoic acid (RA) and/or arsenic trioxide, which both trigger PML-RARA degradation through nonoverlapping pathways. Yet, the cellular and molecular determinants of treatment efficacy remain disputed. We demonstrate that a functional Pml-transformation-related protein 53 (Trp53) axis is required to eradicate leukemia-initiating cells in a mouse model of APL. Upon RA-induced PML-RARA degradation, normal Pml elicits NB reformation and induces a Trp53 response exhibiting features of senescence but not apoptosis, ultimately abrogating APL-initiating activity. Apart from triggering PML-RARA degradation, arsenic trioxide also targets normal PML to enhance NB reformation, which may explain its clinical potency, alone or with RA. This Pml-Trp53 checkpoint initiated by therapy-triggered NB restoration is specific for PML-RARA-driven APL, but not the RA-resistant promyelocytic leukemia zinc finger (PLZF)-RARA variant. Yet, as NB biogenesis is druggable, it could be therapeutically exploited in non-APL malignancies.

A retrospective review of vital signs and clinical outcomes of febrile infants younger than 3 months old presenting to the emergency department.

PubMed

Chong, Shu-Ling; Ong, Gene Yong-Kwang; Chin, Wendy Yi Wen; Chua, John Mingzhou; Nair, Praseetha; Ong, Alicia Shu Zhen; Ng, Kee Chong; Maconochie, Ian

2018-01-01

Febrile infants younger than 3 months old present a diagnostic dilemma to the emergency physician. We aim to describe a large population of febrile infants less than 3 months old presenting to a pediatric emergency department (ED) and to assess the performance of current heart rate guidelines in the prediction of serious infections (SI). We performed a retrospective review of febrile infants younger than 3 months old, between March 2015 and Feb 2016, in a large tertiary pediatric ED. We documented the primary outcome of SI for each infant, as well as the clinical findings, vital signs, and Severity Index Score (SIS). We assessed the performance of the Paediatric Canadian Triage and Acuity Scale (PaedCTAS), Advanced Pediatric Life Support (APLS) guidelines and Fleming normal reference values, using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under receiver operating characteristics curve (AUC). 1057 infants were analyzed, with 326 (30.6%) infants diagnosed with SI. High temperature, tachycardia, and low SIS score were significantly associated with SI. Item analysis showed that the SIS performance was driven by the presence of mottling (p = 0.003) and high temperature (p<0.001). The APLS guideline had the highest sensitivity (66.0%, 95% CI 60.5-71.1%), NPV (73.3%, 95% CI 69.7-76.5%) and AUC (0.538), while the PaedCTAS (2 standard deviation from normal) had the highest specificity (98.5%, 95% CI 97.3-99.3%) and PPV (55.2%, 95% CI 32.7-71.0%). Current guidelines on infantile heart rates have a variable performance. In our study, the APLS heart rate guidelines performed with the highest sensitivity, but no individual guideline predicted for SIs satisfactorily.

Autophagy contributes to 4-Amino-2-Trifluoromethyl-Phenyl Retinate-induced differentiation in human acute promyelocytic leukemia NB4 cells

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

Li, Yue; Li, Ge; Wang, Ke

As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in treatment of acute promyelocytic leukemia (APL). However, clinical application of ATRA has limitations. Our previous studies suggested that 4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, could induce differentiation of APL cells in vivo and in vitro. To explore the underlying mechanism of ATPR, the effect of ATPR on autophagy of APL cells was observed in the present study. The results showed that the differentiation effect of ATPR on APL cells was accompanied with autophagy induction and PML-RARαmore » degradation via activating Notch1 signaling pathway. Moreover, inhibition of autophagy using 3-methyladenine (3-MA) or small interfering RNA (siRNA) that targets essential autophagy gene ATG5 abrogated the ATPR-induced cell differentiation. Furthermore, when pretreated with DAPT, a γ-secretase inhibitor, the Notch1 signaling pathway was blocked in APL cells, followed by the reduction of ATPR-induced autophagy and differentiation. Taken together, these results suggested that autophagy play an important role in ATPR-induced cell differentiation, which may provide a novel approach to cure APL patients. - Highlights: • ATPR induces autophagy in APL cell line NB4 cells. • Autophagy induction is essential for cell differentiation in NB4 cells. • Notch1 signaling is involved in ATPR-induced autophagy and differentiation in NB4 cells.« less

The impact of oral arsenic and all-trans-retinoic acid on coagulopathy in acute promyelocytic leukemia.

PubMed

Zhu, Hong-Hu; Guo, Zhi-Ping; Jia, Jin-Song; Jiang, Qian; Jiang, Hao; Huang, Xiao-Jun

2018-02-01

The aim of our study was to evaluate the impact of oral arsenic (the realgar-indigo naturalis formula, RIF) and all-trans retinoic acid (ATRA) on coagulopathy in acute promyelocytic leukemia (APL) compared with intravenous arsenic trioxide (ATO) and ATRA during induction. Mitoxantrone was added to all the patients at a dose of 1.4mg/m 2 per day for 5-7 days. D-dimer levels, prothrombin time (PT), fibrinogen (Fbg) levels and the platelet count were comparably analyzed among 83 newly diagnosed APL patients treated with RIF (n=45) or with ATO (n=38). Since induction therapy with RIF and ATRA, the median levels of Fbg, PT and platelets were recovered to the normal range within 4days, 10days and 28days, respectively. The last day of platelet and plasma transfusion was day 12 (range: 0-24 days) and day 3 (range: 0-27 days), respectively. Among the 42 patients with a disseminated intravascular coagulation (DIC) score=4, the consumption of transfused platelets was less in the RIF group than that in the ATO group (P=0.037). In the 17 patients with a DIC score <4, prompt recovery of Fbg levels (P=0.028) was observed in the RIF group compared with that in the ATO group (P=0.401). RIF and ATO showed similar effects on the recovery of coagulopathy in APL patients. RIF had a potential beneficial effect in accelerating the recovery of thrombocytopenia and hypofibrinogenemia for subclinical DIC patients. Copyright © 2017. Published by Elsevier Ltd.

"Here the Scientists Explain What I Said." Coordination Practices Elicited during the Enactment of the Results and Discussion Sections of Adapted Primary Literature

ERIC Educational Resources Information Center

Falk, Hedda; Yarden, Anat

2009-01-01

Adapted primary literature (APL) is a novel text genre that retains the authentic characteristics of primary literature. Learning through APL represents an educational intervention with an authentic scientific context. In this case study, we analyzed the 80-min discourse developed during the enactment of an article from an APL-based curriculum in…

Arsenic speciation in hair and nails of acute promyelocytic leukemia (APL) patients undergoing arsenic trioxide treatment.

PubMed

Chen, Baowei; Cao, Fenglin; Lu, Xiufen; Shen, Shengwen; Zhou, Jin; Le, X Chris

2018-07-01

Arsenic in hair and nails has been used to assess chronic exposure of humans to environmental arsenic. However, it remains to be seen whether it is appropriate to evaluate acute exposure to sub-lethal doses of arsenic typically used in therapeutics. In this study, hair, fingernail and toenail samples were collected from nine acute promyelocytic leukemia (APL) patients who were administered intravenously the daily dose of 10 mg arsenic trioxide (7.5 mg arsenic) for up to 54 days. These hair and nail samples were analyzed for arsenic species using high performance liquid chromatography separation and inductively coupled plasma mass spectrometry detection (HPLC-ICPMS). Inorganic arsenite was the predominant form among water-extractable arsenicals. Dimethylarsinic acid (DMA V ), monomethylarsonic acid (MMA V ), monomethylarsonous acid (MMA III ), monomethylmonothioarsonic acid (MMMTA V ), and dimethylmonothioarsinic acid (DMMTA V ) were also detected in both hair and nail samples. This is the first report of the detection of MMA III and MMMTA V as metabolites of arsenic in hair and nails of APL patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Comparative study of active plasma lenses in high-quality electron accelerator transport lines

NASA Astrophysics Data System (ADS)

van Tilborg, J.; Barber, S. K.; Benedetti, C.; Schroeder, C. B.; Isono, F.; Tsai, H.-E.; Geddes, C. G. R.; Leemans, W. P.

2018-05-01

Electrically discharged active plasma lenses (APLs) are actively pursued in compact high-brightness plasma-based accelerators due to their high-gradient, tunable, and radially symmetric focusing properties. In this manuscript, the APL is experimentally compared with a conventional quadrupole triplet, highlighting the favorable reduction in the energy dependence (chromaticity) in the transport line. Through transport simulations, it is explored how the non-uniform radial discharge current distribution leads to beam-integrated emittance degradation and a charge density reduction at focus. However, positioning an aperture at the APL entrance will significantly reduce emittance degradation without additional loss of charge in the high-quality core of the beam. An analytical model is presented that estimates the emittance degradation from a short beam driving a longitudinally varying wakefield in the APL. Optimizing laser plasma accelerator operation is discussed where emittance degradation from the non-uniform discharge current (favoring small beams inside the APL) and wakefield effects (favoring larger beam sizes) is minimized.

Comparative study of active plasma lenses in high-quality electron accelerator transport lines

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

van Tilborg, J.; Barber, S. K.; Benedetti, C.

Electrically discharged active plasma lenses (APLs) are actively pursued in compact high-brightness plasma-based accelerators due to their high-gradient, tunable, and radially symmetric focusing properties. In this paper, the APL is experimentally compared with a conventional quadrupole triplet, highlighting the favorable reduction in the energy dependence (chromaticity) in the transport line. Through transport simulations, it is explored how the non-uniform radial discharge current distribution leads to beam-integrated emittance degradation and a charge density reduction at focus. However, positioning an aperture at the APL entrance will significantly reduce emittance degradation without additional loss of charge in the high-quality core of the beam.more » An analytical model is presented that estimates the emittance degradation from a short beam driving a longitudinally varying wakefield in the APL. Finally, optimizing laser plasma accelerator operation is discussed where emittance degradation from the non-uniform discharge current (favoring small beams inside the APL) and wakefield effects (favoring larger beam sizes) is minimized.« less

Comparative study of active plasma lenses in high-quality electron accelerator transport lines

DOE PAGES

van Tilborg, J.; Barber, S. K.; Benedetti, C.; ...

2018-03-13

Electrically discharged active plasma lenses (APLs) are actively pursued in compact high-brightness plasma-based accelerators due to their high-gradient, tunable, and radially symmetric focusing properties. In this paper, the APL is experimentally compared with a conventional quadrupole triplet, highlighting the favorable reduction in the energy dependence (chromaticity) in the transport line. Through transport simulations, it is explored how the non-uniform radial discharge current distribution leads to beam-integrated emittance degradation and a charge density reduction at focus. However, positioning an aperture at the APL entrance will significantly reduce emittance degradation without additional loss of charge in the high-quality core of the beam.more » An analytical model is presented that estimates the emittance degradation from a short beam driving a longitudinally varying wakefield in the APL. Finally, optimizing laser plasma accelerator operation is discussed where emittance degradation from the non-uniform discharge current (favoring small beams inside the APL) and wakefield effects (favoring larger beam sizes) is minimized.« less

ATO/ATRA/anthracycline-chemotherapy sequential consolidation achieves long-term efficacy in primary acute promyelocytic leukemia.

PubMed

Long, Zi-Jie; Hu, Yuan; Li, Xu-Dong; He, Yi; Xiao, Ruo-Zhi; Fang, Zhi-Gang; Wang, Dong-Ning; Liu, Jia-Jun; Yan, Jin-Song; Huang, Ren-Wei; Lin, Dong-Jun; Liu, Quentin

2014-01-01

The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3, ATO) has been effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL), but the long-term efficacy and safety among newly diagnosed APL patients are unclear. In this retrospective study, total 45 newly diagnosed APL patients received ATRA/chemotherapy combination regimen to induce remission. Among them, 43 patients (95.6%) achieved complete remission (CR) after induction therapy, followed by ATO/ATRA/anthracycline-based chemotherapy sequential consolidation treatment with a median follow-up of 55 months. In these patients, the estimated overall survival (OS) and the relapse-free survival (RFS) were 94.4% ± 3.9% and 94.6 ± 3.7%, respectively. The toxicity profile was mild and reversible. No secondary carcinoma was observed. These results demonstrated the high efficacy and minimal toxicity of ATO/ATRA/anthracycline-based chemotherapy sequential consolidation treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for APL.

The role of clinically significant antiphospholipid antibodies in systemic lupus erythematosus.

PubMed

Taraborelli, M; Lazzaroni, M G; Martinazzi, N; Fredi, M; Cavazzana, I; Franceschini, F; Tincani, A

2016-12-16

The objective is to investigate the role of clinically significant antiphospholipid antibodies (aPL) in a cohort of systemic lupus erythematosus (SLE) patients. All SLE patients followed for at least 5 years and with available aPL profile at the beginning of the follow-up in our center were studied. Clinically significant aPL were defined as: positive lupus anticoagulant test, anti-cardiolipin and/or anti- β2Glycoprotein I IgG/IgM >99th percentile on two or more occasions at least 12 weeks apart. Patients with and without clinically significant aPL were compared by univariate (Chi square or Fisher's exact test for categorical variables and Student's t or Mann-Whitney test for continuous variables) and multivariate analysis (logistic regression analysis). P values <0.05 were considered significant. Among 317 SLE patients studied, 117 (37%) had a clinically significant aPL profile at baseline. Such patients showed at univariate analysis an increased prevalence of deep venous thrombosis, pulmonary embolism, cardiac valvular disease, cognitive dysfunction and antiphospholipid syndrome (APS), but a reduced prevalence of acute cutaneous lupus and anti-extractable nuclear antigens (ENA) when compared with patients without clinically significant aPL. Multivariate analysis confirmed the association between clinically significant aPL and reduced risk of acute cutaneous lupus [p=0.003, odds ratio (OR) 0.43] and ENA positivity (p<0.001, OR 0.37), with increased risk of cardiac valvular disease (p=0.024, OR 3.1) and APS (p<0.0001, OR 51.12). Triple positivity was the most frequent profile and was significantly associated to APS (p<0.0001, OR 28.43). Our study showed that one third of SLE patients had clinically significant aPL, and that this is associated with an increased risk, especially for triple positive, of APS, and to a different clinical and serological pattern of disease even in the absence of APS.

Deciphering mechanisms underlying the genetic variation of general production and liver quality traits in the overfed mule duck by pQTL analyses.

PubMed

François, Yoannah; Vignal, Alain; Molette, Caroline; Marty-Gasset, Nathalie; Davail, Stéphane; Liaubet, Laurence; Marie-Etancelin, Christel

2017-04-19

The aim of this study was to analyse the mechanisms that underlie phenotypic quantitative trait loci (QTL) in overfed mule ducks by identifying co-localized proteomic QTL (pQTL). The QTL design consisted of three families of common ducks that were progeny-tested by using 294 male mule ducks. This population of common ducks was genotyped using a genetic map that included 334 genetic markers located across 28 APL chromosomes (APL for Anas platyrhynchos). Mule ducks were phenotyped for 49 traits related to growth, metabolism, overfeeding ability and meat and fatty liver quality, and 326 soluble fatty liver proteins were quantified. One hundred and seventy-six pQTL and 80 phenotypic QTL were detected at the 5% chromosome-wide significance threshold. The great majority of the identified pQTL were trans-acting and localized on a chromosome other than that carrying the coding gene. The most significant pQTL (1% genome-wide significance) were found for alpha-enolase on APL18 and fatty acid synthase on APL24. Some proteins were associated with numerous pQTL (for example, 17 and 14 pQTL were detected for alpha-enolase and apolipoprotein A1, respectively) and pQTL hotspots were observed on some chromosomes (APL18, 24, 25 and 29). We detected 66 co-localized phenotypic QTL and pQTL for which the significance of the two-trait QTL (2t-QTL) analysis was higher than that of the strongest QTL using a single-trait approach. Among these, 16 2t-QTL were pleiotropic. For example, on APL15, melting rate and abundance of two alpha-enolase spots appeared to be impacted by a single locus that is involved in the glycolytic process. On APLZ, we identified a pleiotropic QTL that modified both the blood level of glucose at the beginning of the force-feeding period and the concentration of glutamate dehydrogenase, which, in humans, is involved in increased glucose absorption by the liver when the glutamate dehydrogenase 1 gene is mutated. We identified pleiotropic loci that affect metabolic pathways linked to glycolysis or lipogenesis, and in the end to fatty liver quality. Further investigation, via transcriptomics and metabolomics approaches, is required to confirm the biomarkers that were found to impact the genetic variability of these phenotypic traits.

Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.

PubMed

Trabanelli, Sara; Chevalier, Mathieu F; Martinez-Usatorre, Amaia; Gomez-Cadena, Alejandra; Salomé, Bérengère; Lecciso, Mariangela; Salvestrini, Valentina; Verdeil, Grégory; Racle, Julien; Papayannidis, Cristina; Morita, Hideaki; Pizzitola, Irene; Grandclément, Camille; Bohner, Perrine; Bruni, Elena; Girotra, Mukul; Pallavi, Rani; Falvo, Paolo; Leibundgut, Elisabeth Oppliger; Baerlocher, Gabriela M; Carlo-Stella, Carmelo; Taurino, Daniela; Santoro, Armando; Spinelli, Orietta; Rambaldi, Alessandro; Giarin, Emanuela; Basso, Giuseppe; Tresoldi, Cristina; Ciceri, Fabio; Gfeller, David; Akdis, Cezmi A; Mazzarella, Luca; Minucci, Saverio; Pelicci, Pier Giuseppe; Marcenaro, Emanuela; McKenzie, Andrew N J; Vanhecke, Dominique; Coukos, George; Mavilio, Domenico; Curti, Antonio; Derré, Laurent; Jandus, Camilla

2017-09-19

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth.

[Harringtonine induces apoptosis in NB4 cells through down-regulation of Mcl-1].

PubMed

Wu, Chunxiao; Shen, Hongqiang; Xia, Dajing

2013-07-01

To investigate the growth inhibition effect, cytotoxicity and apoptotic induction of harringtonine (HT) in human acute promyelocytic leukemia (APL) NB4 cells,and the related mechanism. NB4 cells were treated with HT. Total cell numbers were counted by hemocytometer, and cell viabilities were determined by trypan blue exclusion. Apoptotic cells were determined by fluorescence microscopy and FACS after staining with AO and EB or PI, respectively. The cleavage of PARP and the activation of Bax and the expression of anti-apoptotic proteins were determined by Western Blot. siRNA was used to silence the expression of target genes. Primary cells were isolated following Ficoll-Hypaque density gradient centrifugation method. HT inhibited cell growth and induced apoptosis of NB4 cells in a dose- and time-dependent manner. Apoptosis induced by HT was correlated with the down-regulation of Mcl-1 and the cleavage of PARP, while HT did not affect the protein level of Bax and Bak or change the protein level of Bcl-2. The silence of Bcl-XL sensitized HT-induced apoptosis in NB4 cells.Apoptosis induced by HT in primarily cultured APL cells was also correlated with the down-regulation of Mcl-1. HT inhibits cell growth and induces apoptosis in NB4 cells and primarily cultured APL cells, which may be associated with down-regulation of Mcl-1.

Acute Promyelocytic Leukemia Presenting as Focal Neurologic Findings and Deteriorating Mental Status.

PubMed

Dolan, Matthew; Ngaruiya, Christine

2017-01-01

Acute promyelocytic leukemia (APL) is a rare but particularly malignant form of acute leukemia that is characterized by a rapid progression to fatal hemorrhage. Survival rates of patients with APL have increased with the introduction of all-trans retinoic acid (ATRA), but early deaths caused by hemorrhage still persist. A man with undiagnosed APL presenting with focal neurologic findings and deteriorating altered mental status caused by an intracranial hemorrhage is discussed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is important to consider APL when diagnosing etiologies for intracranial hemorrhage. In addition to standard care, early administration of ATRA is recommended upon clinical suspicion of the disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Analysis performed in support of the Ad-Hoc Working Group of RTCA SC-159 on RAIM/FDE issues

DOT National Transportation Integrated Search

2002-01-01

In 1999, the FAA requested that RTCA SC-159 address one of the recommendations from the study performed by the Johns Hopkins University (JHU) Applied Physics Lab (APL) on the use of GPS and augmented GPS for aviation applications. This recommendation...

Autonomous Operations Mission Development Suite

NASA Technical Reports Server (NTRS)

Toro Medina, Jaime A.

2016-01-01

This is a presentation related to the development of Autonomous Operations Systems at NASA Kennedy Space Center. It covers a high level description of the work of FY14, FY15, FY16 for the AES IGODU and APL projects.

Multiple Autonomous Discrete Event Controllers for Constellations

NASA Technical Reports Server (NTRS)

Esposito, Timothy C.

2003-01-01

The Multiple Autonomous Discrete Event Controllers for Constellations (MADECC) project is an effort within the National Aeronautics and Space Administration Goddard Space Flight Center's (NASA/GSFC) Information Systems Division to develop autonomous positioning and attitude control for constellation satellites. It will be accomplished using traditional control theory and advanced coordination algorithms developed by the Johns Hopkins University Applied Physics Laboratory (JHU/APL). This capability will be demonstrated in the discrete event control test-bed located at JHU/APL. This project will be modeled for the Leonardo constellation mission, but is intended to be adaptable to any constellation mission. To develop a common software architecture. the controllers will only model very high-level responses. For instance, after determining that a maneuver must be made. the MADECC system will output B (Delta)V (velocity change) value. Lower level systems must then decide which thrusters to fire and for how long to achieve that (Delta)V.

Simulating soil phosphorus dynamics for a phosphorus loss quantification tool.

PubMed

Vadas, Peter A; Joern, Brad C; Moore, Philip A

2012-01-01

Pollution of fresh waters by agricultural phosphorus (P) is a water quality concern. Because soils can contribute significantly to P loss in runoff, it is important to assess how management affects soil P status over time, which is often done with models. Our objective was to describe and validate soil P dynamics in the Annual P Loss Estimator (APLE) model. APLE is a user-friendly spreadsheet model that simulates P loss in runoff and soil P dynamics over 10 yr for a given set of runoff, erosion, and management conditions. For soil P dynamics, APLE simulates two layers in the topsoil, each with three inorganic P pools and one organic P pool. It simulates P additions to soil from manure and fertilizer, distribution among pools, mixing between layers due to tillage and bioturbation, leaching between and out of layers, crop P removal, and loss by surface runoff and erosion. We used soil P data from 25 published studies to validate APLE's soil P processes. Our results show that APLE reliably simulated soil P dynamics for a wide range of soil properties, soil depths, P application sources and rates, durations, soil P contents, and management practices. We validated APLE specifically for situations where soil P was increasing from excessive P inputs, where soil P was decreasing due to greater outputs than inputs, and where soil P stratification occurred in no-till and pasture soils. Successful simulations demonstrate APLE's potential to be applied to major management scenarios related to soil P loss in runoff and erosion. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

Arsenic trioxide at conventional dosage does not aggravate hemorrhage in the first-line treatment of adult acute promyelocytic leukemia.

PubMed

Cui, Wen; Wang, Jin; Nie, Rui-Min; Zhao, Ling-Ling; Gao, Meng-Qing; Zhu, Hong-Ming; Chen, Li; Hu, Jiong; Li, Jun-Min; Shen, Zhi-Xiang; Wang, Zhen-Yi; Chen, Sai-Juan; Chen, Zhu; Wang, Kan-Kan; Xi, Xiao-Dong; Mi, Jian-Qing

2018-04-01

The arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) therapy has demonstrated a tremendous success in the first-line treatment of acute promyelocytic leukemia (APL). Actually, early death (ED) is currently thought as a major challenge in APL. ATO has been reported to inhibit platelet function in vitro, and whether it increases the ED rate by exacerbating the hemorrhagic symptoms remains to be investigated. Effects of ATO on platelet aggregation and adhesion were evaluated in vitro and in thirty-two complete remission (CR) and four newly diagnosed APL patients. Furthermore, concentrations of plasma total arsenic were monitored in APL patients via ICP-MS. The inhibition of platelet function, either aggregation or adhesion, did occur in vitro when the concentration of ATO reached 2 μmol/L. However, in CR APL patients receiving ATO with normal platelet count, the platelets responded normally when being activated and so did those in the newly diagnosed patients with thrombocytopenia. Our data further showed that the conventional dosage of ATO reached a plasma concentration substantially below the required concentration to inhibit platelets. In the first-line treatment of APL, the use of ATO is safe and effective and does not compromise the hemostatic potential that may eventually increase ED rate. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Characteristics features and factors influencing early death in Acute promyelocytic leukemia; Experience from United Arab Emirates (UAE).

PubMed

Hassan, Inaam Bashir; Zaabi, Mariam R Al; Alam, Arif; Hashim, Mohammed Jawad; Tallman, Martin S; Kristensen, Jorgen

2017-07-01

Although acute promyelocytic leukemia (APL) is a curable hematologic malignancy, early death (ED) remains a significant cause of treatment failure especially in developing countries. In a retrospective data analysis of 67 adult APL patients diagnosed in United Arab Emirates we report an ED rate of 11.9% which is comparable to that reported from more developed countries. We identified the following parameters at presentation as significant predictor of increased ED: Age >40 years (P = 0.015), fever (P = 0.030), WBC count >20 × 10 9 /L (P = 0.010), the breakpoints other than bcr1 (P = 0.043) and fibrinogen level <1.5 g/L (P = 0.025). Delay in ATRA administration beyond 24 h from admission and fibrinogen <150 mg/dL were also significant predictors of ED, but only among high-risk patients (P = 0.035 and P = 0.033, respectively). WBC count >10 × 10 9 /L and expression of HLA-DR (P = 0.018) or CD2 (P = 0.017) were significant predictors for differentiation syndrome (DS) which was found to be a predictor of ED (P = 0.002). Reducing the APL related ED rate in centers with limited resources is feasible provided early initiation of ATRA administration and early correction of coagulopathy in high-risk patients in addition to prompt treatment of DS. To our knowledge this is the first report from the Arabian Gulf describing ED in APL.

Workspace Program for Complex-Number Arithmetic

NASA Technical Reports Server (NTRS)

Patrick, M. C.; Howell, Leonard W., Jr.

1986-01-01

COMPLEX is workspace program designed to empower APL with complexnumber capabilities. Complex-variable methods provide analytical tools invaluable for applications in mathematics, science, and engineering. COMPLEX written in APL.

Intelligent microchip networks: an agent-on-chip synthesis framework for the design of smart and robust sensor networks

NASA Astrophysics Data System (ADS)

Bosse, Stefan

2013-05-01

Sensorial materials consisting of high-density, miniaturized, and embedded sensor networks require new robust and reliable data processing and communication approaches. Structural health monitoring is one major field of application for sensorial materials. Each sensor node provides some kind of sensor, electronics, data processing, and communication with a strong focus on microchip-level implementation to meet the goals of miniaturization and low-power energy environments, a prerequisite for autonomous behaviour and operation. Reliability requires robustness of the entire system in the presence of node, link, data processing, and communication failures. Interaction between nodes is required to manage and distribute information. One common interaction model is the mobile agent. An agent approach provides stronger autonomy than a traditional object or remote-procedure-call based approach. Agents can decide for themselves, which actions are performed, and they are capable of flexible behaviour, reacting on the environment and other agents, providing some degree of robustness. Traditionally multi-agent systems are abstract programming models which are implemented in software and executed on program controlled computer architectures. This approach does not well scale to micro-chip level and requires full equipped computers and communication structures, and the hardware architecture does not consider and reflect the requirements for agent processing and interaction. We propose and demonstrate a novel design paradigm for reliable distributed data processing systems and a synthesis methodology and framework for multi-agent systems implementable entirely on microchip-level with resource and power constrained digital logic supporting Agent-On-Chip architectures (AoC). The agent behaviour and mobility is fully integrated on the micro-chip using pipelined communicating processes implemented with finite-state machines and register-transfer logic. The agent behaviour, interaction (communication), and mobility features are modelled and specified on a machine-independent abstract programming level using a state-based agent behaviour language (APL). With this APL a high-level agent compiler is able to synthesize a hardware model (RTL, VHDL), a software model (C, ML), or a simulation model (XML) suitable to simulate a multi-agent system using the SeSAm simulator framework. Agent communication is provided by a simple tuple-space database implemented on node level providing fault tolerant access of global data. A novel synthesis development kit (SynDK) based on a graph-structured database approach is introduced to support the rapid development of compilers and synthesis tools, used for example for the design and implementation of the APL compiler.

Evaluation of the Vienna APL corrections using reprocessed GNSS series

NASA Astrophysics Data System (ADS)

Steigenberger, P.; Dach, R.

2011-12-01

The Institute of Geodesy and Geophysics of the Vienna University of Technology recently started an operational service to provide non-tidal atmospheric pressure loading (APL) corrections. As the series is based on European Centre for Medium-Range Weather Forecasts (ECMWF) pressure data, it is fully consistent with the Vienna Mapping Function 1 (VMF1) atmospheric delay correction model for microwave measurements. Whereas VMF1 is widely used for, e.g., observations of Global Navigation Satellite Systems (GNSS), applying APL corrections is not yet a standard nowadays. The Center for Orbit Determination in Europe (CODE) - a joint venture between the Astronomical Institute of the University of Bern (AIUB, Bern, Switzerland), the Federal Office of Topography (swisstopo, Wabern, Switzerland), the Federal Office for Cartography and Geodesy (BKG, Frankfurt am Main, Germany), and the Insitute for Astronomical and Physical Geodesy, TU Muenchen (IAPG, Munich, Germany) - uses a recently generated series of reprocessed multi-GNSS data (considering GPS and GLONASS) to evaluate the APL corrections provided by the Vienna group. The results are also used to investigate the propagation of the APL effect in GNSS-derived results if no corrections are applied.

Background and applications of astrodynamics for space missions of the johns hopkins applied physics laboratory.

PubMed

Dunham, David W; Farquhar, Robert W

2004-05-01

This paper describes astrodynamic techniques applied to develop special orbital designs for past and future space missions of the Applied Physics Laboratory (APL) of Johns Hopkins University, and background about those techniques. The paper does not describe the long history of low Earth-orbiting missions at APL, but rather concentrates on the astrodynamically more interesting high-altitude and interplanetary missions that APL has undertaken in recent years. The authors developed many of their techniques in preparation for, and during, the Third International Sun-Earth Explorer (ISEE-3) halo orbit mission while they worked for the Goddard Space Flight Center (GSFC) of NASA during the 1970s and 1980s. Later missions owed much to the ground breaking work of the trajectory designs for ISEE-3 (later known as the International Cometary Explorer, or ICE). This experience, and other new ideas, were applied to the APL near Earth asteroid rendezvous (NEAR) and comet nucleus tour (CONTOUR) discovery missions, as well as to APL's future MESSENGER, STEREO, and New Horizons missions. These will be described in the paper.

Association of human papilloma virus with atypical and malignant oral papillary lesions.

PubMed

McCord, Christina; Xu, Jing; Xu, Wei; Qiu, Xin; Muhanna, Nidal; Irish, Jonathan; Leong, Iona; McComb, Richard John; Perez-Ordonez, Bayardo; Bradley, Grace

2014-06-01

This study aimed to examine atypical and malignant papillary oral lesions for low- and high-risk human papillomavirus (HPV) infection and to correlate HPV infection with clinical and pathologic features. Sections of 28 atypical papillary lesions (APLs) and 14 malignant papillary lesions (MPLs) were examined for HPV by in situ hybridization and for p16 and MIB-1 by immunohistochemistry; 24 conventional papillomas were studied for comparison. Low-risk HPV was found in 10 of 66 cases, including 9 APLs and 1 papilloma. All low-risk HPV-positive cases showed suprabasilar MIB-1 staining, and the agreement was statistically significant (P < .0001). Diffuse p16 staining combined with high-risk HPV was not seen in any of the cases. A subset of HPV(-) APLs progressed to carcinoma. Oral papillary lesions are a heterogeneous group. Low-risk HPV infection is associated with a subset of APLs with a benign clinical course. Potentially malignant APLs and MPLs are not associated with low- or high-risk HPV. Copyright © 2014 Elsevier Inc. All rights reserved.

Revisiting the differentiation paradigm in acute promyelocytic leukemia.

PubMed

Ablain, Julien; de The, Hugues

2011-06-02

As the result of intense clinical and basic research, acute promyelocytic leukemia (APL) has progressively evolved from a deadly to a curable disease. Historically, efforts aimed at understanding the molecular bases for therapy response have repeatedly illuminated APL pathogenesis. The classic model attributes this therapeutic success to the transcriptional reactivation elicited by retinoic acid and the resulting overcoming of the differentiation block characteristic of APL blasts. However, in clinical practice, retinoic acid by itself only rarely yields prolonged remissions, even though it induces massive differentiation. In contrast, as a single agent, arsenic trioxide neither directly activates transcription nor triggers terminal differentiation ex vivo, but cures many patients. Here we review the evidence from recent ex vivo and in vivo studies that allow a reassessment of the role of differentiation in APL cure. We discuss alternative models in which PML-RARA degradation and the subsequent loss of APL cell self-renewal play central roles. Rather than therapy aimed at inducing differentiation, targeting cancer cell self-renewal may represent a more effective goal, achievable by a broader range of therapeutic agents.

30-Day In-vivo Performance of a Wearable Artificial Pump-Lung for Ambulatory Respiratory Support

PubMed Central

Wu, Zhongjun J; Zhang, Tao; Bianchi, Giacomo; Wei, Xufeng; Son, Ho-Sung; Zhou, Kang; Sanchez, Pablo; Garcia, Jose; Griffith, Bartley P

2011-01-01

Background The purpose of this study was to evaluate the long-term in-vivo hemodynamics, gas transfer and biocompatibility of an integrated artificial pump-lung (APL) developed for ambulatory respiratory support. Methods The study was conducted in an ovine model by surgically placing the APL between the right atrium and pulmonary artery. Nine sheep were implanted. Heparin was infused as an anticoagulant. The device flow, gas transfer and plasma free hemoglobin (PFH) were measured daily. Hematological data, platelet activation and blood biochemistry were assessed twice a week. After 30 days, the sheep were euthanized for necropsy. The explanted devices were examined for gross thrombosis. Results Five sheep survived for 29 to 31 days and were electively terminated. Four sheep expired or were terminated early due to mechanical failure of IV lines or device. The APL devices in the five long-term animals were capable of delivering an oxygen transfer rate of 148±18 ml/min at a flow rate of 2.99±0.46 l/min with blood oxygen saturation of 96.7±1.3%. The device flow and oxygen transfer were stable over 30 days. The animals had normal end-organ functions except for surgery-related transient alteration in kidney function, liver function, and cell and tissue injury. There was no hemolysis. The device flow path and membrane surface were free of gross thrombus. Conclusions The APL exhibited the capability of providing respiratory support with excellent biocompatibility, long-term reliability and the potential for bridging to lung transplant. PMID:22115337

A Recursive Method for Calculating Certain Partition Functions.

ERIC Educational Resources Information Center

Woodrum, Luther; And Others

1978-01-01

Describes a simple recursive method for calculating the partition function and average energy of a system consisting of N electrons and L energy levels. Also, presents an efficient APL computer program to utilize the recursion relation. (Author/GA)

Computer enhancement through interpretive techniques

NASA Technical Reports Server (NTRS)

Foster, G.; Spaanenburg, H. A. E.; Stumpf, W. E.

1972-01-01

The improvement in the usage of the digital computer through the use of the technique of interpretation rather than the compilation of higher ordered languages was investigated by studying the efficiency of coding and execution of programs written in FORTRAN, ALGOL, PL/I and COBOL. FORTRAN was selected as the high level language for examining programs which were compiled, and A Programming Language (APL) was chosen for the interpretive language. It is concluded that APL is competitive, not because it and the algorithms being executed are well written, but rather because the batch processing is less efficient than has been admitted. There is not a broad base of experience founded on trying different implementation strategies which have been targeted at open competition with traditional processing methods.

Antiphospholipid antibody-induced miR-146a-3p drives trophoblast interleukin-8 secretion through activation of Toll-like receptor 8.

PubMed

Gysler, Stefan M; Mulla, Melissa J; Guerra, Marta; Brosens, Jan J; Salmon, Jane E; Chamley, Lawrence W; Abrahams, Vikki M

2016-07-01

What is the role of microRNAs (miRs) in antiphospholipid antibody (aPL)-induced trophoblast inflammation? aPL-induced up-regulation of trophoblast miR-146a-3p is mediated by Toll-like receptor 4 (TLR4), and miR-146a-3p in turn drives the cells to secrete interleukin (IL)-8 by activating the RNA sensor, TLR8. Obstetric antiphospholipid syndrome (APS) is an autoimmune disorder characterized by circulating aPL and an increased risk of pregnancy complications. We previously showed that aPL recognizing beta2 glycoprotein I (β2GPI) elicit human first trimester trophoblast secretion of IL-8 by activating TLR4. Since some miRs control TLR responses, their regulation in trophoblast cells by aPL and functional role in the aPL-mediated inflammatory response was investigated. miRs can be released from cells via exosomes, and therefore, miR exosome expression was also examined. A panel of miRs was selected based on their involvement with TLR signaling: miR-9; miR-146a-5p and its isomiR, miR-146a-3p; miR-155, miR-210; and Let-7c. Since certain miRs can activate the RNA sensor, TLR8, this was also investigated. For in vitro studies, the human first trimester extravillous trophoblast cell line, HTR8 was studied. HTR8 cells transfected to express a TLR8 dominant negative (DN) were also used. Plasma was evaluated from pregnant women who have aPL, either with or without systemic lupus erythematous (SLE) (n = 39); SLE patients without aPL (n = 30); and healthy pregnant controls (n = 20). Trophoblast HTR8 wildtype and TLR8-DN cells were incubated with or without aPL (mouse anti-human β2GPI mAb) for 48-72 h. HTR8 cells were also treated with or without aPL in the presence and the absence of a TLR4 antagonist (lipopolysaccharide from Rhodobacter sphaeroides; LPS-RS), specific miR inhibitors or specific miR mimics. miR expression levels in trophoblast cells, trophoblast-derived exosomes and exosomes isolated from patient plasma were measured by qPCR. Trophoblast IL-8 secretion was measured by ELISA. aPL significantly increased trophoblast cellular and exosome expression of miR-146a-5p, miR-146a-3p, miR-155 and miR-210. aPL-induced up-regulation of trophoblast miR-146a-5p, miR-146a-3p and miR-210, but not miR-155, was inhibited by the TLR4 antagonist, LPS-RS. While inhibition or overexpression of miR-146a-5p had no effect on aPL-induced trophoblast IL-8 secretion, miR-146a-3p inhibition significantly reduced this response. aPL-induced trophoblast IL-8 secretion was inhibited by the presence of the TLR8-DN. In the absence of aPL, transfection of trophoblast cells with a miR-146a-3p mimic significantly increased IL-8 secretion and this was inhibited by the presence of the TLR8-DN. Patients with aPL and adverse pregnancy outcomes (APOs) expressed significantly higher levels of circulating miR-146a-3p compared with healthy pregnant controls with no pregnancy complications (P < 0.05). While the enrichment of miR-146a-3p in trophoblast-derived exosomes support the role of this miR acting in a paracrine or endocrine manner through exosome delivery, this has not been demonstrated. However, miR-146a-3p may also exert its pro-inflammatory effect intracellularly within the same trophoblast cell targeted by aPL. These findings provide a novel mechanism of trophoblast inflammation through miRs activating RNA-sensing receptors. Furthermore, circulating exosomal-associated miR-146a-3p in APS patients may serve clinically as a biomarker for related APOs. This study was supported in part by grants from the American Heart Association (#10GRNT3640032 to V.M.A.), the March of Dimes Foundation (Gene Discovery and Translational Research Grant #6-FY12-255 to V.M.A.), NICHD, NIH (R01HD049446 to V.M.A.), the Gina M. Finzi Memorial Student Summer Fellowship from the Lupus Foundation of America (to S.M.G.), and the Yale University School of Medicine Medical Student Fellowship (to S.M.G.). The authors declare no competing financial interests. N/A. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Frequency of Aquaporin-4 Immunoglobulin G in Longitudinally Extensive Transverse Myelitis With Antiphospholipid Antibodies.

PubMed

Guerra, Hilda; Pittock, Sean J; Moder, Kevin G; Fryer, James P; Gadoth, Avi; Flanagan, Eoin P

2018-04-11

Antiphospholipid (aPL) antibodies have historically been postulated to cause a poorly understood inflammatory myelitis. Neuromyelitis optica spectrum disorder (NMOSD) causes an inflammatory longitudinally extensive transverse myelitis (LETM). In 2004, aquaporin-4 immunoglobulin G (AQP4-IgG) was first reported as a highly specific (>99%) serum diagnostic biomarker of NMOSD, distinguishing it from other disorders (eg, multiple sclerosis). We sought to assess the frequency of AQP4-IgG (and thus NMOSD diagnosis) in LETM with aPL antibodies. We searched Mayo Clinic records (from January 1, 1996, through December 31, 2014) for patients with (1) LETM and (2) aPL or β 2 -glycoprotein I antibodies and (3) a serum sample available. AQP4-IgG was evaluated in the 24 included patients and in 20 controls with aPL antibodies but without myelitis. Seropositivity for AQP4-IgG was confirmed in 11 of 24 patients with LETM (46%), confirming an AQP4-IgG-seropositive NMOSD diagnosis rather than aPL-associated LETM. Six of 11 AQP4-IgG-seropositive patients (54%) were initially diagnosed as having aPL/lupus-associated myelitis. Recurrent LETM was exclusive to AQP4-IgG-seropositive patients (P=.003). Alternative diagnoses assigned to the remaining 13 AQP4-IgG-seronegative patients included idiopathic transverse myelitis (n=5), seronegative NMOSD (n=2), spinal cord infarct attributed to aPL antibodies (n=2), spinal cord sarcoidosis (n=1), varicella-zoster virus myelitis (n=1), postinfectious myelitis (n=1), and multiple sclerosis (n=1). All 20 controls were seronegative for AQP4-IgG. Clotting disorders occurred in 36% of patients (4 of 11) with LETM with both aPL antibodies and AQP4-IgG. AQP4-IgG should be tested in all patients with LETM and aPL antibodies because AQP4-IgG-seropositive NMOSD accounts for almost half of all cases. Clotting disorders are common in patients with LETM with dual positivity for AQP4-IgG and aPL antibodies. Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Molecular mechanisms of cisplatin cytotoxicity in acute promyelocytic leukemia cells.

PubMed

Kumar, Sanjay; Tchounwou, Paul B

2015-12-01

Cis-diamminedichloroplatinum (II) (cisplatin) is a widely used anti-tumor drug for the treatment of a broad range of human malignancies with successful therapeutic outcomes for head and neck, ovarian, and testicular cancers. It has been found to inhibit cell cycle progression and to induce oxidative stress and apoptosis in acute promyelocytic leukemia (APL) cells. However, its molecular mechanisms of cytotoxic action are poorly understood. We hypothesized that cisplatin induces cytotoxicity through DNA adduct formation, oxidative stress, transcriptional factors (p53 and AP-1), cell cycle regulation, stress signaling and apoptosis in APL cells. We used the APL cell line as a model, and applied a variety of molecular tools to elucidate the cytotoxic mode of action of cisplatin. We found that cisplatin inhibited cell proliferation by a cytotoxicity, characterized by DNA damage and modulation of oxidative stress. Cisplatin also activated p53 and phosphorylated activator protein (AP-1) component, c-Jun at serine (63, 73) residue simultaneously leading to cell cycle arrest through stimulation of p21 and down regulation of cyclins and cyclin dependent kinases in APL cell lines. It strongly activated the intrinsic pathway of apoptosis through alteration of the mitochondrial membrane potential, release of cytochrome C, and up-regulation of caspase 3 activity. It also down regulated the p38MAPK pathway. Overall, this study highlights the molecular mechanisms that underline cisplatin toxicity to APL cells, and provides insights into selection of novel targets and/or design of therapeutic agents to treat APL.

Arsenic trioxide promotes mitochondrial DNA mutation and cell apoptosis in primary APL cells and NB4 cell line.

PubMed

Meng, Ran; Zhou, Jin; Sui, Meng; Li, ZhiYong; Feng, GuoSheng; Yang, BaoFeng

2010-01-01

This study aimed to investigate the effects of arsenic trioxide (As(2)O(3)) on the mitochondrial DNA (mtDNA) of acute promyelocytic leukemia (APL) cells. The NB4 cell line was treated with 2.0 micromol/L As(2)O(3) in vitro, and the primary APL cells were treated with 2.0 micromol/L As(2)O(3) in vitro and 0.16 mg kg(-1) d(-1) As(2)O(3) in vivo. The mitochondrial DNA of all the cells above was amplified by PCR, directly sequenced and analyzed by Sequence Navigatore and Factura software. The apoptosis rates were assayed by flow cytometry. Mitochondrial DNA mutation in the D-loop region was found in NB4 and APL cells before As(2)O(3) use, but the mutation spots were remarkably increased after As(2)O(3) treatment, which was positively correlated to the rates of cellular apoptosis, the correlation coefficient: r (NB4-As2O3)=0.973818, and r (APL-As2O3)=0.934703. The mutation types include transition, transversion, codon insertion or deletion, and the mutation spots in all samples were not constant and regular. It is revealed that As(2)O(3) aggravates mtDNA mutation in the D-loop region of acute promyelocytic leukemia cells both in vitro and in vivo. Mitochondrial DNA might be one of the targets of As(2)O(3) in APL treatment.

In Vivo Activation of cAMP Signaling Induces Growth Arrest and Differentiation in Acute Promyelocytic Leukemia

PubMed Central

Guillemin, Marie-Claude; Raffoux, Emmanuel; Vitoux, Dominique; Kogan, Scott; Soilihi, Hassane; Lallemand-Breitenbach, Valérie; Zhu, Jun; Janin, Anne; Daniel, Marie-Thérèse; Gourmel, Bernard; Degos, Laurent; Dombret, Hervé; Lanotte, Michel; de Thé, Hugues

2002-01-01

Differentiation therapy for acute myeloid leukemia uses transcriptional modulators to reprogram cancer cells. The most relevant clinical example is acute promyelocytic leukemia (APL), which responds dramatically to either retinoic acid (RA) or arsenic trioxide (As2O3). In many myeloid leukemia cell lines, cyclic adenosine monophosphate (cAMP) triggers growth arrest, cell death, or differentiation, often in synergy with RA. Nevertheless, the toxicity of cAMP derivatives and lack of suitable models has hampered trials designed to assess the in vivo relevance of theses observations. We show that, in an APL cell line, cAMP analogs blocked cell growth and unraveled As2O3-triggered differentiation. Similarly, in RA-sensitive or RA-resistant mouse models of APL, continuous infusions of 8-chloro-cyclic adenosine monophosphate (8-Cl-cAMP) triggered major growth arrest, greatly enhanced both spontaneous and RA- or As2O3-induced differentiation and accelerated the restoration of normal hematopoiesis. Theophylline, a well-tolerated phosphodiesterase inhibitor which stabilizes endogenous cAMP, also impaired APL growth and enhanced spontaneous or As2O3-triggered cell differentiation in vivo. Accordingly, in an APL patient resistant to combined RA–As2O3 therapy, theophylline induced blast clearance and restored normal hematopoiesis. Taken together, these results demonstrate that in vivo activation of cAMP signaling contributes to APL clearance, independently of its RA-sensitivity, thus raising hopes that other myeloid leukemias may benefit from this therapeutic approach. PMID:12438428

Treatment of osteoarthritis of the first carpometacarpal joint by resection-suspension-interposition arthoplasty using the split abductor pollicis longus tendon.

PubMed

Harenberg, P S; Jakubietz, M G; Jakubietz, R G; Schmidt, K; Meffert, R H

2013-02-01

Reduction of pain and gain of functionality in symptomatic osteoarthritis of the first carpometacarpal joint. Idiopathic, rheumatic, or posttraumatic osteoarthritis of the first carpometacarpal joint. RELATIVE CONTRAINDICATIONS: Poor general condition, poor condition of the hand's soft tissue/skin, chronic regional pain syndrome, current or recent infections of the hand, heavy manual labor (decision on a by-case basis). Supine position, hand pronated or slightly tilted. Upper arm tourniquet (Esmarch's method). Loupe magnification. Incision over the first extensor compartment. Exposure and incision of the thumb's basal joint. Resection of the trapezium. Exposure of the abductor pollicis longus (APL) tendon. Longitudinal split of the tendon harvesting the distally based ulnar part of the tendon. The split APL tendon is wrapped around the flexor carpi radialis (FCR) muscle tendon, suturing it to the tendon and back to itself. The rest of the split APL tendon is placed into the gap between the scaphoid and the first metacarpal bone, which is followed by wound closure. Plaster cast (thumb abduction splint) for 4 weeks. Stable commercially available wrist brace for at least 2 more weeks. There were no significant differences between the FCR arthroplasty (Epping's method) and the APL arthroplasty (Wulle's technique) regarding pain (visual analog scale), disability/usability (DASH score), or range of motion. Patients who had undergone APL arthroplasty showed significantly better grip and pinch strength. Furthermore, the operating time was significantly shorter and scars were significantly smaller in APL arthroplasty.

Difference in causes and prognostic factors of early death between cohorts with de novo and relapsed acute promyelocytic leukemia.

PubMed

Zhao, Hongli; Zhao, Yanqiu; Zhang, Yingmei; Hou, Jinxiao; Yang, Huiyuan; Cao, Fenglin; Yang, Yiju; Hou, Wenyi; Sun, Jiayue; Jin, Bo; Fu, Jinyue; Li, Haitao; Wang, Ping; Ge, Fei; Zhou, Jin

2018-03-01

Early death (ED) remains the most critical issue in the current care of patients with acute promyelocytic leukemia (APL). Very limited data are available regarding ED in patients with relapsed APL. In this retrospective study, 285 de novo and 79 relapsed patients were included. All patients received single-agent arsenic trioxide as induction therapy. The differences in baseline clinical features, incidence, causes, and prognostic factors of ED were compared between the two patient cohorts. The relapse cohort exhibited a better overall condition than the de novo cohort upon hospital admission. The ED rate in the relapsed patients (24.1%) was somewhat higher than that in the de novo patients (17.9%), although the difference was not significant (P = 0.219). For both cohorts, hemorrhage was the main cause of ED, followed by differentiation syndrome, infection, and other causes. Increased serum creatinine level, older age, male sex, white blood cell (WBC) count > 10 × 10 9 /L, and fibrinogen < 1 g/L were independently risk factors for ED in the de novo patients, whereas WBC count > 10 × 10 9 /L, elevated serum uric acid level, and D-dimer > 4 mg/L were independent risk factors for ED in the relapsed patients. These data furnish clinically relevant information that might be useful for designing more appropriate risk-adapted treatment protocols aimed at reducing ED rate in patients with relapsed APL.

A retrospective review of vital signs and clinical outcomes of febrile infants younger than 3 months old presenting to the emergency department

PubMed Central

Chong, Shu-Ling; Ong, Gene Yong-Kwang; Chin, Wendy Yi Wen; Chua, John Mingzhou; Nair, Praseetha; Ong, Alicia Shu Zhen; Ng, Kee Chong; Maconochie, Ian

2018-01-01

Objectives Febrile infants younger than 3 months old present a diagnostic dilemma to the emergency physician. We aim to describe a large population of febrile infants less than 3 months old presenting to a pediatric emergency department (ED) and to assess the performance of current heart rate guidelines in the prediction of serious infections (SI). Materials and methods We performed a retrospective review of febrile infants younger than 3 months old, between March 2015 and Feb 2016, in a large tertiary pediatric ED. We documented the primary outcome of SI for each infant, as well as the clinical findings, vital signs, and Severity Index Score (SIS). We assessed the performance of the Paediatric Canadian Triage and Acuity Scale (PaedCTAS), Advanced Pediatric Life Support (APLS) guidelines and Fleming normal reference values, using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under receiver operating characteristics curve (AUC). Results 1057 infants were analyzed, with 326 (30.6%) infants diagnosed with SI. High temperature, tachycardia, and low SIS score were significantly associated with SI. Item analysis showed that the SIS performance was driven by the presence of mottling (p = 0.003) and high temperature (p<0.001). The APLS guideline had the highest sensitivity (66.0%, 95% CI 60.5–71.1%), NPV (73.3%, 95% CI 69.7–76.5%) and AUC (0.538), while the PaedCTAS (2 standard deviation from normal) had the highest specificity (98.5%, 95% CI 97.3–99.3%) and PPV (55.2%, 95% CI 32.7–71.0%). Conclusions Current guidelines on infantile heart rates have a variable performance. In our study, the APLS heart rate guidelines performed with the highest sensitivity, but no individual guideline predicted for SIs satisfactorily. PMID:29304160

[Adaptation to hypoxia and hyperoxia improves physical endurance: the role of reactive oxygen species and redox-signaling].

PubMed

Sazontova, T G; Glazachev, O S; Bolotova, A V; Dudnik, E N; Striapko, N V; Bedareva, I V; Anchishkina, N A; Arkhipenko, Iu V

2012-06-01

We have conducted theoretical foundation, experimental analysis and a pilot study of a new method of adaptation to hypoxia and hyperoxia in the prevention of hypoxic and stress-induced disorders and improving the body's tolerance to physical stress. It has been shown in the experimental part that a combination of physical exercise with adaptation to hypoxia-hyperoxia significantly increased tolerance to acute physical load (APL) and its active phase. Analysis of lipid peroxidation processes, antioxidant enzymes and HSPs showed that short-term training for physical exercise by itself compensates the stressor, but not the hypoxic component of the APL, the combination of training with adaptation to hypoxia-hyperoxia completely normalizes the stressor and hypoxic components of APL. The pilot study has been performed to evaluate the effectiveness of hypoxic-hyperoxic training course in qualified young athletes with over-training syndrome. After completing the course of hypoxia-hyperoxia adaptation, 14 sessions, accompanied by light mode sports training, the athletes set the normalization of autonomic balance, increased resistance to acute hypoxia in hypoxic test, increased physical performance--increased PWC170, maximal oxygen consumption (VO2max) parameters, their relative values to body mass, diminished shift of rate pressure product in the load. Thus, we confirmed experimental findings that hypoxic-hyperoxic training optimizes hypoxic (increased athletes resistance to proper hypoxia) and stress (myocardium economy in acute physical stress testing) components in systemic adaptation and restoration of athletes' with over-training syndrome.

Microgranular variant of acute promyelocytic leukemia with der(17) ins(17;15): A case report and review of the literature

PubMed Central

GUAN, HONGZAI; LIU, JING; GUO, XIAOFANG; WU, CHUNMEI; YU, HUAWEI

2015-01-01

Acute promyelocytic leukemia (APL) with variant translocations is rare. The patient of the present case report, a 2-year-old male with a microgranular variant of APL carrying der(17) ins(17;15) translocation, exhibited fever and epistaxis. The complete blood count showed marked leukocytosis with 72% atypical promyelocytes, anemia and thrombocytopenia. Conventional cytogenetic analysis of the bone marrow cells revealed a karyotype of 47, XY, add(3)(q29), −7, ins(17;15)(q12;q14q22),+21,+mar. The promyelocytic leukemia/retinoic acid receptor α (PML/RARα) rearrangement and insertion were confirmed by fluorescence in situ hybridization. The PML/RARα transcripts were not detected by the reverse transcription polymerase chain reaction, and the patient was diagnosed with microgranular variant M3 APL. The patient achieved remission after a 30-day treatment and was still in remission during a recent follow-up. The present findings suggest that the ins(17;15) variant in APL may not be associated with an unfavorable prognosis. In summary, we reported an extremely rare case of APL with der(17) ins(17;15) abnormality in a pediatric patient and reviewed the literature. PMID:26622430

Pathogenesis and treatment of leukemia: an Asian perspective.

PubMed

Kwong, Yok-Lam

2012-03-01

Leukemias occur worldwide, but there are important geographic differences in incidences. Three leukemias with special Asian perspectives, acute promyelocytic leukemia (APL), T-cell large granular lymphocyte (T-LGL) leukemia and NK-cell leukemia. In APL, China has made contributions in discovering the efficacy of all-trans retinoic acid (ATRA) and arsenic trioxide. Some APL patients are potentially curable after treatment with ATRA or arsenic trioxide as a single agent. Combined treatment of APL with ATRA and arsenic trioxide induces remission with deeper molecular response. An oral formulation of arsenic trioxide is available, making outpatient treatment feasible. Future regimens for APL should examine how ATRA and arsenic trioxide can be optimally combined with other synergistic drugs. Asian patients with T-LGL leukemia present more frequently with pure red cell aplasia, but less frequently with neutropenia, recurrent infection, splenomegaly and rheumatoid arthritis as compared with Western patients. These differences have potential effects on treatment and disease pathogenesis. NK-cell leukemia is rapidly fatal and occurs almost exclusively in Asian and South American patients. Conventional anthracycline-based chemotherapy designed for B-cell lymphomas do not work in NK-cell leukemias. Novel therapeutic approaches targeting cellular signaling pathways or preferentially upregulated genes are needed to improve outcome.

Eradication of acute promyelocytic leukemia-initiating cells by PML/RARA-targeting.

PubMed

Nasr, Rihab; de Thé, Hugues

2010-06-01

Acute promyelocytic leukemia (APL) is characterized by a t(15;17) translocation that yields a PML/RARA fusion protein. Expression of PML/RARA, a potent transcriptional repressor, induces APL in mice. Both retinoic acid (RA) and arsenic trioxide directly target PML/RARA-mediated transcriptional repression and protein stability, inducing rapid differentiation of the promyelocytes and clinical remission in most APL patients. RA also triggers growth arrest and progressive clearance of leukemia initiating cells (LIC), both ex vivo and in vivo. Suboptimal RA concentrations or expression of the PLZF/RARA variant allows complete RA-induced differentiation, but neither LIC clearance nor disease remission. Thus, RA-induced differentiation and LIC clearance may be uncoupled. The RA/arsenic trioxide association, which dramatically synergizes for PML/RARA degradation but not for differentiation, rapidly clears LIC in a proteasome-dependent manner, resulting in APL eradication in murine models and patients. Collectively, these results demonstrate that LIC clearance, which mirrors PML/RARA degradation, is the primary basis for APL cure by the RA/arsenic trioxide association, rather than differentiation. Oncogene degradation could be a generally applicable therapeutic strategy to clear LICs in several types of tumors.

Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus‐Prone Mice

PubMed Central

Oaks, Zachary; Winans, Thomas; Caza, Tiffany; Fernandez, David; Liu, Yuxin; Landas, Steve K.; Banki, Katalin

2016-01-01

Objective Antiphospholipid antibodies (aPL) constitute a diagnostic criterion of systemic lupus erythematosus (SLE), and aPL have been functionally linked to liver disease in patients with SLE. Since the mechanistic target of rapamycin (mTOR) is a regulator of oxidative stress, a pathophysiologic process that contributes to the development of aPL, this study was undertaken in a mouse model of SLE to examine the involvement of liver mitochondria in lupus pathogenesis. Methods Mitochondria were isolated from lupus‐prone MRL/lpr, C57BL/6.lpr, and MRL mice, age‐matched autoimmunity‐resistant C57BL/6 mice as negative controls, and transaldolase‐deficient mice, a strain that exhibits oxidative stress in the liver. Electron transport chain (ETC) activity was assessed using measurements of oxygen consumption. ETC proteins, which are regulators of mitochondrial homeostasis, and the mTOR complexes mTORC1 and mTORC2 were examined by Western blotting. Anticardiolipin (aCL) and anti–β2‐glycoprotein I (anti‐β2GPI) autoantibodies were measured by enzyme‐linked immunosorbent assay in mice treated with rapamycin or mice treated with a solvent control. Results Mitochondrial oxygen consumption was increased in the livers of 4‐week‐old, disease‐free MRL/lpr mice relative to age‐matched controls. Levels of the mitophagy initiator dynamin‐related protein 1 (Drp1) were depleted while the activity of mTORC1 was increased in MRL/lpr mice. In turn, mTORC2 activity was decreased in MRL and MRL/lpr mice. In addition, levels of aCL and anti‐β2GPI were elevated preceding the development of nephritis in 4‐week‐old MRL, C57BL/6.lpr, and MRL/lpr mice. Transaldolase‐deficient mice showed increased oxygen consumption, depletion of Drp1, activation of mTORC1, and elevated expression of NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3), a pro‐oxidant subunit of ETC complex I, as well as increased production of aCL and anti‐β2GPI autoantibodies. Treatment with rapamycin selectively blocked mTORC1 activation, NDUFS3 expression, and aPL production both in transaldolase‐deficient mice and in lupus‐prone mice. Conclusion In lupus‐prone mice, mTORC1‐dependent mitochondrial dysfunction contributes to the generation of aPL, suggesting that such mechanisms may represent a treatment target in patients with SLE. PMID:27332042

Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus-Prone Mice.

PubMed

Oaks, Zachary; Winans, Thomas; Caza, Tiffany; Fernandez, David; Liu, Yuxin; Landas, Steve K; Banki, Katalin; Perl, Andras

2016-11-01

Antiphospholipid antibodies (aPL) constitute a diagnostic criterion of systemic lupus erythematosus (SLE), and aPL have been functionally linked to liver disease in patients with SLE. Since the mechanistic target of rapamycin (mTOR) is a regulator of oxidative stress, a pathophysiologic process that contributes to the development of aPL, this study was undertaken in a mouse model of SLE to examine the involvement of liver mitochondria in lupus pathogenesis. Mitochondria were isolated from lupus-prone MRL/lpr, C57BL/6.lpr, and MRL mice, age-matched autoimmunity-resistant C57BL/6 mice as negative controls, and transaldolase-deficient mice, a strain that exhibits oxidative stress in the liver. Electron transport chain (ETC) activity was assessed using measurements of oxygen consumption. ETC proteins, which are regulators of mitochondrial homeostasis, and the mTOR complexes mTORC1 and mTORC2 were examined by Western blotting. Anticardiolipin (aCL) and anti-β 2 -glycoprotein I (anti-β 2 GPI) autoantibodies were measured by enzyme-linked immunosorbent assay in mice treated with rapamycin or mice treated with a solvent control. Mitochondrial oxygen consumption was increased in the livers of 4-week-old, disease-free MRL/lpr mice relative to age-matched controls. Levels of the mitophagy initiator dynamin-related protein 1 (Drp1) were depleted while the activity of mTORC1 was increased in MRL/lpr mice. In turn, mTORC2 activity was decreased in MRL and MRL/lpr mice. In addition, levels of aCL and anti-β 2 GPI were elevated preceding the development of nephritis in 4-week-old MRL, C57BL/6.lpr, and MRL/lpr mice. Transaldolase-deficient mice showed increased oxygen consumption, depletion of Drp1, activation of mTORC1, and elevated expression of NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3), a pro-oxidant subunit of ETC complex I, as well as increased production of aCL and anti-β 2 GPI autoantibodies. Treatment with rapamycin selectively blocked mTORC1 activation, NDUFS3 expression, and aPL production both in transaldolase-deficient mice and in lupus-prone mice. In lupus-prone mice, mTORC1-dependent mitochondrial dysfunction contributes to the generation of aPL, suggesting that such mechanisms may represent a treatment target in patients with SLE. © 2016, The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Transfer Kinetics at the Aqueous/Non-Aqueous Phase Liquid Interface. A Statistical Mechanic Approach

NASA Astrophysics Data System (ADS)

Doss, S. K.; Ezzedine, S.; Ezzedine, S.; Ziagos, J. P.; Hoffman, F.; Gelinas, R. J.

2001-05-01

Many modeling efforts in the literature use a first-order, linear-driving-force model to represent the chemical dissolution process at the non-aqueous/aqueous phase liquid (NAPL/APL) interface. In other words, NAPL to APL phase flux is assumed to be equal to the difference between the solubility limit and the "bulk aqueous solution" concentrations times a mass transfer coefficient. Under such assumptions, a few questions are raised: where, in relation to a region of pure NAPL, does the "bulk aqueous solution" regime begin and how does it behave? The answers are assumed to be associated with an arbitrary, predetermined boundary layer, which separates the NAPL from the surrounding solution. The mass transfer rate is considered to be, primarily, limited by diffusion of the component through the boundary layer. In fact, compositional models of interphase mass transfer usually assume that a local equilibrium is reached between phases. Representing mass flux as a rate-limiting process is equivalent to assuming diffusion through a stationary boundary layer with an instantaneous local equilibrium and linear concentration profile. Some environmental researchers have enjoyed success explaining their data using chemical engineering-based correlations. Correlations are strongly dependent on the experimental conditions employed. A universally applicable theory for NAPL dissolution in natural systems does not exist. These correlations are usually expressed in terms of the modified Sherwood number as a function of Reynolds, Peclet, and Schmidt numbers. The Sherwood number may be interpreted as the ratio between the grain size and the thickness of the Nernst stagnant film. In the present study, we show that transfer kinetics at the NAPL/APL interface under equilibrium conditions disagree with approaches based on the Nernst stagnant film concept. It is unclear whether local equilibrium assumptions used in current models are suitable for all situations.A statistical mechanic framework has been chosen to study the transfer kinetic processes at the microscale level. The rationale for our approach is based on both the activation energy of transfer of an ion and its velocity across the NAPL/APL interface. There are four major energies controlling the interfacial NAPL dissolution kinetics: (de)solvation energy, interfacial tension energy, electrostatic energy, and thermal fluctuation energy. Transfer of an ion across the NAPL/APL interface is accelerated by the viscous forces which can be described using the averaged Langevin master equation. The resulting energies and viscous forces were combined using the Boltzmann probability distribution. Asymptotic time limits of the resulting kinetics lead to instantaneous local equilibrium conditions that contradict the Nernst equilibrium equation. The NAPL/APL interface is not an ideal one: it does not conserve energy and heat. In our case the interface is treated as a thin film or slush zone that alters the thermodynamic variables. Such added zone, between the two phases, is itself a phase, and, therefore, the equilibrium does not occur between two phases but rather three. All these findings led us to develop a new non-linearly coupled flow and transport system of equations which is able to account for specific chemical dissolution processes and precludes the need for empirical mass-transfer parameters. Work performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract W-7405-Eng-48.

Hughes syndrome and epilepsy: when to test for antiphospholipid antibodies?

PubMed

Noureldine, M H A; Harifi, G; Berjawi, A; Haydar, A A; Nader, M; Elnawar, R; Sweid, A; Al Saleh, J; Khamashta, M A; Uthman, I

2016-11-01

Epilepsy and seizures are reported among the neurological manifestations of antiphospholipid syndrome (APS) at a prevalence rate of approximately 8%, which is nearly 10 times the prevalence of epilepsy in the general population. The association of seizures with antiphospholipid antibodies (aPL) is even more significant in the presence of systemic lupus erythematosus (SLE). In this review, we discuss the epidemiological, pathophysiological, laboratory, clinical, and radiological aspects of this association, and derive suggestions on when to consider testing for aPL in epileptic patients and how to manage seizures secondary to APS based on literature data. Epilepsy due to APS should be considered in young patients presenting with seizures of unknown origin. Temporal lobe epilepsy seems to be particularly prevalent in APS patients. The pathogenesis is complex and may not only involve micro-thrombosis, but also a possible immune-mediated neuronal damage. Patients with seizures and positive aPL tend to develop thrombocytopenia and livedo racemosa more frequently compared with those without aPL. Magnetic resonance imaging (MRI) remains the imaging modality of choice in these patients. The presence of SLE and the presence of neurological symptoms significantly correlate with the presence of white matter changes on MRI. In contrast, the correlation between aPL positivity and the presence of white matter changes is very weak. Furthermore, MRI can be normal in more than 30-40% of neuropsychiatric lupus patients with or without aPL. aPL testing is recommended in young patients presenting with atypical seizures and multiple hyper-intensity lesions on brain MRI in the absence of other possible conditions. New MRI techniques can better understand the pathology of brain damage in neuro-APS. The therapeutic management of epileptic APS patients relies on anti-epileptic treatment and anticoagulant agents when there is evidence of a thrombotic event. In the absence of consensual recommendations, the decision of lifelong anticoagulation is discussed on a case-by-case basis. The anti-thrombotic benefit of hydroxychloroquine and statins is supported by several studies.

Contribution of Socioeconomic Status to Racial/Ethnic Disparities in Adverse Pregnancy Outcomes Among Women With Systemic Lupus Erythematosus.

PubMed

Kaplowitz, Elianna T; Ferguson, Sancia; Guerra, Marta; Laskin, Carl A; Buyon, Jill P; Petri, Michelle; Lockshin, Michael D; Sammaritano, Lisa R; Branch, D Ware; Merrill, Joan T; Katz, Patricia; Salmon, Jane E

2018-02-01

We examined rates of adverse pregnancy outcomes (APO) by race/ethnicity among women with systemic lupus erythematosus (SLE), with and without antiphospholipid antibodies (aPL), and whether socioeconomic status (SES) accounted for differences. Data were from the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study, a multicenter study that enrolled 346 patients with SLE and 62 patients with SLE and aPL (50% white, 20% African American, 17% Hispanic, 12% Asian/Pacific Islander). Measures of SES were educational attainment, median community income, and community education. Logistic regression analyses were conducted to determine odds of APO for each racial/ethnic group, controlling first for age and clinical variables, and then for SES. The frequency of APO in white women with SLE, with and without aPL, was 29% and 11%, respectively. For African American and Hispanic women it was approximately 2-fold greater. In African American women with SLE alone, adjustment for clinical variables attenuated the odds ratio (OR) from 2.7 (95% confidence interval [95% CI] 1.3-5.5) to 2.3 (95% CI 1.1-5.1), and after additional adjustment for SES, there were no longer significant differences in APO compared to whites. In contrast, in SLE patients with aPL, whites, African Americans, and Hispanics had markedly higher risks of APO compared to white SLE patients without aPL (OR 3.5 [95% CI 1.4-7.7], OR 12.4 [95% CI 1.9-79.8], and OR 10.4 [95% CI 2.5-42.4], respectively), which were not accounted for by clinical or SES covariates. This finding suggests that for African American women with SLE without aPL, SES factors are key contributors to disparities in APO, despite monthly care from experts, whereas other factors contribute to disparities in SLE with aPL. © 2017, American College of Rheumatology.

Risk-adapted treatment of acute promyelocytic leukemia: results from International Consortium for Childhood APL.

PubMed

Testi, Anna Maria; Pession, Andrea; Diverio, Daniela; Grimwade, David; Gibson, Brenda; de Azevedo, Amilcar Cardoso; Moran, Lorena; Leverger, Guy; Elitzur, Sarah; Hasle, Henrik; van der Werff Ten Bosch, Jutte; Smith, Owen; De Rosa, Marisa; Piciocchi, Alfonso; Lo Coco, Francesco; Foà, Robin; Locatelli, Franco; Kaspers, Gertjan J L

2018-05-22

Pediatric acute promyelocytic leukemia (APL), a rare childhood neoplasm, can be cured with all-trans retinoic acid (ATRA) and anthracycline. However, most published trials to date have employed high cumulative doses of anthracyclines. Here, we report the outcome of patients with newly diagnosed APL enrolled into the International Consortium for Childhood APL (ICC-APL-01) trial, which reduced anthracycline exposure but extended that of ATRA. The study recruited 258 children/adolescents with molecularly/cytogenetically-proven APL. Patients were stratified into standard-risk (SR) and high-risk (HR) according to the baseline WBC count (< or ≥10x10 9 /L); both groups received identical induction treatment with ATRA (25 mg/m 2 /day, for 30 consecutive days) and 3 doses of idarubicin (12 mg/m 2 /dose). Two or three blocks of consolidation therapy were administered to SR and HR patients, respectively, while maintenance therapy with low-dose chemotherapy and ATRA cycles was given to all patients for 2 years. The cumulative dose of daunorubicin-equivalent anthracyclines in SR and HR patients was lower than that of previous studies, being 355 mg/m 2 and 405 mg/m 2 in SR and HR patients, respectively. Hematologic remission was obtained in 97% of patients; 8 children died of intracranial hemorrhage in the first 2 weeks following diagnosis. The 5-year overall and event-free survival for the whole cohort were 94.6% and 79.9%, respectively; they were 98.4% and 89.4% in SR and 84.3% and 74.2% in HR patients (p=0.002 and p=0.043, respectively). These data demonstrate that extended use of ATRA coupled to a risk-adapted consolidation can achieve high cure rates in childhood APL and limit anthracycline exposure. The trial was registered at www.clinicaltrials.gov with the following identification number EudractCT 2008-002311-40. Copyright © 2018 American Society of Hematology.

Aspirin-triggered lipoxin prevents antiphospholipid antibody effects on human trophoblast migration and endothelial cell interactions.

PubMed

Alvarez, Angela M; Mulla, Melissa J; Chamley, Lawrence W; Cadavid, Angela P; Abrahams, Vikki M

2015-02-01

Antiphospholipid antibodies (aPL) interfere with several physiologic functions of human trophoblasts, including reducing their ability to migrate, decreasing their production of angiogenic factors, and inducing an inflammatory response. This may provide the underlying mechanism by which aPL responses lead to recurrent pregnancy loss or preeclampsia in women with obstetric antiphospholipid syndrome (APS). Although treatment with heparin may reduce the rate of recurrent pregnancy loss, the risk of preeclampsia remains high. Therefore, alternative treatments are needed for the management of pregnant patients with APS. Since aspirin-triggered lipoxins (ATLs) have immune and angiogenic modulatory properties, the objective of this study was to determine the effects of the ATL 15-epi-lipoxin A4 on the function of aPL-altered human trophoblasts in the first trimester of pregnancy. A first-trimester human trophoblast cell line (HTR8) was treated with mouse anti-human β2 -glycoprotein I monoclonal antibodies (aPL) in the presence or absence of the ATL 15-epi-lipoxin A4 . Trophoblast migration and interactions with endometrial endothelial cells were measured using Transwell and coculture assays. Trophoblast secretion of cytokines and angiogenic factors was measured by enzyme-linked immunosorbent assay. Treatment of HTR8 cells with ATL reversed the aPL-induced decrease in trophoblast migration, an effect that appeared to be regulated through restoration of interleukin-6 production. Using a model of spiral artery transformation, aPL and sera from APS patients with pregnancy morbidity disrupted trophoblast-endothelial cell interactions, and treatment with ATL restored the stability of the cocultures. In contrast, ATL treatment did not resolve the proinflammatory and antiangiogenic responses of trophoblasts induced by aPL. These findings indicate that ATLs may have some benefits in terms of preventing the effects of aPL on trophoblast function, which raises the possibility of the use of ATLs as an adjuvant therapy in women with aPL. Copyright © 2015 by the American College of Rheumatology.

Ground control system for the midcourse space experiment UTC clock

NASA Technical Reports Server (NTRS)

Dragonette, Richard

1994-01-01

One goal of the Midcourse Space Experiment (MSX) spacecraft Operations Planning Center is to maintain the onboard satellite UTC clock (UTC(MSX)) to within 1 millisecond of UTC(APL) (the program requirement is 10 msec). The UTC(MSX) clock employs as its time base an APL built 5 MHz quartz oscillator, which is expected to have frequency instabilities (aging rate + drift rate + frequency offset) that will cause the clock to drift approximately two to ten milliseconds per day. The UTC(MSX) clock can be advanced or retarded by the APL MSX satellite ground control center by integer multiples of 1 millisecond. The MSX Operations Planning Center is developing software which records the drift of UTC(MSX) relative to UTC(APL) and which schedules the time of day and magnitude of UTC(MSX) clock updates up to 48 hours in advance. Because of the manner in which MSX spacecraft activities are scheduled, MSX clock updates are planned 24 to 48 hours in advance, and stored in the satellite's computer controller for later execution. Data will be collected on the drift of UTC(MSX) relative to UTC(APL) over a three to five day period. Approximately six times per day, the time offset between UTC(MSX) and UTC(APL) will be measured by APL with a resolution of less than 100 microseconds. From this data a second order analytical model of the clock's drift will be derived. This model will be used to extrapolate the offset of the MSX clock in time from the present to 48 hours in the future. MSX clock updates will be placed on the spacecraft's daily schedule whenever the predicted clock offset exceeds 0.5 milliseconds. The paper includes a discussion of how the empirical model of the MSX clock is derived from satellite telemetry data, as well as the algorithm used to schedule MSX clock updates based on the model.

Reduced ADAMTS13 activity is associated with thrombotic risk in systemic lupus erythematosus.

PubMed

Martin-Rodriguez, S; Reverter, J C; Tàssies, D; Espinosa, G; Heras, M; Pino, M; Escolar, G; Diaz-Ricart, M

2015-10-01

Severe deficiency of ADAMTS13 activity leads to von Willebrand factor (VWF) ultralarge multimers with high affinity for platelets, causing thrombotic thrombocytopenic purpura. Other pathological conditions with moderate ADAMTS13 activity exhibit a thrombotic risk. We examined the ADAMTS13 activity in systemic lupus erythematosus (SLE) and its value as a thrombotic biomarker. ADAMTS13 activity, VWF antigen and multimeric structure, and vascular cell adhesion molecule 1 (VCAM-1) were measured in plasma samples from 50 SLE patients and 50 healthy donors. Disease activity (systemic lupus erythematosus disease activity index; SLEDAI) and organ damage (systemic lupus international collaborating clinics) scores, thrombotic events, antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPLs) were registered. SLE patients showed decreased ADAMTS13 activity and high VWF levels compared with controls (66 ± 27% vs. 101 ± 8%, P < 0.01, and 325 ± 151% vs. 81 ± 14%, P < 0.001). VCAM-1 levels were higher in SLE patients (P < 0.05). Considering three groups of SLE patients depending on ADAMTS13 activity (>60%, 60-40% and <40%), comparative analysis showed significant association between ADAMTS13 activity and SLEDAI (P < 0.05), presence of aPLs (P < 0.001), APS (P < 0.01) and thrombotic events (P < 0.01). Reduced ADAMTS13 activity together with increased VWF levels were especially notable in patients with active disease and with aPLs. ADAMTS13 activity, in combination with other laboratory parameters, could constitute a potential prognostic biomarker of thrombotic risk in SLE. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Paternity leave experiences of NHS doctors.

PubMed

Gordon, Hannah; Szram, Joanna

2013-10-01

This study assesses NHS doctors' experiences of paternity leave and evaluates whether practices have changed since the introduction of additional paternity leave (APL) in April 2011. An anonymised online survey designed to discover experiences and uptake of APL and ordinary paternity leave (OPL) was distributed to all members of the London Deanery Synapse® network. In total, 364 fathers responded. Their seniority ranged from foundation trainees to consultants. Following the formal introduction of OPL in 2003, the number of fathers taking any paternity leave increased (from 50% to 95.6%). The majority of respondents (76.7%) felt well supported by their employer. Since the introduction of APL, 3% of respondents took additional leave. Reasons for the low uptake of APL included the impracticalities of the law, poor awareness and perceived attitudes and implications for training. Problems with OPL included the inadequate provision of cover and difficulties in timing the leave appropriately.

Status and test report on the LANL-Boeing APLE/HPO flying-wire beam-profile monitor. Status report

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

Wilke, M.; Barlow, D.; Fortgang, C.

1994-07-01

The High-Power Oscillator (HPO) demonstration of the Average Power Laser Experiment (APLE) is a collaboration by Los Alamos National Laboratory and Boeing to demonstrate a 10 kW average power, 10 {mu}m free electron laser (FEL). As part of the collaboration, Los Alamos National Laboratory (LANL) is responsible for many of the electron beam diagnostics in the linac, transport, and laser sections. Because of the high duty factor and power of the electron beam, special diagnostics are required. This report describes the flying wire diagnostic required to monitor the beam profile during high-power, high-duty operation. The authors describe the diagnostic andmore » prototype tests on the Los Alamos APLE Prototype Experiment (APEX) FEL. They also describe the current status of the flying wires being built for APLE.« less

Antiglutamate Receptor Antibodies and Cognitive Impairment in Primary Antiphospholipid Syndrome and Systemic Lupus Erythematosus

PubMed Central

Gerosa, Maria; Poletti, Barbara; Pregnolato, Francesca; Castellino, Gabriella; Lafronza, Annalisa; Silani, Vincenzo; Riboldi, Piersandro; Meroni, Pier Luigi; Merrill, Joan T.

2016-01-01

Systemic lupus erythematosus (SLE) and antiphospholipid syndrome have an increased risk to develop cognitive impairment. A possible role for antiphospholipid antibodies (aPL) and antiglutamate receptor (anti-NMDA) antibodies in the pathogenesis of neurological manifestations of these two conditions, have been suggested. In particular, the role of anti-NMDA antibodies in the pathogenesis of neuropsychiatric SLE is supported by several experimental studies in animal models and by the finding of a correlation between anti-NMDA positivity in cerebrospinal fluid and neurological manifestations of SLE. However, data from the literature are controversial, as several studies have reported a correlation of these antibodies with mild cognitive impairment in SLE, but more recent studies have not confirmed this finding. The synergism between anti-NMDA and other concomitant autoantibodies, such as aPL, can be hypothesized to play a role in inducing the tissue damage and eventually the functional abnormalities. In line with this hypothesis, we have found a high incidence of at least one impaired cognitive domain in a small cohort of patients with primary APS (PAPS) and SLE. Interestingly, aPL were associated with low scoring for language ability and attention while anti-NMDA titers and mini-mental state examination scoring were inversely correlated. However, when patients were stratified according to the presence/absence of aPL, the correlation was confirmed in aPL positive patients only. Should those findings be confirmed, the etiology of the prevalent defects found in PAPS patients as well as the synergism between aPL and anti-NMDA antibodies would need to be explored. PMID:26870034

RARα-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia

PubMed Central

Guidez, Fabien; Parks, Sarah; Wong, Henna; Jovanovic, Jelena V.; Mays, Ashley; Gilkes, Amanda F.; Mills, Kenneth I.; Guillemin, Marie-Claude; Hobbs, Robin M.; Pandolfi, Pier Paolo; de Thé, Hugues; Solomon, Ellen; Grimwade, David

2007-01-01

Leukemia-associated chimeric oncoproteins often act as transcriptional repressors, targeting promoters of master genes involved in hematopoiesis. We show that CRABPI (encoding cellular retinoic acid binding protein I) is a target of PLZF, which is fused to RARα by the t(11;17)(q23;q21) translocation associated with retinoic acid (RA)-resistant acute promyelocytic leukemia (APL). PLZF represses the CRABPI locus through propagation of chromatin condensation from a remote intronic binding element culminating in silencing of the promoter. Although the canonical, PLZF-RARα oncoprotein has no impact on PLZF-mediated repression, the reciprocal translocation product RARα-PLZF binds to this remote binding site, recruiting p300, inducing promoter hypomethylation and CRABPI gene up-regulation. In line with these observations, RA-resistant murine PLZF/RARα+RARα/PLZF APL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RARα APL. RARα-PLZF confers RA resistance to a retinoid-sensitive acute myeloid leukemia (AML) cell line in a CRABPI-dependent fashion. This study supports an active role for PLZF and RARα-PLZF in leukemogenesis, identifies up-regulation of CRABPI as a mechanism contributing to retinoid resistance, and reveals the ability of the reciprocal fusion gene products to mediate distinct epigenetic effects contributing to the leukemic phenotype. PMID:18000064

Simultaneous determination of all-trans and 13-cis retinoic acids and their 4-oxo metabolites by adsorption liquid chromatography after solid-phase extraction.

PubMed

Lefebvre, P; Agadir, A; Cornic, M; Gourmel, B; Hue, B; Dreux, C; Degos, L; Chomienne, C

1995-04-07

All-trans retinoic acid (all-trans RA), the active metabolite of vitamin A, has been demonstrated to be an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (APL), the AML3 subtype of the FAB cytological classification. Complete remission is obtained by inducing terminal granulocytic differentiation of the leukemic cells. To study all-trans RA pharmacokinetics in patients with APL, a rapid, precise and selective high-performance liquid chromatographic (HPLC) assay was developed. This method is easy and shows good repeatability (C.V. = 8.41-12.44%), reproducibility (C.V. = 9.19-14.73%), accuracy (C.V. = 3.5-11%) and sensitivity with a detection limit of 5 pmol/ml. The analysis is performed using normal-phase HPLC in an isocratic mode with UV detection after solid-phase extraction on octadecyl (C18) columns. The mobile phase is hexane-dichloromethane-dioxane (78:18:4, v/v) containing 1% acetic acid.

ACARA - AVAILABILITY, COST AND RESOURCE ALLOCATION

NASA Technical Reports Server (NTRS)

Viterna, L. A.

1994-01-01

ACARA is a program for analyzing availability, lifecycle cost, and resource scheduling. It uses a statistical Monte Carlo method to simulate a system's capacity states as well as component failure and repair. Component failures are modelled using a combination of exponential and Weibull probability distributions. ACARA schedules component replacement to achieve optimum system performance. The scheduling will comply with any constraints on component production, resupply vehicle capacity, on-site spares, or crew manpower and equipment. ACARA is capable of many types of analyses and trade studies because of its integrated approach. It characterizes the system performance in terms of both state availability and equivalent availability (a weighted average of state availability). It can determine the probability of exceeding a capacity state to assess reliability and loss of load probability. It can also evaluate the effect of resource constraints on system availability and lifecycle cost. ACARA interprets the results of a simulation and displays tables and charts for: (1) performance, i.e., availability and reliability of capacity states, (2) frequency of failure and repair, (3) lifecycle cost, including hardware, transportation, and maintenance, and (4) usage of available resources, including mass, volume, and maintenance man-hours. ACARA incorporates a user-friendly, menu-driven interface with full screen data entry. It provides a file management system to store and retrieve input and output datasets for system simulation scenarios. ACARA is written in APL2 using the APL2 interpreter for IBM PC compatible systems running MS-DOS. Hardware requirements for the APL2 system include 640K of RAM, 2Mb of extended memory, and an 80386 or 80486 processor with an 80x87 math co-processor. A dot matrix printer is required if the user wishes to print a graph from a results table. A sample MS-DOS executable is provided on the distribution medium. The executable contains licensed material from the APL2 for the IBM PC product which is program property of IBM; Copyright IBM Corporation 1988 - All rights reserved. It is distributed with IBM's permission. The standard distribution medium for this program is a set of three 5.25 inch 360K MS-DOS format diskettes. The contents of the diskettes are compressed using the PKWARE archiving tools. The utility to unarchive the files, PKUNZIP.EXE, is included. ACARA was developed in 1992.

The Initial Atmospheric Transport (IAT) Code: Description and Validation

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

Morrow, Charles W.; Bartel, Timothy James

The Initial Atmospheric Transport (IAT) computer code was developed at Sandia National Laboratories as part of their nuclear launch accident consequences analysis suite of computer codes. The purpose of IAT is to predict the initial puff/plume rise resulting from either a solid rocket propellant or liquid rocket fuel fire. The code generates initial conditions for subsequent atmospheric transport calculations. The Initial Atmospheric Transfer (IAT) code has been compared to two data sets which are appropriate to the design space of space launch accident analyses. The primary model uncertainties are the entrainment coefficients for the extended Taylor model. The Titan 34Dmore » accident (1986) was used to calibrate these entrainment settings for a prototypic liquid propellant accident while the recent Johns Hopkins University Applied Physics Laboratory (JHU/APL, or simply APL) large propellant block tests (2012) were used to calibrate the entrainment settings for prototypic solid propellant accidents. North American Meteorology (NAM )formatted weather data profiles are used by IAT to determine the local buoyancy force balance. The IAT comparisons for the APL solid propellant tests illustrate the sensitivity of the plume elevation to the weather profiles; that is, the weather profile is a dominant factor in determining the plume elevation. The IAT code performed remarkably well and is considered validated for neutral weather conditions.« less

Speech recognition for embedded automatic positioner for laparoscope

NASA Astrophysics Data System (ADS)

Chen, Xiaodong; Yin, Qingyun; Wang, Yi; Yu, Daoyin

2014-07-01

In this paper a novel speech recognition methodology based on Hidden Markov Model (HMM) is proposed for embedded Automatic Positioner for Laparoscope (APL), which includes a fixed point ARM processor as the core. The APL system is designed to assist the doctor in laparoscopic surgery, by implementing the specific doctor's vocal control to the laparoscope. Real-time respond to the voice commands asks for more efficient speech recognition algorithm for the APL. In order to reduce computation cost without significant loss in recognition accuracy, both arithmetic and algorithmic optimizations are applied in the method presented. First, depending on arithmetic optimizations most, a fixed point frontend for speech feature analysis is built according to the ARM processor's character. Then the fast likelihood computation algorithm is used to reduce computational complexity of the HMM-based recognition algorithm. The experimental results show that, the method shortens the recognition time within 0.5s, while the accuracy higher than 99%, demonstrating its ability to achieve real-time vocal control to the APL.

The clinical significance of antiphospholipid antibodies in systemic lupus erythematosus

PubMed Central

Ünlü, Ozan; Zuily, Stephane; Erkan, Doruk

2016-01-01

Antiphospholipid syndrome (APS) is the association of thrombosis and/or pregnancy morbidity with antiphospholipid antibodies (aPL). Thirty to forty percent of systemic lupus erythematosus (SLE) patients are tested positive for aPL, which may have an impact on the SLE presentation, management, and prognosis. Compared with SLE patients without aPL, those with aPL have a higher prevalence of thrombosis, pregnancy morbidity, valve disease, pulmonary hypertension, livedo reticularis, thrombocytopenia, hemolytic anemia, acute/chronic renal vascular lesions, and moderate/severe cognitive impairment; worse quality of life; and higher risk of organ damage. The use of low-dose aspirin (LDA) is controversial for primary thrombosis and pregnancy morbidity prevention because of the lack of strong prospective controlled data. Similarly, the use of anticoagulation is controversial for patients with an aPL-related nephropathy. Until further studies are available, physicians should discuss the risk/benefits of LDA or anticoagulation as well as the available literature with patients. PMID:27708976

Nanotechnology Enabled Enhancement of Enzyme Activity and Thermostability: Study on Impaired Pectate Lyase from Attenuated Macrophomina phaseolina in Presence of Hydroxyapatite Nanoparticle

PubMed Central

Dutta, Nalok; Mukhopadhyay, Arka; Dasgupta, Anjan Kr.; Chakrabarti, Krishanu

2013-01-01

In this paper we show that hydroxyapatite nanoparticles (NP) can not only act as a chaperon (by imparting thermostability) but can serve as a synthetic enhancer of activity of an isolated extracellular pectate lyase (APL) with low native state activity. The purified enzyme (an attenuated strain of Macrophomina phaseolina) showed feeble activity at 50°C and pH 5.6. However, on addition of 10.5 µg/ml of hydroxyapatite nanoparticles (NP), APL activity increased 27.7 fold with a 51 fold increase in half-life at a temperature of 90°C as compared to untreated APL. The chaperon like activity of NP was evident from entropy–enthalpy compensation profile of APL. The upper critical temperature for such compensation was elevated from 50°C to 90°C in presence of NP. This dual role of NP in enhancing activity and conferring thermostability to a functionally impaired enzyme is reported for the first time. PMID:23691068

Endosomal Redox Signaling in the Antiphospholipid Syndrome.

PubMed

Lackner, Karl J; Manukyan, Davit; Müller-Calleja, Nadine

2017-04-01

It is well established that the antiphospholipid syndrome (APS) is caused by antiphospholipid antibodies (aPL). While several underlying mechanisms have been described in the past, many open questions remain. Here, we will review data on endosomal signaling and, in particular, redox signaling in APS. Endosomal redox signaling has been implicated in several cellular processes including signaling of proinflammatory cytokines. We have shown that certain aPL can activate endosomal NADPH-oxidase (NOX) in several cell types followed by induction of proinflammatory and procoagulant cellular responses in vitro. Involvement of endosomes in aPL signaling has also been reported by others. In wild-type mice but not in NOX-deficient mice, aPL accelerate venous thrombus formation underscoring the relevance of endosomal NOX. Furthermore, hydroxychloroquine (HCQ) inhibits activation of endosomal NOX and prevents thrombus formation in aPL-treated mice. Endosomal redox signaling is an important novel mechanism involved in APS pathogenesis. This makes endosomes a potential target for future treatment approaches of APS.

Arsenic Trioxide – An Old Drug Rediscovered

PubMed Central

Emadi, Ashkan; Gore, Steven D.

2010-01-01

Over the last 17 years, clinical trials conducted worldwide have demonstrated the efficacy of arsenic trioxide (As2O3) in the treatment of relapsed acute promyelocytic leukemia (APL). Currently, the role of As2O3 in front-line therapy is under investigation. Recent trials in the US have demonstrated that the addition of As2O3 to standard treatment regimens improves survival outcomes in patients with APL and may allow a reduction in cytotoxic chemotherapy exposure. As2O3 has also shown efficacy in other malignancies, particularly multiple myeloma and myelodysplastic syndromes. Therapeutic doses of As2O3 are well tolerated, with no evidence of long-term toxicity. Adverse events include APL differentiation syndrome, electrocardiographic abnormalities, and mild elevations in liver enzymes. This review highlights trials investigating the role of As2O3 in induction and consolidation for newly diagnosed APL, as well as its role in other hematologic malignancies. The chemistry, mechanisms of action, and clinical side effects of As2O3 are also discussed. PMID:20471733

Safety and fitness electronic records system (SAFER) : draft master test plan

DOT National Transportation Integrated Search

1995-12-31

The purpose of this plan is to establish a formal set of guidelines and activities to be : adhered to and performed by JHU/APL and the developer to ensure that the SAFER System has been tested successfully and is fully compliant with the SAFER System...

In-Service Support Plan for Electromagnetic Environment Effects.

DTIC Science & Technology

1978-05-05

assure highly motivated and trained Fleet personnel are placed in positions to initiate formal EME deficiency reports. The human factors and technological...Assistant I )eputy C hief of Naval Material AD P Automiated Data Processing ALRE-I1 Air-LUmnhed G uided Weapons System Perform-rance Re- port APL

PinAPL-Py: A comprehensive web-application for the analysis of CRISPR/Cas9 screens.

PubMed

Spahn, Philipp N; Bath, Tyler; Weiss, Ryan J; Kim, Jihoon; Esko, Jeffrey D; Lewis, Nathan E; Harismendy, Olivier

2017-11-20

Large-scale genetic screens using CRISPR/Cas9 technology have emerged as a major tool for functional genomics. With its increased popularity, experimental biologists frequently acquire large sequencing datasets for which they often do not have an easy analysis option. While a few bioinformatic tools have been developed for this purpose, their utility is still hindered either due to limited functionality or the requirement of bioinformatic expertise. To make sequencing data analysis of CRISPR/Cas9 screens more accessible to a wide range of scientists, we developed a Platform-independent Analysis of Pooled Screens using Python (PinAPL-Py), which is operated as an intuitive web-service. PinAPL-Py implements state-of-the-art tools and statistical models, assembled in a comprehensive workflow covering sequence quality control, automated sgRNA sequence extraction, alignment, sgRNA enrichment/depletion analysis and gene ranking. The workflow is set up to use a variety of popular sgRNA libraries as well as custom libraries that can be easily uploaded. Various analysis options are offered, suitable to analyze a large variety of CRISPR/Cas9 screening experiments. Analysis output includes ranked lists of sgRNAs and genes, and publication-ready plots. PinAPL-Py helps to advance genome-wide screening efforts by combining comprehensive functionality with user-friendly implementation. PinAPL-Py is freely accessible at http://pinapl-py.ucsd.edu with instructions and test datasets.

Retrospective analysis of 119 cases of pediatric acute promyelocytic leukemia: Comparisons of four treatment regimes

PubMed Central

LI, EN-QIN; XU, LING; ZHANG, ZHI-QUAN; XIAO, YAN; GUO, HAI-XIA; LUO, XUE-QUN; HU, QUN; LAI, DONG-BO; TU, LI-MING; JIN, RUN-MING

2012-01-01

Clinical trials have demonstrated that pediatric acute promyelocytic leukemia (APL) is highly curable. Small-scale studies have reported on the treatment of APL using one or two treatment regimes. Here, we report a multiple center-based study of 119 cases of pediatric APL treated with four regimes based on all-trans-retinoic acid (ATRA). We retrospectively analyzed the clinical characteristics, laboratorial test results and treatment outcome of the pediatric APL patients. Regime 1 used an in-house developed protocol, regime 2 was modified from the PETHEMA LPA99 protocol, regime 3 was modified from the European-APL93 protocol, and regime 4 used a protocol suggested by the British Committee for Standards in Haematology. The overall complete remission rates for the four regimes were 88.9, 87.5, 97.1 and 87.5%, respectively, which exhibited no statistical difference. However, more favorable results were observed for regimes 2 and 3 than regimes 1 and 4, in terms of the estimated 3.5-year disease-free survivals, relapse rates, drug toxicity (including hepatotoxicity, cardiac arrhythmia, and differentiation syndrome) and sepsis. In conclusion, the overall outcomes were more favorable after treatment with regimes 2 and 3 than with regimes 1 and 4, and this may have been due to the specific compositions of regimes 2 and 3. PMID:23060929

PMLRARα binds to Fas and suppresses Fas-mediated apoptosis through recruiting c-FLIP in vivo

PubMed Central

Tao, Rong-Hua; Berkova, Zuzana; Wise, Jillian F.; Rezaeian, Abdol-Hossein; Daniluk, Urszula; Ao, Xue; Hawke, David H.; Karp, Judith E.; Lin, Hui-Kuan; Molldrem, Jeffrey J.

2011-01-01

Defective Fas signaling leads to resistance to various anticancer therapies. Presence of potential inhibitors of Fas which could block Fas signaling can explain cancer cells resistance to apoptosis. We identified promyelocytic leukemia protein (PML) as a Fas-interacting protein using mass spectrometry analysis. The function of PML is blocked by its dominant-negative form PML–retinoic acid receptor α (PMLRARα). We found PMLRARα interaction with Fas in acute promyelocytic leukemia (APL)–derived cells and APL primary cells, and PML-Fas complexes in normal tissues. Binding of PMLRARα to Fas was mapped to the B-box domain of PML moiety and death domain of Fas. PMLRARα blockage of Fas apoptosis was demonstrated in U937/PR9 cells, human APL cells and transgenic mouse APL cells, in which PMLRARα recruited c-FLIPL/S and excluded procaspase 8 from Fas death signaling complex. PMLRARα expression in mice protected the mice against a lethal dose of agonistic anti-Fas antibody (P < .001) and the protected tissues contained Fas-PMLRARα-cFLIP complexes. Taken together, PMLRARα binds to Fas and blocks Fas-mediated apoptosis in APL by forming an apoptotic inhibitory complex with c-FLIP. The presence of PML-Fas complexes across different tissues implicates that PML functions in apoptosis regulation and tumor suppression are mediated by direct interaction with Fas. PMID:21803845

Alabama Public Library Service Annual Report, 1995.

ERIC Educational Resources Information Center

Alabama Public Library Service, Montgomery.

This annual report summarizes activities of the Alabama Public Library Service (APLS) for the fiscal year 1995. The APLS is charged with improving library services throughout the state to ensure that all citizens have access to quality library and information services. During fiscal year 1995, major building renovations were completed with the…

Swift UVOT Observations of SN2018apl/ASASSN-18gq

NASA Astrophysics Data System (ADS)

Brown, Peter J.

2018-04-01

SN2018apl/ASASSN-18gq (ATEL #11500) was observed by the Neil Gehrels Swift Observatory beginning 2018-04-03 15:28:06. We measured the magnitudes below from summed images from the first orbit of observations using the Swift Optical Ultraviolet Supernova Archive (SOUSA; Brown et al. 2014).

Teaching a Biotechnology Curriculum Based on Adapted Primary Literature

ERIC Educational Resources Information Center

Falk, Hedda; Brill, Gilat; Yarden, Anat

2008-01-01

Adapted primary literature (APL) refers to an educational genre specifically designed to enable the use of research articles for learning biology in high school. The present investigation focuses on the pedagogical content knowledge (PCK) of four high-school biology teachers who enacted an APL-based curriculum in biotechnology. Using a…

Ground truth methods for optical cross-section modeling of biological aerosols

NASA Astrophysics Data System (ADS)

Kalter, J.; Thrush, E.; Santarpia, J.; Chaudhry, Z.; Gilberry, J.; Brown, D. M.; Brown, A.; Carter, C. C.

2011-05-01

Light detection and ranging (LIDAR) systems have demonstrated some capability to meet the needs of a fastresponse standoff biological detection method for simulants in open air conditions. These systems are designed to exploit various cloud signatures, such as differential elastic backscatter, fluorescence, and depolarization in order to detect biological warfare agents (BWAs). However, because the release of BWAs in open air is forbidden, methods must be developed to predict candidate system performance against real agents. In support of such efforts, the Johns Hopkins University Applied Physics Lab (JHU/APL) has developed a modeling approach to predict the optical properties of agent materials from relatively simple, Biosafety Level 3-compatible bench top measurements. JHU/APL has fielded new ground truth instruments (in addition to standard particle sizers, such as the Aerodynamic particle sizer (APS) or GRIMM aerosol monitor (GRIMM)) to more thoroughly characterize the simulant aerosols released in recent field tests at Dugway Proving Ground (DPG). These instruments include the Scanning Mobility Particle Sizer (SMPS), the Ultraviolet Aerodynamic Particle Sizer (UVAPS), and the Aspect Aerosol Size and Shape Analyser (Aspect). The SMPS was employed as a means of measuring smallparticle concentrations for more accurate Mie scattering simulations; the UVAPS, which measures size-resolved fluorescence intensity, was employed as a path toward fluorescence cross section modeling; and the Aspect, which measures particle shape, was employed as a path towards depolarization modeling.

Long-term neurodevelopmental outcome of children born to prospectively followed pregnancies of women with systemic lupus erythematosus and/or antiphospholipid syndrome.

PubMed

Nalli, C; Iodice, A; Andreoli, L; Galli, J; Lojacono, A; Motta, M; Fazzi, E; Tincani, A

2017-04-01

Background Systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS) are autoimmune diseases that affect women of childbearing age. Maternal IgG antiphospholipid antibodies (aPL) can cross the placenta during pregnancy and theoretically reach the fetal brain. Some studies showed an increased number of learning disabilities in these children. Objectives To evaluate the long-term neurodevelopmental outcome of 40 children (median age 7.4 years) born to mothers with SLE and/or APS carrying positive IgG aPL during the third trimester of pregnancy. Methods Children were checked for neurological physical exam and intellectual/cognitive functioning by the Wechsler scale for corrected age. We submitted to the mothers the Child Behavior CheckList (CBCL) and a homemade set of questions created by pediatric neurologists. Results In all children neurological physical exam and intelligence levels were found to be normal. A cognitive impairment or a discrepant cognitive profile was found in 3 (7%) and 11 (28%) children, respectively. Learning disabilities were diagnosed in 3 children (19% of school-age children), all born to mothers with triple aPL positivity. A history of epilepsy was shown in four children (10%). Children born to women with SLE and/or APS may need a long-term follow-up focusing on milestones of neurodevelopment in order to detect and correct any alteration as early as possible.

Antitumor Lipids--Structure, Functions, and Medical Applications.

PubMed

Kostadinova, Aneliya; Topouzova-Hristova, Tanya; Momchilova, Albena; Tzoneva, Rumiana; Berger, Martin R

2015-01-01

Cell proliferation and metastasis are considered hallmarks of tumor progression. Therefore, efforts have been made to develop novel anticancer drugs that inhibit both the proliferation and the motility of tumor cells. Synthetic antitumor lipids (ATLs), which are chemically divided into two main classes, comprise (i) alkylphospholipids (APLs) and (ii) alkylphosphocholines (APCs). They represent a new entity of drugs with distinct antiproliferative properties in tumor cells. These compounds do not interfere with the DNA or mitotic spindle apparatus of the cell, instead, they incorporate into cell membranes, where they accumulate and interfere with lipid metabolism and lipid-dependent signaling pathways. Recently, it has been shown that the most commonly studied APLs inhibit proliferation by inducing apoptosis in malignant cells while leaving normal cells unaffected and are potent sensitizers of conventional chemo- and radiotherapy, as well as of electrical field therapy. APLs resist catabolic degradation to a large extent, therefore accumulate in the cell and interfere with lipid-dependent survival signaling pathways, notably PI3K-Akt and Raf-Erk1/2, and de novo phospholipid biosynthesis. They are internalized in the cell membrane via raft domains and cause downstream reactions as inhibition of cell growth and migration, cell cycle arrest, actin stress fibers collapse, and apoptosis. This review summarizes the in vitro, in vivo, and clinical trials of most common ATLs and their mode of action at molecular and biochemical levels. © 2015 Elsevier Inc. All rights reserved.

Design guidelines for adapting scientific research articles: An example from an introductory level, interdisciplinary program on soft matter

NASA Astrophysics Data System (ADS)

Langbeheim, Elon; Safran, Samuel A.; Yerushalmi, Edit

2013-01-01

We present design guidelines for using Adapted Primary Literature (APL) as part of current interdisciplinary topics to introductory physics students. APL is a text genre that allows students to comprehend a scientific article, while maintaining the core features of the communication among scientists, thus representing an authentic scientific discourse. We describe the adaptation of a research paper by Nobel Laureate Paul Flory on phase equilibrium in polymer-solvent mixtures that was presented to high school students in a project-based unit on soft matter. The adaptation followed two design strategies: a) Making explicit the interplay between the theory and experiment. b) Re-structuring the text to map the theory onto the students' prior knowledge. Specifically, we map the theory of polymer-solvent systems onto a model for binary mixtures of small molecules of equal size that was already studied in class.

Adsorptive detoxification of fermentation inhibitors in acid pretreated liquor using functionalized polymer designed by molecular simulation.

PubMed

Devendra, Leena P; Pandey, Ashok

2017-11-01

Acid pretreatment is the most common method employed in the lignocellulosic biorefinery leading to the separation of pentose and hexose sugar. The liquor obtained after pretreatment (acid pretreatment liquor or APL) needs to be detoxified prior to fermentation. The aim of this study was to design functional groups on a polymer matrix which are selective in their interaction to inhibitors with little or no specificity to sugars. Molecular modeling was used as a tool to design a suitable adsorbent for selective adsorption of inhibitors from a complex mixture of APL. Phenyl glycine-p-sulfonic acid loaded on chloromethylated polystyrene polymer was designed as an adsorbent for selective interaction with inhibitors. Experimental verification of the selectivity was successfully achieved. The current study provides insights on the adsorptive separation processes at the molecular level by design of specific adsorbent which can be tailor made for the better selectivity of the desired component.

Information surfing with the JHU/APL coherent imager

NASA Astrophysics Data System (ADS)

Ratto, Christopher R.; Shipley, Kara R.; Beagley, Nathaniel; Wolfe, Kevin C.

2015-05-01

The ability to perform remote forensics in situ is an important application of autonomous undersea vehicles (AUVs). Forensics objectives may include remediation of mines and/or unexploded ordnance, as well as monitoring of seafloor infrastructure. At JHU/APL, digital holography is being explored for the potential application to underwater imaging and integration with an AUV. In previous work, a feature-based approach was developed for processing the holographic imagery and performing object recognition. In this work, the results of the image processing method were incorporated into a Bayesian framework for autonomous path planning referred to as information surfing. The framework was derived assuming that the location of the object of interest is known a priori, but the type of object and its pose are unknown. The path-planning algorithm adaptively modifies the trajectory of the sensing platform based on historical performance of object and pose classification. The algorithm is called information surfing because the direction of motion is governed by the local information gradient. Simulation experiments were carried out using holographic imagery collected from submerged objects. The autonomous sensing algorithm was compared to a deterministic sensing CONOPS, and demonstrated improved accuracy and faster convergence in several cases.

Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure.

PubMed

de Thé, Hugues; Pandolfi, Pier Paolo; Chen, Zhu

2017-11-13

Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions. Copyright © 2017 Elsevier Inc. All rights reserved.

A Prospective Open-label Pilot Study of Fluvastatin on Pro-inflammatory and Pro-thrombotic Biomarkers in Antiphospholipid Antibody Positive Patients

PubMed Central

Erkan, Doruk; Willis, Rohan; Murthy, Vijaya L.; Basra, Gurjot; Vega, JoAnn; Ruiz Limón, Patricia; Carrera, Ana Laura; Papalardo, Elizabeth; Martínez-Martínez, Laura Aline; González, Emilio B.; Pierangeli, Silvia S.

2014-01-01

Objective: To determine if pro-inflammatory and pro-thrombotic biomarkers are differentially upregulated in persistently antiphospholipid antibody (aPL)-positive patients, and to examine the effects of fluvastatin on these biomarkers. Methods: Four groups of patients (age 18-65) were recruited: a) Primary Antiphospholipid Syndrome (PAPS); b) Systemic Lupus Erythematosus (SLE) with APS (SLE/APS); c) Persistent aPL positivity without SLE or APS (Primary aPL); and d) Persistent aPL positivity with SLE but no APS (SLE/aPL). The frequency-matched control group, used for baseline data comparison, was identified from a databank of healthy persons. Patients received fluvastatin 40 mg daily for three months. At three months, patients stopped the study medication and they were followed for another three months. Blood samples for 12 pro-inflammatory and pro-thrombotic biomarkers were collected monthly for six months. Results: Based on the comparison of the baseline samples of 41 aPL-positive patients with 30 healthy controls, 9/12 (75%) biomarkers (interleukin [IL]-6, IL1β, vascular endothelial growth factor [VEGF], tumor necrosis factor [TNF]-□α, interferon [IFN]-α, inducible protein-10 [IP10], soluble CD40 ligand [sCD40L], soluble tissue factor [sTF], and intracellular cellular adhesion molecule [ICAM]-1) were significantly elevated. Twenty-four patients completed the study; fluvastatin significantly and reversibly reduced the levels of 6/12 (50%) biomarkers (IL1β, VEGF, TNFα, IP10, sCD40L, and sTF). Conclusion: Our prospective mechanistic study demonstrates that pro-inflammatory and pro-thrombotic biomarkers, which are differentially upregulated in persistently aPL-positive patients, can be reversibly reduced by fluvastatin. Thus, statin-induced modulation of the aPL effects on target cells can be a valuable future approach in the management of aPL-positive patients. PMID:23933625

Redistribution of cell cycle by arsenic trioxide is associated with demethylation and expression changes of cell cycle related genes in acute promyelocytic leukemia cell line (NB4).

PubMed

Hassani, Saeed; Khaleghian, Ali; Ahmadian, Shahin; Alizadeh, Shaban; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir; Ghaffari, Seyed H

2018-01-01

PML-RARα perturbs the normal epigenetic setting, which is essential to oncogenic transformation in acute promyelocytic leukemia (APL). Transcription induction and recruitment of DNA methyltransferases (DNMTs) by PML-RARα and subsequent hypermethylation are components of this perturbation. Arsenic trioxide (ATO), an important drug in APL therapy, concurrent with degradation of PML-RARα induces cell cycle change and apoptosis. How ATO causes cell cycle alteration has remained largely unexplained. Here, we investigated DNA methylation patterns of cell cycle regulatory genes promoters, the effects of ATO on the methylated genes and cell cycle distribution in an APL cell line, NB4. Analysis of promoter methylation status of 22 cell cycle related genes in NB4 revealed that CCND1, CCNE1, CCNF, CDKN1A, GADD45α, and RBL1 genes were methylated 60.7, 84.6, 58.6, 8.7, 33.4, and 73.7%, respectively, that after treatment with 2 μM ATO for 48 h, turn into 0.6, 13.8, 0.1, 6.6, 10.7, and 54.5% methylated. ATO significantly reduced the expression of DNMT1, 3A, and 3B. ATO induced the expression of CCND1, CCNE1, and GADD45α genes, suppressed the expression of CCNF and CDKN1A genes, which were consistent with decreased number of cells in G1 and S phases and increased number of cells in G2/M phase. In conclusion, demethylation and alteration in the expression level of the cell cycle related genes may be possible mechanisms in ATO-induced cell cycle arrest in APL cells. It may suggest that ATO by demethylation of CCND1 and CCNE1 and their transcriptional activation accelerates G1 and S transition into the G2/M cell cycle arrest.

Nutritional status in stage V dialyzed patient versus CKD patient on conservative therapy across different economic status.

PubMed

Vijayan, Madhusudan; Abraham, Georgi; Alex, Merina E; Vijayshree, N; Reddy, Yuvaram; Fernando, Edwin; Mathew, Milly; Nair, Sanjeev; Yuvaraj, Anand

2014-04-01

This aim of this multi-centric cross-sectional study was to assess the nutritional status in Indian chronic kidney disease (CKD) patients and to compare the nutritional indicators between stage 5 dialyzed (CKD-D) patients below the poverty line (BPL), and stage 3-4 non-dialyzed (CKD-ND) patients above (APL) and below the poverty line. Patients were selected from a government medical college hospital, a charity-based outpatient dialysis unit, and a non-profit tertiary care center. The study groups included BPL CKD-ND (n = 100), BPL CKD-D (n = 98), and APL CKD-ND (n = 92) patients, based on a cut-off of per capita income US $1.25 a day. Patients were enquired by a qualified renal dietitian about their pattern of diet, and daily energy and protein intake by 24 h recall method. Anthropometric measurements and biochemical investigations were made and compared. Nutritional indicators were low in all three groups compared to those prescribed by European Best Practice Guidelines (EBPG). BPL CKD-D patients had low serum albumin levels (32.44444 ± 6.279961 g/L; p = 0.017) and 41.83% of them were underweight. The APL CKD-ND group registered the lowest mean daily energy (22.576 ± 6.289 kcal/kg/day) and protein intake (0.71 ± 0.06 g/kg/day), due to dietary restrictions imposed on them by themselves and unqualified renal dietitians. The APL group had better indicators of nutritional status in terms of mid-upper arm circumference (p = 0.001), triceps skin fold thickness (p < 0.001), and serum hemoglobin (p < 0.001). Several nutritional parameters were below the recommended international guidelines for all the three groups, though the high income group had better parameters from several indicators. There is an urgent need for nutritional counseling for CKD-D and CKD-ND patients.

Ethacrynic acid and a derivative enhance apoptosis in arsenic trioxide-treated myeloid leukemia and lymphoma cells: the role of glutathione S-transferase P1-1

PubMed Central

Wang, Rui; Liu, Changda; Xia, Lijuan; Zhao, Guisen; Gabrilove, Janice; Waxman, Samuel; Jing, Yongkui

2012-01-01

Purpose Arsenic trioxide (ATO) as a single agent is used for treatment of acute promyelocytic leukemia (APL) with minimal toxicity but therapeutic effect of ATO in other types of malignancies has not been achieved. We tested whether a combination with ethacrynic acid (EA), a glutathione S-transferase P1-1 (GSTP1-1) inhibitor and a reactive oxygen species (ROS) inducer will extend the therapeutic effect of ATO beyond APL. Experimental Design The combined apoptotic effects of ATO plus EA were tested in non-APL leukemia and lymphoma cell lines. The role of ROS, GSTP1-1, glutathione, and Mcl-1 in apoptosis was determined. The selective response to this combination of cells with and without GSTP1-1 expression was compared. Results ATO/EA combination synergistically induced apoptosis in myeloid leukemia and lymphoma cells. This treatment produced high ROS levels, activated c-jun-NH2-terminal kinase and reduced Mcl-1 protein. This led to the decrease of mitochondrial transmembrane potential, release of cytochrome c and, subsequently, to activation of caspase 3 and 9. Induction of apoptosis in leukemia and lymphoma cells expressing GSTP1-1 required that high EA concentrations be combined with ATO. Silencing of GSTP1 in leukemia cells sensitized them to ATO/EA-induced apoptosis. In a sub-group of B-cell lymphoma which do not express GSTP1-1, lower concentrations of EA and its more potent derivative, ethacrynic acid butyl-ester, decreased intracellular glutathione levels and synergistically induced apoptosis when combined with ATO. Conclusion B-cell lymphoma cells lacking GSTP1-1 are more sensitive than myeloid leukemia cells to ATO/EA-induced apoptosis. PMID:23082001

Robotic Lunar Landers for Science and Exploration

NASA Technical Reports Server (NTRS)

Chavers, D. G.; Cohen, B. A.; Bassler, J. A.; Hammond, M. S.; Harris, D. W.; Hill, L. A.; Eng, D.; Ballard, B. W.; Kubota, S. D.; Morse, B. J.;

77 FR 33459 - Notice of Agreements Filed

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-06

... the agreement, adjust the amount of space to be exchanged, and delete obsolete language from the...: Hyundai Merchant Marine Co., Ltd., Mistsui O.S.K. Lines, Ltd., and APL Co. Pte Ltd. and American President...; Washington, DC 20006-4007. Synopsis: The agreement authorizes Hyundai to charter space to MOL and APL in the...

*Assessing differential transcriptional regulation of IL-8 expression by human airway epithelial cells exposed to diesel exhaust particles

EPA Science Inventory

Background: Exposure to Diesel Exhaust Particles (DEP) induces inflammatory signaling characterized by MAP kinase-mediated activation of NFkB and AP-l in vitro and in bronchial biopsies obtained from human subjects exposed to DEP. NFkB and AP-l activation results in the upregulat...

Risk of thrombosis with anti-phospholipid syndrome in systemic lupus erythematosus treated with thrombopoietin-receptor agonists.

PubMed

Guitton, Zelie; Terriou, Louis; Lega, Jean-Christophe; Nove-Josserand, Raphaele; Hie, Miguel; Amoura, Zahir; Bussel, James B; Hamidou, Mohamed; Rosenthal, Eric; Lioger, Bertrand; Chauveau, Dominique; Chaminade, Axel; Magy-Bertrand, Nadine; Michel, Marc; Audia, Sylvain; Godeau, Bertrand; Mahevas, Matthieu

2018-05-10

The use of thrombopoietin-receptor agonists (TPO-RAs) has increased as a second-line therapy in ITP, but the efficacy and safety of such drugs has not been evaluated in SLE-associated ITP. This was a multicentre retrospective cohort study from 2009 to 2016. Participating centres (n = 11) were secondary- or tertiary-care hospitals belonging to the French national network for adult ITP. We included 18 patients with SLE-ITP treated with TPO-RAs; 10 (55%) had aPL, 5 (27%) showing definite APS. Except for one patient, all (94%) achieved response with TPO-RAs overall. After a median follow-up of 14.7 months with TPO-RAs, four arterial thrombosis events (including one catastrophic APS) occurred in four patients. Two venous thrombosis events occurred in a patient without APS or aPLs. Our results suggest that aPLs should be systematically screened before TPO-RA initiation in patients with SLE. With aPL positivity, alternative therapy should be discussed (if possible), especially in patients with definite APS or suboptimal adherence to anti-coagulation therapy.

Role of the histone deacetylase complex in acute promyelocytic leukaemia.

PubMed

Lin, R J; Nagy, L; Inoue, S; Shao, W; Miller, W H; Evans, R M

1998-02-19

Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex through a class of silencing mediators termed SMRT or N-CoR. Mutant forms of RARalpha, created by chromosomal translocations with either the PML (for promyelocytic leukaemia) or the PLZF (for promyelocytic leukaemia zinc finger) locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML-RARalpha APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF-RARalpha patients respond very poorly, if at all. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.

Summary of International Border Crossings Roundtable Meeting Held in Buffalo, New York, June 7, 1993

DOT National Transportation Integrated Search

1996-11-30

The purpose of this plan is to establish a formal set of guidelines and activities to be adhered to and performed by JHU/APL and the developer to ensure that the SAFER System has been tested successfully and is fully compliant with the SAFER System r...

Fuel Performance Evaluation for the Solid-Fueled Ramjet

DTIC Science & Technology

1984-10-01

Aeronautics W. DYER/ 2dL JOHN Dean of Science and Engineering NOTE: The Postdoctoral Research Associate Program (National Research Council...8. AFWAL/PORT 2 Wright-Patterson AFB, OH 45433 R. D. Stull 9. JHU/APL (Group AEO) 1 Dr. F. Billig 10. NAVSEA 1 SEA 62R2 Washington, DC 20361

Growth Performance, Carcass Characteristics and Meat Yield of Boer Goats Fed Diets Containing Leaves or Whole Parts of Andrographis paniculata.

PubMed

Yusuf, A L; Goh, Y M; Samsudin, A A; Alimon, A R; Sazili, A Q

2014-04-01

The study was conducted to determine the effect of feeding diets containing Andrographis paniculata leaves (APL), whole Andrographis paniculata plant (APWP) and a control without Andrographis paniculata (AP0), on growth performance, carcass characteristics and meat yield of 24 intact Boer bucks. The results obtained indicated that inclusion of Andrographis paniculata significantly improved feed intake, weight gain, feed efficiency and live weight. The ratios of carcass to fat, lean to bone, lean to fat, and composition of meat were also improved. In addition, there were significant differences (p<0.05) between the dietary treatments in dressing percentage and chilling loss. Goats fed on AP0 (control) had significantly higher proportions of fat and bone, as well as thicker back fat than the supplemented animals (APL and APWP). Higher gut fill in animals fed Andrographis paniculata suggested slow rate of digestion, which could have improved utilization and absorption of nutrients by the animals. Goats fed Andrographis paniculata also produced higher meat yield and relatively lower fat contents (p<0.05).

Growth Performance, Carcass Characteristics and Meat Yield of Boer Goats Fed Diets Containing Leaves or Whole Parts of Andrographis paniculata

PubMed Central

Yusuf, A. L.; Goh, Y. M.; Samsudin, A. A.; Alimon, A. R.; Sazili, A. Q.

2014-01-01

The study was conducted to determine the effect of feeding diets containing Andrographis paniculata leaves (APL), whole Andrographis paniculata plant (APWP) and a control without Andrographis paniculata (AP0), on growth performance, carcass characteristics and meat yield of 24 intact Boer bucks. The results obtained indicated that inclusion of Andrographis paniculata significantly improved feed intake, weight gain, feed efficiency and live weight. The ratios of carcass to fat, lean to bone, lean to fat, and composition of meat were also improved. In addition, there were significant differences (p<0.05) between the dietary treatments in dressing percentage and chilling loss. Goats fed on AP0 (control) had significantly higher proportions of fat and bone, as well as thicker back fat than the supplemented animals (APL and APWP). Higher gut fill in animals fed Andrographis paniculata suggested slow rate of digestion, which could have improved utilization and absorption of nutrients by the animals. Goats fed Andrographis paniculata also produced higher meat yield and relatively lower fat contents (p<0.05). PMID:25049980

Arsenic-induced PML targeting onto nuclear bodies: Implications for the treatment of acute promyelocytic leukemia

PubMed Central

Zhu, Jun; Koken, Marcel H. M.; Quignon, Frédérique; Chelbi-Alix, Mounira K.; Degos, Laurent; Wang, Zhen Yi; Chen, Zhu; de Thé, Hugues

1997-01-01

Acute promyelocytic leukemia (APL) is associated with the t(15;17) translocation, which generates a PML/RARα fusion protein between PML, a growth suppressor localized on nuclear matrix-associated bodies, and RARα, a nuclear receptor for retinoic acid (RA). PML/RARα was proposed to block myeloid differentiation through inhibition of nuclear receptor response, as does a dominant negative RARα mutant. In addition, in APL cells, PML/RARα displaces PML and other nuclear body (NB) antigens onto nuclear microspeckles, likely resulting in the loss of PML and/or NB functions. RA leads to clinical remissions through induction of terminal differentiation, for which the respective contributions of RARα (or PML/RARα) activation, PML/RARα degradation, and restoration of NB antigens localization are poorly determined. Arsenic trioxide also leads to remissions in APL patients, presumably through induction of apoptosis. We demonstrate that in non-APL cells, arsenic recruits the nucleoplasmic form of several NB antigens onto NB, but induces the degradation of PML only, identifying a powerful tool to approach NB function. In APL cells, arsenic targets PML and PML/RARα onto NB and induces their degradation. Thus, RA and arsenic target RARα and PML, respectively, but both induce the degradation of the PML/RARα fusion protein, which should contribute to their therapeutic effects. The difference in the cellular events triggered by these two agents likely stems from RA-induced transcriptional activation and arsenic effects on NB proteins. PMID:9108090

Utility and impact of early t(15;17) identification by Fluorescence In Situ Hybridization (FISH) in clinical decision making for patients in Acute Promyelocytic Leukemia (APL).

PubMed

Kolhe, R; Mangaonkar, A; Mansour, J; Clemmons, A; Shaw, J; Dupont, B; Walczak, L; Mondal, A; Rojiani, A; Jillella, A; Kota, V

2015-08-01

Acute Promyelocytic Leukemia (APL) is a curable malignancy with studies showing above 90% survival. However, population-based studies looking at survival suggest that approximately 30% of patients with APL die during induction. Early demonstration of t(15;17) will lead to accurate decision making regarding treatment. The aim of this project was to validate earlier time frames for the Abbott Molecular Vysis LSI promyelocytic leukemia (PML)/ retinoic acid receptor alpha (RARA) fluorescence in situ hybridization (FISH) probe (ASR 6-16 h). Twenty patients (15 APL cases and five non-APL cases) were selected for validating various hybridization times for the FISH probe. Expected normal signal pattern was two red and two green signals (2R2G), and the most common expected abnormal signal pattern was two fusion (yellow) signals, one red and one green (2F1R1G) and/or one fusion, one red and one green (1F1R1G). The specificity of the probe ranged from 84% at 2 h, 86% at 4 h, 84% at 6 h, and 87% for overnight hybridization. The sensitivity increased from 79% at 2 h, 80% at 4 h, 81% at 6 h to 87% for overnight hybridization. Based on the validation studies, we recommend reading of FISH results at the 4-h incubation mark for a preliminary diagnosis and confirmation with overnight hybridization. © 2015 John Wiley & Sons Ltd.

Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial.

PubMed

Platzbecker, Uwe; Avvisati, Giuseppe; Cicconi, Laura; Thiede, Christian; Paoloni, Francesca; Vignetti, Marco; Ferrara, Felicetto; Divona, Mariadomenica; Albano, Francesco; Efficace, Fabio; Fazi, Paola; Sborgia, Marco; Di Bona, Eros; Breccia, Massimo; Borlenghi, Erika; Cairoli, Roberto; Rambaldi, Alessandro; Melillo, Lorella; La Nasa, Giorgio; Fiedler, Walter; Brossart, Peter; Hertenstein, Bernd; Salih, Helmut R; Wattad, Mohammed; Lübbert, Michael; Brandts, Christian H; Hänel, Mathias; Röllig, Christoph; Schmitz, Norbert; Link, Hartmut; Frairia, Chiara; Pogliani, Enrico Maria; Fozza, Claudio; D'Arco, Alfonso Maria; Di Renzo, Nicola; Cortelezzi, Agostino; Fabbiano, Francesco; Döhner, Konstanze; Ganser, Arnold; Döhner, Hartmut; Amadori, Sergio; Mandelli, Franco; Ehninger, Gerhard; Schlenk, Richard F; Lo-Coco, Francesco

2017-02-20

Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 10 9 /L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.

ALPS - A LINEAR PROGRAM SOLVER

NASA Technical Reports Server (NTRS)

Viterna, L. A.

1994-01-01

Linear programming is a widely-used engineering and management tool. Scheduling, resource allocation, and production planning are all well-known applications of linear programs (LP's). Most LP's are too large to be solved by hand, so over the decades many computer codes for solving LP's have been developed. ALPS, A Linear Program Solver, is a full-featured LP analysis program. ALPS can solve plain linear programs as well as more complicated mixed integer and pure integer programs. ALPS also contains an efficient solution technique for pure binary (0-1 integer) programs. One of the many weaknesses of LP solvers is the lack of interaction with the user. ALPS is a menu-driven program with no special commands or keywords to learn. In addition, ALPS contains a full-screen editor to enter and maintain the LP formulation. These formulations can be written to and read from plain ASCII files for portability. For those less experienced in LP formulation, ALPS contains a problem "parser" which checks the formulation for errors. ALPS creates fully formatted, readable reports that can be sent to a printer or output file. ALPS is written entirely in IBM's APL2/PC product, Version 1.01. The APL2 workspace containing all the ALPS code can be run on any APL2/PC system (AT or 386). On a 32-bit system, this configuration can take advantage of all extended memory. The user can also examine and modify the ALPS code. The APL2 workspace has also been "packed" to be run on any DOS system (without APL2) as a stand-alone "EXE" file, but has limited memory capacity on a 640K system. A numeric coprocessor (80X87) is optional but recommended. The standard distribution medium for ALPS is a 5.25 inch 360K MS-DOS format diskette. IBM, IBM PC and IBM APL2 are registered trademarks of International Business Machines Corporation. MS-DOS is a registered trademark of Microsoft Corporation.

Pandemic influenza immunization in primary antiphospholipid syndrome (PAPS): a trigger to thrombosis and autoantibody production?

PubMed

de Medeiros, D Martins; Silva, C A; Bueno, C; Ribeiro, A C Medeiros; Viana, V dos Santos T; Carvalho, J Freire; Bonfa, E

2014-11-01

The objective of this report is to conduct short- and long-term evaluation of a large panel of antiphospholipid (aPL) autoantibodies following pandemic influenza A/H1N1 non-adjuvant vaccine in primary antiphospholipid syndrome (PAPS) patients and healthy controls. Forty-five PAPS and 33 healthy controls were immunized with H1N1 vaccine. They were prospectively assessed at pre-vaccination, and three weeks and six months after vaccination. aPL autoantibodies were determined by an enzyme-linked immunosorbent assay (ELISA) and included IgG/IgM: anticardiolipin (aCL), anti-beta2glycoprotein I (anti-β2GPI); anti-annexin V, anti-phosphatidyl serine and anti-prothrombin antibodies. Anti-Sm was determined by ELISA and anti-double-stranded DNA (anti-dsDNA) by indirect immunofluorescence. Arterial and venous thrombosis were also clinically assessed. Pre-vaccination frequency of at least one aPL antibody was significantly higher in PAPS patients versus controls (58% vs. 24%, p = 0.0052). The overall frequencies of aPL antibody at pre-vaccination, and three weeks and six months after immunization remained unchanged in patients (p = 0.89) and controls (p = 0.83). The frequency of each antibody specificity for patients and controls remained stable in the three evaluated periods (p > 0.05). At three weeks, two PAPS patients developed a new but transient aPL antibody (aCL IgG and IgM), whereas at six months new aPL antibodies were observed in six PAPS patients and none had high titer. Anti-Sm and anti-dsDNA autoantibodies were uniformly negative and no new arterial or venous thrombosis were observed throughout the study. This is the first study to demonstrate that pandemic influenza vaccine in PAPS patients does not trigger short- and long-term thrombosis or a significant production of aPL-related antibodies (ClinicalTrials.gov, #NCT01151644). © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Effects of dietary supplementation of leaves and whole plant of Andrographis paniculata on rumen fermentation, fatty acid composition and microbiota in goats.

PubMed

Yusuf, Aisha L; Adeyemi, Kazeem D; Samsudin, Anjas A; Goh, Yong M; Alimon, Abdul Razak; Sazili, Awis Q

2017-11-24

The nature and amount of dietary medicinal plants are known to influence rumen fermentation and nutrient digestibility in ruminants. Nonetheless, changes in nutrient digestibility and rumen metabolism in response to dietary Andrographis paniculata (AP) in goats are unknown. This study examined the effects of dietary supplementation of leaves and whole plant of AP on nutrient digestibility, rumen fermentation, fatty acids and rumen microbial population in goats. Twenty-four Boer crossbred bucks (4 months old; average body weight of 20.18 ± 0.19 kg) were randomly assigned to three dietary groups of eight goats each. The dietary treatments included a control diet (Basal diet without additive), basal diet +1.5% (w/w) Andrographis paniculata leaf powder (APL) and basal diet +1.5% (w/w) Andrographis paniculata whole plant powder (APW). The trial lasted 100 d following 14 d of adjustment. The rumen pH and concentration of propionate were greater (P < 0.05) in goats fed the APL and APW diets than those fed the control diet. The concentrations of ammonia nitrogen and acetate were greater (P < 0.05) in the control goats than the APL and APW goats. The digestibilities of crude protein, dry matter, acid detergent fibre and neutral detergent fibre were greater (P < 0.05) in the APL and APW goats compared to the control goats. Dietary APL and APW decreased (P < 0.05) the ruminal concentration of C18:0 and increased (P < 0.05) the ruminal concentration of C18:2n-6 and C18:3n-3. The APL goats had greater (P < 0.05) ruminal concentration of C18:1 trans-11 and CLA cis-9 trans-11 than the APW and control goats. Dietary treatments had no significant effect on the population of protozoa and methanogens in the rumen of goats. The ruminal populations of Ruminococcus albus, Ruminococcus flavefaciens and Fibrobacter succinogenes were greater (P < 0.05) in the APL and APW goats than the control goats. Dietary supplementation of leaves and whole plant of Andrographis paniculata can be used to manipulate rumen metabolism for improved nutrient digestibility in goats.

Opportunities for Space Science Education Using Current and Future Solar System Missions

NASA Astrophysics Data System (ADS)

Matiella Novak, M.; Beisser, K.; Butler, L.; Turney, D.

2010-12-01

The Education and Public Outreach (E/PO) office in The Johns Hopkins University Applied Physics Laboratory (APL) Space Department strives to excite and inspire the next generation of explorers by creating interactive education experiences. Since 1959, APL engineers and scientists have designed, built, and launched 61 spacecraft and over 150 instruments involved in space science. With the vast array of current and future Solar System exploration missions available, endless opportunities exist for education programs to incorporate the real-world science of these missions. APL currently has numerous education and outreach programs tailored for K-12 formal and informal education, higher education, and general outreach communities. Current programs focus on Solar System exploration missions such as the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM), Miniature Radio Frequency (Mini-RF) Moon explorer, the Radiation Belt Storm Probes (RBSP), New Horizons mission to Pluto, and the Thermosphere Ionosphere Mesosphere Energetics and Dynamics (TIMED) Satellite, to name a few. Education and outreach programs focusing on K-12 formal education include visits to classrooms, summer programs for middle school students, and teacher workshops. APL hosts a Girl Power event and a STEM (Science, Technology, Engineering, and Mathematics) Day each year. Education and outreach specialists hold teacher workshops throughout the year to train educators in using NASA spacecraft science in their lesson plans. High school students from around the U.S. are able to engage in NASA spacecraft science directly by participating in the Mars Exploration Student Data Teams (MESDT) and the Student Principal Investigator Programs. An effort is also made to generate excitement for future missions by focusing on what mysteries will be solved. Higher education programs are used to recruit and train the next generation of scientists and engineers. The NASA/APL Summer Internship Program offers a unique glimpse into the Space Department’s “end-to-end” approach to mission design and execution. College students - both undergraduate and graduate - are recruited from around the U.S. to work with APL scientists and engineers who act as mentors to the students. Many students are put on summer projects that allow them to work with existing spacecraft systems, while others participate in projects that investigate the operational and science objectives of future planned spacecraft systems. In many cases these interns have returned to APL as full-time staff after graduation.

Alabama Public Library Service, 1987 Annual Report.

ERIC Educational Resources Information Center

Alabama Public Library Service, Montgomery.

Designed to provide an overview of the range and quality of services provided by the Alabama Public Library Service (APLS), this annual report focuses on the 1987 activities of APLS. A report on the activities of the Library Development Division shows the allocation of state aid and Library Services and Construction Act (LCSA) Titles I and III…

Alabama Public Library Service, The State Library Agency. 1986 Annual Report.

ERIC Educational Resources Information Center

Alabama Public Library Service, Montgomery.

Designed to provide an overview of the range and quality of services provided by the Alabama Public Library Service (APLS), this annual report focuses on the 1986 activities of APLS; the state's public library directory and statistical report will be published separately. A discussion of the activities of the Library Development Division includes…

Arsenic trioxide induced rhabdomyolysis, a rare but severe side effect, in an APL patient: a case report.

PubMed

He, Haiyan; An, Ran; Hou, Jian; Fu, Weijun

2017-06-01

Arsenic trioxide (ATO), a component of the traditional Chinese medicine arsenic sublimate, promotes apoptosis and induces leukemic cell differentiation. Combined with all-trans-retinotic acid (ATRA), ATO has become the first-line induction therapy in treating acute promyelocytic leukemia (APL). The most common side effects of ATO include hepatotoxicity, gastrointestinal symptoms, water-sodium retention, and nervous system damage. In this report, we present a rare side effect, rhabdomyolysis, in a 68-year-old female APL patient who was treated with ATO. After taking 10 mg ATO daily for 6 days, she presented shortness of breath, myodynia, elevated creatine kinase, and acute renal insufficiency. This report describes the first case of ATO-induced rhabdomyolysis.

APL - North Pacific Acoustic Laboratory

DTIC Science & Technology

2011-09-01

including marine mammals ) measurements in the NE Pacific Ocean. The Laboratory consists of the legacy SOSUS hydrophone receiver network in the...exposure in the marine environment. Philippine Sea- Ambient noise levels measured during the 2010-2011 Philippine Sea experiment on the Scripps...sound speed perturbations and the characteristics of the ambient acoustic noise field. Scattering and diffraction resulting from internal waves and

Grid-Optimization Program for Photovoltaic Cells

NASA Technical Reports Server (NTRS)

Daniel, R. E.; Lee, T. S.

1986-01-01

CELLOPT program developed to assist in designing grid pattern of current-conducting material on photovoltaic cell. Analyzes parasitic resistance losses and shadow loss associated with metallized grid pattern on both round and rectangular solar cells. Though performs sensitivity studies, used primarily to optimize grid design in terms of bus bar and grid lines by minimizing power loss. CELLOPT written in APL.

Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives.

PubMed

McCulloch, Derek; Brown, Christina; Iland, Harry

2017-01-01

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with a unique morphological appearance, associated coagulopathy and canonical balanced translocation of genetic material between chromosomes 15 and 17. APL was first described as a distinct subtype of AML in 1957 by Dr Leif Hillestad who recognized the pattern of an acute leukemia associated with fibrinolysis, hypofibrinogenemia and catastrophic hemorrhage. In the intervening years, the characteristic morphology of APL has been described fully with both classical hypergranular and variant microgranular forms. Both are characterized by a balanced translocation between the long arms of chromosomes 15 and 17, [t(15;17)(q24;q21)], giving rise to a unique fusion gene PML-RARA and an abnormal chimeric transcription factor (PML-RARA), which disrupts normal myeloid differentiation programs. The success of current treatments for APL is in marked contrast to the vast majority of patients with non-promyelocytic AML. The overall prognosis in non-promyelocytic AML is poor, and although there has been an improvement in overall survival in patients aged <60 years, only 30%-40% of younger patients are still alive 5 years after diagnosis. APL therapy has diverged from standard AML therapy through the empirical discovery of two agents that directly target the molecular basis of the disease. The evolution of treatment over the last 4 decades to include all- trans retinoic acid and arsenic trioxide, with chemotherapy limited to patients with high-risk disease, has led to complete remission in 90%-100% of patients in trials and rates of overall survival between 86% and 97%.

Positive dermal hypersensitivity and specific antibodies in workers exposed to bio-engineered enzymes

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

Biagini, R.E.; Henningsen, G.M.; Driscoll, R.

1991-03-15

Thirty-six employees who produced industrial enzymes from bio-engineered strains of bacteria and fungi were evaluated by skin prick testing and enzyme linked immunosorbent assays for specific IgE and IgG antibodies. The workers complained of asthma- and flu-like' symptoms which generally lessened away from work. The enzymes evaluated were {alpha}-amylase from A. niger (ind-AAN), B. licheniformis (ind-AAL) and B. subtilis (ind-AAS); purified {alpha}-amylase from B. subtilis (AAS) and A. niger (AAN); alkaline protease from B. licheniformis (ind-APL) and purified alkaline protease (APL); amylase glucosidase from A. niger (ind-AGN) and purified amylase glucosidase (AGN). Significantly positive skin tests were found for APL,more » AGN and ind-AAN. Significantly elevated specific IgE results were observed for AAN, AGN, and ind-AAN; elevated specific IgGs were observed for AAN, ind-AAN, ind-AAS, ind-AAL and ind-AGN. Radioimmunoassays of air filter samples (using sera with high Ab titers) for 4 of the ind-enzymes showed only ind-AAN at extremely high environmental levels. These results indicate that occupational exposure to some ind-enzymes causes immediate onset dermal hypersensitivity reactions. The results are equivocal as to whether these reactions are IgE mediated, as IgE titers were low. Contrary to this, IgG titers were extremely high and suggest that these biomarkers can be used as indicators of both individual exposure and environmental analyses.« less

Tissue transglutaminase contributes to the all-trans-retinoic acid-induced differentiation syndrome phenotype in the NB4 model of acute promyelocytic leukemia.

PubMed

Csomós, Krisztián; Német, István; Fésüs, László; Balajthy, Zoltán

2010-11-11

Treatment of acute promyelocytic leukemia (APL) with all-trans-retinoic acid (ATRA) results in terminal differentiation of leukemic cells toward neutrophil granulocytes. Administration of ATRA leads to massive changes in gene expression, including down-regulation of cell proliferation-related genes and induction of genes involved in immune function. One of the most induced genes in APL NB4 cells is transglutaminase 2 (TG2). RNA interference-mediated stable silencing of TG2 in NB4 cells (TG2-KD NB4) coupled with whole genome microarray analysis revealed that TG2 is involved in the expression of a large number of ATRA-regulated genes. The affected genes participate in granulocyte functions, and their silencing lead to reduced adhesive, migratory, and phagocytic capacity of neutrophils and less superoxide production. The expression of genes related to cell-cycle control also changed, suggesting that TG2 regulates myeloid cell differentiation. CC chemokines CCL2, CCL3, CCL22, CCL24, and cytokines IL1B and IL8 involved in the development of differentiation syndrome are expressed at significantly lower level in TG2-KD NB4 than in wild-type NB4 cells upon ATRA treatment. Based on our results, we propose that reduced expression of TG2 in differentiating APL cells may suppress effector functions of neutrophil granulocytes and attenuate the ATRA-induced inflammatory phenotype of differentiation syndrome.

Circulating cell-derived microparticles in severe preeclampsia and in fetal growth restriction.

PubMed

Alijotas-Reig, Jaume; Palacio-Garcia, Carles; Farran-Codina, Immaculada; Ruiz-Romance, Mar; Llurba, Elisa; Vilardell-Tarres, Miquel

2012-02-01

The behavior of the circulating microparticles (cMP) in severe preeclampsia (PE) and fetal growth restriction (FGR) is disputed. METHOD OF STUDY  Non-matched case-control study. Seventy cases of severe PE/HELLP/FGR were compared to 38 healthy pregnant women. Twenty healthy non-pregnant women acted as a control. cMP were analyzed using flow cytometry. Results are given as total (annexin-A5-ANXA5+), platelet (CD41+), leukocyte (CD45+), endothelial (CD144+CD31+//CD41-), and CD41-negative cMP/μL of plasma. Antiphospholipid antibodies (aPL) were analyzed through usual methods. Platelet and endothelial cMP increased in healthy pregnant women. PE whole group (PE±FGR) showed an increase in endothelial and CD41-negative, but not in platelet-derived, cMP. Comparing PE whole group versus healthy pregnant, we found cMP levels of endothelial and CD41- had increased. The cMP results obtained in PE group were similar to those of the PE whole group. Comparing PE group to isolated FGR, significant CD41-negative cMP increase was found in PE. According to its aPL positivity, a trend to decrease in leukocyte and endothelial-derived cMP was found in PE group. Normal pregnancy is accompanied by endothelial and platelet cell activation. Endothelial cell activation has been shown in PE but not in isolated FGR. In PE, aPL may contribute to endothelial and possibly to leukocyte cell activation. © 2011 John Wiley & Sons A/S.

75 FR 37874 - Buy America Waiver Notification

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-30

... steel tubing API 5L, grade X52-PSLI, for construction of Federal-aid project IM-HPP-080-5(086) in New... is appropriate to use non- domestic Steel tubing, APL 5L, grade X52-PSLI, in New Jersey State. In... review to locate potential domestic manufacturers for the steel tubing, APL 5L, grade X52-PSLI. Based on...

Bayesian network meta-analysis comparing five contemporary treatment strategies for newly diagnosed acute promyelocytic leukaemia

PubMed Central

Ren, Yong; Duan, Chongyang; Chen, Shangwu; Xu, Anlong

2016-01-01

Acute promyelocytic leukemia (APL) is a curable subtype of acute myeloid leukemia. The optimum regimen for newly diagnosed APL remains inconclusive. In this Bayesian network meta-analysis, we compared the effectiveness of five regimens-arsenic trioxide (ATO) + all-trans retinoic acid (ATRA), realgar-indigo naturalis formula (RIF) which contains arsenic tetrasulfide + ATRA, ATRA + anthracycline-based chemotherapy (CT), ATO alone and ATRA alone, based on fourteen randomized controlled trials (RCTs), which included 1407 newly diagnosed APL patients. According to the results, the ranking efficacy of the treatment, including early death and complete remission in the induction stage, was the following: 1. ATO/RIF + ATRA; 2. ATRA + CT; 3. ATO, and 4. ATRA. For long-term benefit, ATO/RIF + ATRA significantly improved overall survival (OS) (hazard ratio = 0.35, 95%CI 0.15–0.82, p = 0.02) and event-free survival (EFS) (hazard ratio = 0.32, 95%CI 0.16–0.61, p = 0.001) over ATRA + CT regimen for the low-to-intermediate-risk patients. Thus, ATO + ATRA and RIF + ATRA might be considered the optimum treatments for the newly diagnosed APL and should be recommended as the standard care for frontline therapy. PMID:27322078

Bayesian network meta-analysis comparing five contemporary treatment strategies for newly diagnosed acute promyelocytic leukaemia.

PubMed

Wu, Fenfang; Wu, Di; Ren, Yong; Duan, Chongyang; Chen, Shangwu; Xu, Anlong

2016-07-26

Acute promyelocytic leukemia (APL) is a curable subtype of acute myeloid leukemia. The optimum regimen for newly diagnosed APL remains inconclusive. In this Bayesian network meta-analysis, we compared the effectiveness of five regimens-arsenic trioxide (ATO) + all-trans retinoic acid (ATRA), realgar-indigo naturalis formula (RIF) which contains arsenic tetrasulfide + ATRA, ATRA + anthracycline-based chemotherapy (CT), ATO alone and ATRA alone, based on fourteen randomized controlled trials (RCTs), which included 1407 newly diagnosed APL patients. According to the results, the ranking efficacy of the treatment, including early death and complete remission in the induction stage, was the following: 1. ATO/RIF + ATRA; 2. ATRA + CT; 3. ATO, and 4. ATRA. For long-term benefit, ATO/RIF + ATRA significantly improved overall survival (OS) (hazard ratio = 0.35, 95%CI 0.15-0.82, p = 0.02) and event-free survival (EFS) (hazard ratio = 0.32, 95%CI 0.16-0.61, p = 0.001) over ATRA + CT regimen for the low-to-intermediate-risk patients. Thus, ATO + ATRA and RIF + ATRA might be considered the optimum treatments for the newly diagnosed APL and should be recommended as the standard care for frontline therapy.

Anti-prothrombin antibodies are associated with adverse pregnancy outcome.

PubMed

Marozio, Luca; Curti, Antonella; Botta, Giovanni; Canuto, Emilie M; Salton, Loredana; Tavella, Anna Maria; Benedetto, Chiara

2011-11-01

Women with antiphospholipid antibodies (aPL) such as lupus anticoagulant, anticardiolipin antibodies, and anti-β(2) glycoprotein-1 antibodies are at high risk of late pregnancy complications, such as severe pre-eclampsia, placental insufficiency, and fetal loss. It has been observed that aPL consists of a heterogeneous group of antibodies targeting several phospholipid-binding plasma proteins, including also anti-prothrombin (anti-PT), anti-protein S (anti-PS), and anti-protein C (anti-PC) antibodies. Their potential role in late pregnancy complications is not known. The aim of this work was to investigate the association between those autoantibodies and histories for adverse pregnancy outcome. Anti-PT, anti-PS, and anti-PC antibodies were evaluated in 163 patients with previous severe pre-eclampsia, fetal death, and/or placental abruption and in as many women with previous uneventful pregnancies, negative for aPL. The prevalence of anti-PT antibodies was higher in cases than in controls (OR, 95% CI: 10.92, 4.52-26.38). The highest prevalence was observed in subjects with fetal death. Anti-PT antibodies appear to be associated with adverse pregnancy outcome, irrespectively of aPL. © 2011 John Wiley & Sons A/S.

Retinoic Acid and Arsenic Synergize to Eradicate Leukemic Cells in a Mouse Model of Acute Promyelocytic Leukemia

PubMed Central

Lallemand-Breitenbach, Valérie; Guillemin, Marie-Claude; Janin, Anne; Daniel, Marie-Thérèse; Degos, Laurent; Kogan, Scott C.; Michael Bishop, J.; de Thé, Hugues

1999-01-01

In acute promyelocytic leukemia (APL) patients, retinoic acid (RA) triggers differentiation while arsenic trioxide (arsenic) induces both a partial differentiation and apoptosis. Although their mechanisms of action are believed to be distinct, these two drugs both induce the catabolism of the oncogenic promyelocytic leukemia (PML)/RARα fusion protein. While APL cell lines resistant to one agent are sensitive to the other, the benefit of combining RA and arsenic in cell culture is controversial, and thus far, no data are available in patients. Using syngenic grafts of leukemic blasts from PML/RARα transgenic mice as a model for APL, we demonstrate that arsenic induces apoptosis and modest differentiation, and prolongs mouse survival. Furthermore, combining arsenic with RA accelerates tumor regression through enhanced differentiation and apoptosis. Although RA or arsenic alone only prolongs survival two- to threefold, associating the two drugs leads to tumor clearance after a 9-mo relapse-free period. These studies establishing RA/arsenic synergy in vivo prompt the use of combined arsenic/RA treatments in APL patients and exemplify how mouse models of human leukemia can be used to design or optimize therapies. PMID:10190895

Influence of acute promyelocytic leukemia therapeutic drugs on nuclear pore complex density and integrity.

PubMed

Lång, Anna; Øye, Alexander; Eriksson, Jens; Rowe, Alexander D; Lång, Emma; Bøe, Stig Ove

2018-05-15

During cell division, a large number of nuclear proteins are released into the cytoplasm due to nuclear envelope breakdown. Timely nuclear import of these proteins following exit from mitosis is critical for establishment of the G1 nuclear environment. Dysregulation of post-mitotic nuclear import may affect the fate of newly divided stem or progenitor cells and may lead to cancer. Acute promyelocytic leukemia (APL) is a malignant disorder that involves a defect in blood cell differentiation at the promyelocytic stage. Recent studies suggest that pharmacological concentrations of the APL therapeutic drugs, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), affect post-mitotic nuclear import of the APL-associated oncoprotein PML/RARA. In the present study, we have investigated the possibility that ATRA and ATO affect post-mitotic nuclear import through interference with components of the nuclear import machinery. We observe reduced density and impaired integrity of nuclear pore complexes after ATRA and/or ATO exposure. Using a post-mitotic nuclear import assay, we demonstrate distinct import kinetics among different nuclear import pathways while nuclear import rates were similar in the presence or absence of APL therapeutic drugs. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Planting local seed for growth to nationwide E/PO efforts

NASA Astrophysics Data System (ADS)

Fox, N.; Beisser, K.; Mendez, F.; Cockrell, D.; Wilhide, B.

The Johns Hopkins University Applied Physics Laboratory (JHU/APL) is the home to hundreds of scientists and engineers, all involved in research, design and implementation of space missions. Many of these people actively seek out ways to raise awareness and interest in the local community by visiting schools, giving public lectures and supporting events held at the laboratory. During the past few years, APL has begun to foster a number of firm partnerships with organizations to further these community opportunities and provide a test bed for both formal and informal education activities through the Space Department E/PO office One of our ongoing partnerships is with the Maryland Science Center in Baltimore. A continual challenge faced by museums is how to stay current and allow visitors to experience the immediacy and excitement of scientific discovery. To help meet these challenges, the Maryland Science Center houses "SpaceLink", the Nation's first space, science and astronomy update center. Part media center, part discovery room, and part newsroom, the exhibit is a multi-purpose Professional Development Site for educators and a "classroom of the future" for K 12 students. APL scientists and- engineers regularly support SpaceLink's flexible programming, including scientist in residence, monthly credited seminars for educators (Teachers' Thursdays), a menu of Classroom Programs on request, Distance Learning Teacher Presentations, and special Live Events to highlight mission milestones and space-related anniversaries. This allows the guest scientists and engineers to interact directly with the public. These events also compliment the APL exhibits housed at the Science Center. JHU/APL offers an exciting environment for the study of applications in space by hosting the annual Maryland Summer Center for Space Science sponsored by the Maryland State Department of Education. Rising 6t h and 7t h grade students learn to harness the power of technology and keep pace with the expanding knowledge of space science. They experience the process involved in planning/launching a simulated space mission, including design/fabrication of instrumentation for a spacecraft. They are part of a Mission Team that built a spacecraft scale model complete with instrumentation and even give a full mission overview oral presentation to their peers. During this 2 week experience, the students interact with the APL scientists and engineers directly responsible for the featured missions. Scientists and engineers team up with Comcast Cablevision of Maryland, Cable in the Classroom, and the Maryland State Department of Education to give Maryland middle school students a true outer space experience focusing on specific NASA missions. The students move from behind their desks to behind the scenes of a deep- space mission at JHU/APL. The students hear mission briefings and take part in a special student press conference with mission team members. They don clean-room suits and tour the Lab's space facilities, including the Mission Operations Center, the space environment simulation lab, the vibration test lab, and the satellite communications facility. These local programs for outreach opportunities have often served as the test bed for national programs and partnerships. In this presentation we will review the local programs to show how the organizations benefit from the partnership with APL and also how the APL outreach programs gain a much wider and more appreciative audience. We will also show how these programs are being expanded to a more nationwide focus.

Oridonin stabilizes retinoic acid receptor alpha through ROS-activated NF-κB signaling.

PubMed

Cao, Yang; Wei, Wei; Zhang, Nan; Yu, Qing; Xu, Wen-Bin; Yu, Wen-Jun; Chen, Guo-Qiang; Wu, Ying-Li; Yan, Hua

2015-04-10

Retinoic acid receptor alpha (RARα) plays an essential role in the regulation of many biological processes, such as hematopoietic cell differentiation, while abnormal RARα function contributes to the pathogenesis of certain diseases including cancers, especially acute promyelocytic leukemia (APL). Recently, oridonin, a natural diterpenoid isolated from Rabdosia rubescens, was demonstrated to regulate RARα by increasing its protein level. However, the underlying molecular mechanism for this action has not been fully elucidated. In the APL cell line, NB4, the effect of oridonin on RARα protein was analyzed by western blot and real-time quantitative RT-PCR analyses. Flow cytometry was performed to detect intracellular levels of reactive oxygen species (ROS). The association between nuclear factor-kappa B (NF-κB) signaling and the effect of oridonin was assessed using specific inhibitors, shRNA gene knockdown, and immunofluorescence assays. In addition, primary leukemia cells were treated with oridonin and analyzed by western blot in this study. RARα possesses transcriptional activity in the presence of its ligand, all-trans retinoic acid (ATRA). Oridonin remarkably stabilized the RARα protein, which retained transcriptional activity. Oridonin also moderately increased intracellular ROS levels, while pretreatment with the ROS scavenger, N-acetyl-l-cysteine (NAC), dramatically abrogated RARα stabilization by oridonin. More intriguingly, direct exposure to low concentrations of H2O2 also increased RARα protein but not mRNA levels, suggesting a role for ROS in oridonin stabilization of RARα protein. Further investigations showed that NAC antagonized oridonin-induced activation of NF-κB signaling, while the NF-κB signaling inhibitor, Bay 11-7082, effectively blocked the oridonin increase in RARα protein levels. In line with this, over-expression of IκΒα (A32/36), a super-repressor form of IκΒα, or NF-κB-p65 knockdown inhibited oridonin or H2O2-induced RARα stability. Finally, tumor necrosis factor alpha (TNFα), a classical activator of NF-κB signaling, modulated the stability of RARα protein. Oridonin stabilizes RARα protein by increasing cellular ROS levels, which causes activation of the NF-κB signaling pathway.

Raising a Child in the Punana Leo: Everyone (Men and Women) Play an Important Role

ERIC Educational Resources Information Center

Iokepa-Guerrero, Noelani

2008-01-01

Established in 1983 by a group of parents and teachers, the 'Aha Punana Leo ('APL) was formed. A grassroots organization, 'APL was established to respond to the dismal plight of the Hawaiian language. Just a mere 25 years ago, the Hawaiian language was on the verge of being lost forever. Through the dedicated efforts of a small group of friends…

Econ's optimal decision model of wheat production and distribution-documentation

NASA Technical Reports Server (NTRS)

1977-01-01

The report documents the computer programs written to implement the ECON optical decision model. The programs were written in APL, an extremely compact and powerful language particularly well suited to this model, which makes extensive use of matrix manipulations. The algorithms used are presented and listings of and descriptive information on the APL programs used are given. Possible changes in input data are also given.

Deep Water Acoustics

DTIC Science & Technology

2016-06-28

Sea, the results of which will support all of the objectives listed above. APPROACH APL-UW employed a combination of experimental measurements, data...APPROACH APL-UW employs a combination of experimental measurements, data analysis, simulations, and theoretical development to address the objectives...RD cases, respectively). In the RI case, the UTP moves back and forth along a curve. In the RD case, the UTP traces out an ellipse. The same is true

Threats to the Valid Use of Assessment of Prior Learning in Higher Education: Claimants' Experiences of the Assessment Process

ERIC Educational Resources Information Center

Stenlund, Tova

2012-01-01

Assessment of Prior Learning (APL) refers to a process where adults' prior learning, formal as well as informal, is assessed and acknowledged. In the first section of this paper, APL and current conceptions of validity in assessments and its evaluation are presented. It is argued that participants in the assessment are an important source of…

APL-UW Deep Water Propagation 2015-2017: Philippine Sea Data Analysis

DTIC Science & Technology

2015-09-30

DISTRIBUTION STATEMENT A: Approved for public release: distribution is unlimited APL-UW Deep Water Propagation 2015-2017: Philippine Sea Data...the fundamental statistics of broadband low-frequency acoustical signals evolve during propagation through a dynamically-varying deep ocean. OBJECTIVES...Current models of signal randomization over long ranges in the deep ocean were developed for and tested in the North Pacific Ocean gyre. The

Analysis of ADP-glucose pyrophosphorylase expression during turion formation induced by abscisic acid in Spirodela polyrhiza (greater duckweed)

PubMed Central

2012-01-01

Background Aquatic plants differ in their development from terrestrial plants in their morphology and physiology, but little is known about the molecular basis of the major phases of their life cycle. Interestingly, in place of seeds of terrestrial plants their dormant phase is represented by turions, which circumvents sexual reproduction. However, like seeds turions provide energy storage for starting the next growing season. Results To begin a characterization of the transition from the growth to the dormant phase we used abscisic acid (ABA), a plant hormone, to induce controlled turion formation in Spirodela polyrhiza and investigated their differentiation from fronds, representing their growth phase, into turions with respect to morphological, ultra-structural characteristics, and starch content. Turions were rich in anthocyanin pigmentation and had a density that submerged them to the bottom of liquid medium. Transmission electron microscopy (TEM) of turions showed in comparison to fronds shrunken vacuoles, smaller intercellular space, and abundant starch granules surrounded by thylakoid membranes. Turions accumulated more than 60% starch in dry mass after two weeks of ABA treatment. To further understand the mechanism of the developmental switch from fronds to turions, we cloned and sequenced the genes of three large-subunit ADP-glucose pyrophosphorylases (APLs). All three putative protein and exon sequences were conserved, but the corresponding genomic sequences were extremely variable mainly due to the invasion of miniature inverted-repeat transposable elements (MITEs) into introns. A molecular three-dimensional model of the SpAPLs was consistent with their regulatory mechanism in the interaction with the substrate (ATP) and allosteric activator (3-PGA) to permit conformational changes of its structure. Gene expression analysis revealed that each gene was associated with distinct temporal expression during turion formation. APL2 and APL3 were highly expressed in earlier stages of turion development, while APL1 expression was reduced throughout turion development. Conclusions These results suggest that the differential expression of APLs could be used to enhance energy flow from photosynthesis to storage of carbon in aquatic plants, making duckweeds a useful alternative biofuel feedstock. PMID:22235974

[Antibodies to various phospholipids in SLE patients with primary antiphospholipid syndrome].

PubMed

Reshetniak, T M; Boĭtsekhovskaia, B; Alekberova, Z S; Kalashnikova, L A; Mach, E S; Zabek, Ia

1999-01-01

Antiphospholipid antibodies (aPL) represent a heterogeneous population reacting with negatively charged, less frequently neutral phospholipids and/or phospholipid-binding serum proteins. The study was made of antibodies to a wide spectrum of phospholipids: to negatively charged phospholipids such as phosphatide acid (aPA), cardiolipin (aCL), phosphatidylcholine (aPS), phosphatidylinositol (aPI), phosphatidylglycerol (aPG) and to neutrally charged phospholipid--phosphatidylcholine (aPC)--in 54 patients with systemic lupus erythematosus (SLE) and 29 patients with primary antiphospholipid syndrome (PAPS). The test for lupus anticoagulant (LAC) was also made. aPL in SLE patients free of antiphospholipid syndrome were detected in 61, 36 and 9% (aPC, aPS and aPA, aCL, respectively). aPI and aPG did not exceed normal values. 81% of SLE patients with antiphospholipid syndrome were LAC positive and 88% aPL positive. 60, 53, 44, 40, 13 and 17 were positive to aPC, aPA, aPS, aCL, aPG and aPI, respectively. Among patients with PAPS, the highest positivity was by LAC, occurrence of the other aPL was the same as in SLE patients with antiphospholipid syndrome. aCL, aPA, aPC, aPS, aPG and aPI were found in 55, 52, 41, 38, 31 and 21% of cases, respectively. In clinical manifestations of antiphospholipid syndrome and negative tests for LAC and aCL it is advisable to make tests for aPS and aPC. aPC occur in SLE patients more frequently than the other aPL: in 63% of SLE patients free of antiphospholipid syndrome and in 60% of SLE patients with this syndrome. Antibodies to other phospholipids, but not to cardiolipin, were present in SLE + APS in half of the cases but in SLE + PAPS in one third of the patients. Occurrence of aCL in the serum of SLE + PAPS patients is associated with the presence of antibodies to any other phospholipid irrespective of the charge. The severity of vascular changes did not correlate with the number of aPL variant found in the serum.

Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia.

PubMed

Pandolfi, P P

2001-04-01

Acute promyelocytic leukemia (APL) is associated with reciprocal chromosomal translocations always involving the retinoic acid receptor alpha (RARalpha) gene on chromosome 17 and variable partner genes (X genes) on distinct chromosomes. RARalpha fuses to the PML gene in the vast majority of APL cases, and in a few cases to the PLZF, NPM, NuMA and Stat5b genes, respectively, leading to the generation of RARalpha-X: and X:-RARalpha fusion genes. Both fusion proteins can exert oncogenic functions through their ability to interfere with the activities of X and RARalpha proteins. Here, it will be discussed in detail how an extensive biochemical analysis as well as a systematic in vivo genetic approach in the mouse has allowed the definition of the multiple oncogenic activities of PML-RARalpha, and how it has become apparent that this oncoprotein is able to impair RARalpha at the transcription level and the tumor suppressive function of the PML protein.

From the Sun to Pluto and Beyond - Inspiring the Next Generation of Explorers

NASA Astrophysics Data System (ADS)

Beisser, K.; Matiella Novak, M.; Butler, L.; Turney, D.

2010-12-01

The Johns Hopkins University Applied Physics Laboratory (APL) Space Department currently manages a variety of Solar System exploratory satellite missions on behalf of NASA and in coordination with other universities and institutions. Along with managing these missions on a scientific and operational basis, the Space Department also maintains an education and public outreach staff that provides education and outreach events and activities to inspire, engage and educate the next generation of Solar System explorers. The main objective of the E/PO program is to create hands-on, minds-on learning experiences for students, educators and the general public. From the Sun to Pluto, APL is engineering the future of space exploration - examining Earth’s near-space environment, our star, planetary bodies, and the outer solar system. The E/PO office provides unique opportunities for K-12 students, educators, undergraduate and graduate students, museums, science centers, and the general public to share in the excitement of the missions APL manages for NASA. The E/PO program uses mission and instrument science and engineering to enhance the nation’s formal education system and contribute to public understanding of science, mathematics, and technology, making space exploration an adventure for students of all ages. Current Solar System missions that APL is involved with include missions to Pluto and the Kuiper Belt (New Horizons), exploring the Earth’s outermost layers of atmosphere (TIMED), studying the Sun’s coronal mass ejections (STEREO), mapping the geological and surface features of Mars (CRISM), exploring near-Earth asteroids (NEAR), understanding space weather (RBSP), studying Mercury (MESSENGER), and getting closer to the Sun than any probe has ever been (Solar Probe Plus). APL offers education and outreach opportunities, in coordination with NASA, for all of these missions.

HIV Type 1 from a Patient with Baseline Resistance to CCR5 Antagonists Uses Drug-Bound Receptor for Entry

PubMed Central

Tilton, John C.; Amrine-Madsen, Heather; Miamidian, John L.; Kitrinos, Kathryn M.; Pfaff, Jennifer; Demarest, James F.; Ray, Neelanjana; Jeffrey, Jerry L.; Labranche, Celia C.

2010-01-01

Abstract CCR5 antagonists are a new class of antiretroviral drugs that block viral entry by disrupting interactions between the viral envelope (Env) glycoprotein and coreceptor. During the CCR100136 (EPIC) Phase IIb study of the CCR5 antagonist aplaviroc (APL) in treatment-naive individuals, a patient was identified who harbored virus strains that exhibited partial resistance to APL at the time of virologic failure. Retrospectively, it was found that APL resistance was present at baseline as well. To investigate the mechanism of APL resistance in this patient, we cloned HIV-1 env genes from plasma obtained at baseline and after virologic failure. Approximately 85% of cloned Envs were functional, and all exhibited partial resistance to APL. All Envs were R5-tropic, were partially resistant to other CCR5 antagonists including maraviroc on cells with high CCR5 expression, but remained sensitive to the fusion inhibitor enfuvirtide. Competition studies with natural CCR5 ligands revealed that the mechanism of drug resistance entailed the use of the drug-bound conformation of CCR5 by the Env proteins obtained from this individual. The degree of drug resistance varied between Env clones, and also varied depending on the cell line used or the donor from whom the primary T cells were obtained. Thus, both virus and host factors contribute to CCR5 antagonist resistance. This study shows that R5 HIV-1 strains resistant to CCR5 inhibitors can arise in patients, confirming a mechanism of resistance previously characterized in vitro. In addition, some patients can harbor CCR5 antagonist-resistant viruses prior to treatment, which may have implications for the clinical use of this new class of antiretrovirals. PMID:20055594

Regulation of Hoxb2 by APL-associated PLZF protein.

PubMed

Ivins, Sarah; Pemberton, Kieran; Guidez, Fabien; Howell, Louise; Krumlauf, Robb; Zelent, Arthur

2003-06-12

The PLZF gene is translocated in a subset of all-trans-retinoic acid resistant acute promyelocytic leukaemia (APL) cases, encodes a DNA binding transcription factor and is expressed highly in haematopoietic progenitor cells as well-developing central nervous system (CNS). The spatially restricted and temporally dynamic pattern of PLZF expression in the developing CNS suggested that it might play a role in the circuitry regulating hindbrain segmentation. We have now identified a PLZF binding site (PLZF-RE) in an enhancer region of Hoxb2 that itself is required for directing high-level expression in rhombomers 3 and 5 of the developing hindbrain. The wild-type r3/r5 enhancer linked to a heterologous promoter was responsive to regulation by PLZF, and this activity was lost in variants containing a mutated PLZF-RE. Compared with the wild-type protein, the binding of the APL-associated reciprocal RARalpha-PLZF fusion to PLZF-RE was much stronger, suggesting that the N-terminal PLZF sequences missing from the fusion may play a role in the regulation of DNA binding. Consistent with this, the N-terminal POZ domain was required for cooperative binding of PLZF to a multimerized PLZF-RE. In the context of the r3/r5 enhancer, the PLZF-RE cooperated for PLZF binding with an additional A/T-rich motif positioned downstream of the PLZF-RE. This A/T motif was previously shown to be essential for the regulation of Hoxb2 expression in r3 and r5 in cooperation with another Krüppel-like zinc finger protein Krox 20. The presence of both the PLZF-RE and the A/T-rich motif was required for a maximal effect of PLZF on a heterologous promoter and was essential in vivo to direct the expression of a lacZ reporter in the chick neural tube. Hence, both PLZF and Krox20 cooperate with a common A/T motif in mediating in vivo activity of the Hoxb2 enhancer. Our findings indicate that Hoxb2 is a direct target for regulation by PLZF in the developing CNS and suggest that deregulation of Hox gene expression may contribute to APL pathogenesis.

[Efficacy and safety of rituximab in the treatment of primary antiphospholipid syndrome: analysis of 24 cases from the bibliography review].

PubMed

Pons, Isaac; Espinosa, Gerard; Cervera, Ricard

2015-02-02

Antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid antibodies (aPL) and thrombotic and/or obstetric manifestations. Patients without another associated autoimmune disease are considered to have primary APS. Some patients develop thrombosis recurrence despite anticoagulant treatment and some clinical features do not respond to standard therapy. Rituximab may be an alternative in these cases. We review the published scientific evidence on the use of rituximab in the treatment of primary APS. Description of a case and review of the literature with descriptive analysis of the demographic, clinical, and immunologic features, treatment and outcome of patients. We identified 24 patients (15 women [62.5%]), with a mean age of 37.0 ± 13.4 years. The reasons for the use of rituximab were thrombocytopenia (41.7%), skin involvement (33.3%), neurologic and heart valve involvement (12.5%), hemolytic anemia (8.3%) and pulmonary and renal involvement (4.2%). Lupus anticoagulant was present in 72.7% of the cases, the IgG and IgM isotypes of anticardiolipin antibodies in 75 and 50%, respectively, and the anti-β2GPI (IgG e IgM) antibodies in 80% of patients. Thirteen (54.1%) patients received 2 doses of 1,000 mg of rituximab fortnightly, 10 (41.7%) 4 doses of 375 mg/m(2) weekly and one (4.2%) 8 doses of 375 mg/m(2) weekly. Eleven (45.8%) patients presented a complete clinical response, 7 (29.2%) a partial response and 6 (25%) did not respond to rituximab. Four patients with clinical improvement presented with aPL titer decrease and in one patient, aPL levels did not change. In one patient without clinical response, aPL remained positive. A clinical-immunologic dissociation existed in 2 additional cases. The results obtained suggest a possible potential benefit of rituximab in the treatment of some clinical manifestations of primary APS such as thrombocytopenia, skin and heart valve involvement. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Relapsed Acute Promyelocytic Leukemia Lacks "Classic" Leukemic Promyelocyte Morphology and Can Create Diagnostic Challenges.

PubMed

Dayton, Vanessa J; McKenna, Robert W; Yohe, Sophia L; Dolan, Michelle M; Courville, Elizabeth; Alvarez, Harold; Linden, Michael A

2017-01-01

Although current therapies for acute promyelocytic leukemia (APL), such as all- trans retinoic acid and arsenic trioxide, usually result in remission, some patients relapse. Early recognition of relapse is critical for prompt intervention. In this study, we systematically reviewed morphologic, immunophenotypic, and cytogenetic findings in paired diagnostic and relapsed APL cases and describe and quantify the changes in blast morphology at relapse. By electronic database search, we identified eight paired diagnostic and relapsed APL cases for which peripheral blood or bone marrow smears were available for review. For two cases, diagnostic material was available for relapse after hematopoietic cell transplantation. Neoplastic hypergranular or microgranular promyelocytes with indented or bivalve nuclei predominated at diagnosis in all patients. Most patients had undifferentiated blasts at relapse and/or hypergranular blast equivalents with round to oval nuclei. Classic acute promyelocytic leukemia cells with bivalve nuclei and bundles of cytoplasmic Auer rods were easily identifiable in fewer than half of cases at diagnosis and rare to absent in all relapsed cases. Morphologic features of relapsed APL overlap with other types of acute myeloid leukemia, creating diagnostic challenges, especially if no history is available when relapsing patients seek treatment for care. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Exploring (novel) gene expression during retinoid-induced maturation and cell death of acute promyelocytic leukemia.

PubMed

Benoit, G R; Tong, J H; Balajthy, Z; Lanotte, M

2001-01-01

During recent years, reports have shown that biological responses of acute promyelocytic leukemia (APL) cells to retinoids are more complex than initially envisioned. PML-RARalpha chimeric protein disturbs various biological processes such as cell proliferation, differentiation, and apoptosis. The distinct biological programs that regulate these processes stem from specific transcriptional activation of distinct (but overlapping) sets of genes. These programs are sometimes mutually exclusive and depend on whether the signals are delivered by RAR or RXR agonists. Furthermore, evidence that retinoid nuclear signaling by retinoid, on its own, is not enough to trigger these cellular responses is rapidly accumulating. Indeed, work with NB4 cells show that the fate of APL cells treated by retinoid depends on complex signaling cross-talk. Elucidation of the sequence of events and cascades of transcriptional regulation necessary for APL cell maturation will be an additional tool with which to further improve therapy by retinoids. In this task, the classical techniques used to analyze gene expression have proved time consuming, and their yield has been limited. Global analyses of the APL cell transcriptome are needed. We review the technical approaches currently available (differential display, complementary DNA microarrays), to identify novel genes involved in the determination of cell fate.

Incidence of autoantibodies in the infertile population.

PubMed

Cubillos, J; Lucena, A; Lucena, C; Mendoza, J C; Ruiz, H; Arango, A; Quiroga, G; Ferro, J; Lucena, E

1997-06-01

The purpose of this study was to determine the incidence of autoantibodies in patients with no term pregnancies. Patients selected included 43 with primary infertility and 110 with a history of pregnancy loss. In the first group the incidence of antinuclear antibodies (ANA) and IgG and IgM antiphospholipid antibodies (APL) was 37.2% (p < 0.05) and 53.5% (p < 0.05), respectively. In the group of patients with a history of miscarriage, 31.8% (p < 0.05) were positive for ANA and 38.2% (p < 0.05) for APL. Controls were 35 healthy patients with proven fertility and no history of pregnancy loss or autoimmune disease. In this group the incidence of ANA was 5.7% and 11.4% for APL. The high incidence of autoantibodies found in patients with primary infertility might suggest a direct involvement of these antibodies in reproductive failure and consequently in IVF and assisted fertility procedures. The prevalence of ANA and APL has been extensively described in patients with a history of recurrent pregnancy losses (RPL). In this study we observed antibodies even after the first miscarriage. We therefore conclude that patients with a history of reproductive failure should be immunologically evaluated and treated before undergoing assisted fertilization techniques or before a new pregnancy in those cases of RPL.

Structural Characterization of the E2 Domain of APL-1, a C. Elegans Homolog of Human Amyloid Precursor Protein, and its Heparin Binding Site

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

Hoopes, J.; Liu, X; Xu, X

2010-01-01

The amyloid {beta}-peptide deposit found in the brain tissue of patients with Alzheimer disease is derived from a large heparin-binding protein precursor APP. The biological function of APP and its homologs is not precisely known. Here we report the x-ray structure of the E2 domain of APL-1, an APP homolog in Caenorhabditis elegans, and compare it to the human APP structure. We also describe the structure of APL-1 E2 in complex with sucrose octasulfate, a highly negatively charged disaccharide, which reveals an unexpected binding pocket between the two halves of E2. Based on the crystal structure, we are able tomore » map, using site-directed mutagenesis, a surface groove on E2 to which heparin may bind. Our biochemical data also indicate that the affinity of E2 for heparin is influenced by pH: at pH 5, the binding appears to be much stronger than that at neutral pH. This property is likely caused by histidine residues in the vicinity of the mapped heparin binding site and could be important for the proposed adhesive function of APL-1.« less

PML-RARα kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy.

PubMed

Cicconi, L; Divona, M; Ciardi, C; Ottone, T; Ferrantini, A; Lavorgna, S; Alfonso, V; Paoloni, F; Piciocchi, A; Avvisati, G; Ferrara, F; Di Bona, E; Albano, F; Breccia, M; Cerqui, E; Sborgia, M; Kropp, M G; Santoro, A; Levis, A; Sica, S; Amadori, S; Voso, M T; Mandelli, F; Lo-Coco, F

2016-10-01

The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-α (PML-RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RARα transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.

Guilty as charged: all available evidence implicates complement's role in fetal demise.

PubMed

Girardi, Guillermina

2008-03-01

Appropriate complement inhibition is an absolute requirement for normal pregancy. Uncontrolled complement activation in the maternal-fetal interface leads to fetal death. Here we show that complement activation is a crucial and early mediator of pregnancy loss in two different mouse models of pregnancy loss. Using a mouse model of fetal loss and growth restriction (IUGR) induced by antiphospholipid antibodies (aPL), we examined the role of complement activation in fetal loss and IUGR. We found that C5a-C5aR interaction and neutrophils are key mediators of fetal injury. Treatment with heparin, the standard therapy for pregnant patients with aPL, prevents complement activation and protects mice from pregnancy complications induced by aPL, and anticoagulants that do not inhibit complement do not protect pregnancies. In an antibody-independent mouse model of spontaneous miscarriage and IUGR (CBA/JxDBA/2) we also identified C5a as an essential mediator. Complement activation caused dysregulation of the angiogenic factors required for normal placental development. In CBA/JxDBA/2 mice, we observed inflammatory infiltrates in placentas, functional deficiency of free vascular endothelial growth factor (VEGF), elevated levels of soluble VEGF receptor-1 (sVEGFR-1, also known as sFlt-1; a potent anti-angiogenic molecule), and defective placental development. Inhibition of complement activation blocked the increase in sVEGFR-1 and rescued pregnancies. Our studies in antibody-dependent and antibody-independent models of pregnancy complications identified complement activation as the key mediator of damage and will allow development of new interventions to prevent pregnancy loss and IUGR.

Stepping into the Unknown: Three Models for the Teaching and Learning of the Opening Sections of Scientific Articles

ERIC Educational Resources Information Center

Falk, Hedda; Yarden, Anat

2011-01-01

Different genres of scientific articles have begun to diffuse into science curricula. Among them, adapted primary literature (APL) retains the characteristics of scientific research articles, while adapting their contents to the knowledge level of students in the 11th to 12th grades. We present three models for the teaching and learning of the…

Clinical associations of proinflammatory cytokines, oxidative biomarkers and vitamin D levels in systemic lupus erythematosus.

PubMed

Willis, R; Smikle, M; DeCeulaer, K; Romay-Penabad, Z; Papalardo, E; Jajoria, P; Harper, B; Murthy, V; Petri, M; Gonzalez, E B

2017-12-01

Background The abnormal biological activity of cytokines plays an important role in the pathophysiology of both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Several studies have highlighted the association of vitamin D and certain pro-inflammatory cytokines with disease activity in SLE. However, there are limited data on the association of vitamin D and antiphospholipid antibodies (aPL) with various proinflammatory biomarkers in these patients and their relative impact on clinical outcomes. Methods The serum levels of several aPL, 25-hydroxy-vitamin D, pro-inflammatory cytokines including IFNα, IL-1β, IL-6, IL-8, IP10, sCD40L, TNFα and VEGF were measured in 312 SLE patients from the Jamaican ( n = 45) and Hopkins ( n = 267) lupus cohorts using commercial Milliplex and ELISA assays. Oxidized LDL/β2glycoprotein antigenic complexes (oxLβ2Ag) and their associated antibodies were also measured in the Jamaican cohort. Healthy controls for oxidative marker and cytokine testing were used. Results Abnormally low vitamin D levels were present in 61.4% and 73.3% of Hopkins and Jamaican SLE patients, respectively. Median concentrations of IP10, TNFα, sCD40L and VEGF were elevated in both cohorts, oxLβ2Ag and IL-6 were elevated in the Jamaican cohort, and IFNα, IL-1β and IL-8 were the same or lower in both cohorts compared to controls. IP10 and VEGF were independent predictors of disease activity, aPL, IP10 and IL-6 were independent predictors of thrombosis and IL-8, and low vitamin D were independent predictors of pregnancy morbidity despite there being no association of vitamin D with pro-inflammatory cytokines. Conclusions Our results indicate that aPL-mediated pro-inflammatory cytokine production is likely a major mechanism of thrombus development in SLE patients. We provide presumptive evidence of the role IL-8 and hypovitaminosis D play in obstetric pathology in SLE but further studies are required to characterize the subtle complexities of vitamin D's relationship with cytokine production and disease activity in these patients.

Substorms and Magnetic Flux Erosion

NASA Technical Reports Server (NTRS)

1997-01-01

There were no publications associated with this grant. Instead, we used the funds to place IRM, Prognoz-10, and GOES-5/6/7 data sets on-line. The included copies of WWW pages indicate the nature of these services at APL. Since the time when the work was performed, a more complete set of IRM data has been placed on-line at the University of New Hampshire.

[Perception of health and safety risks among workers pathology laboratories].

PubMed

Alvarado-Cabrero, Isabel; Valencia-Cedillo, Raquel

2015-01-01

Health care workers are experiencing increasing numbers of occupational illnesses. Safety practices in anatomical pathology laboratories (APL) are crucial to prevent unnecessary exposures to both chemical and biological agents. The main goal of this study was to determine if pathologists perceptions and actual practice mirror regulatory guidelines. Current available recommendations for APL were reviewed and used to construct an online survey distributed to pathologists. The survey was completed by 121 participants. Eighty-seven (72 %) of respondents reported receiving inadequate safety training. Most pathologists (82 %) were not well-informed about biosafety practices. Sixty-three (52 %) participants felt that the risks of chemical and infectious disease exposures in the APL were low. Most respondents reported having a needle stick or cut (71 %). Eighty-six (71 %) of participants reported musculo skeletal problems. This study indicated that there is a need for improving training in anatomical pathology safety practices in Mexican laboratories as daily practices do not reflected current guidelines.

Air-sea interaction and remote sensing

NASA Technical Reports Server (NTRS)

Katsaros, Kristina B.; Ataktuerk, Serhad S.

1992-01-01

The first part of the proposed research was a joint effort between our group and the Applied Physics Laboratory (APL), University of Washington. Our own research goal is to investigate the relation between the air-sea exchange processes and the sea state over the open ocean and to compare these findings with our previous results obtained over a small body of water namely, Lake Washington. The goals of the APL researchers are to study (1) the infrared sea surface temperature (SST) signature of breaking waves and surface slicks, and (2) microwave and acoustic scattering from water surface. The task of our group in this joint effort is to conduct measurements of surface fluxes (of momentum, sensible heat, and water vapor) and atmospheric radiation (longwave and shortwave) to achieve our research goal as well as to provide crucial complementary data for the APL studies. The progress of the project is summarized.

Income differences in social control of eating behaviors and food choice priorities among southern rural women in the US: A qualitative study.

PubMed

Vilaro, Melissa J; Barnett, Tracey E; Mathews, Anne; Pomeranz, Jamie; Curbow, Barbara

2016-12-01

The role of social influences on rural women's food choice is not well understood. Rural adults experience high rates of obesity and poor diet quality prompting exploration of how social factors influence food choice in this population. Semi-structured qualitative interviews were conducted with 20 women in rural North Central Florida. Women were purposively sampled and stratified by race and income. Lower income was defined as household income at or below 185% of the federal poverty level (FPL). Women at or below 185% poverty level (BPL) experienced direct social control of their eating behaviors, which occurred when social network members explicitly regulated or otherwise sanctioned eating behaviors or food choices. Women above 185% of the federal poverty level (APL) internalized social norms and self-regulated their eating behaviors to maintain healthy habits. APL women described choosing foods for health reasons whereas BPL women offered a variety of reasons including taste, convenience, family history, price, health, and routine. Findings suggest that women in different income groups have different social influences working to help them regulate eating behaviors as well as diverse priorities influencing their food choices. Future interventions to promote healthy eating may be more effective by incorporating social network members and framing intervention messages so they are consistent with priorities. Copyright © 2016 Elsevier Ltd. All rights reserved.

Causes and prognostic factors for early death in patients with acute promyelocytic leukemia treated with single-agent arsenic trioxide.

PubMed

Hou, Jinxiao; Wang, Shuye; Zhang, Yingmei; Fan, Dachuan; Li, Haitao; Yang, Yiju; Ge, Fei; Hou, Wenyi; Fu, Jinyue; Wang, Ping; Zhao, Hongli; Sun, Jiayue; Yang, Kunpeng; Zhou, Jin; Li, Xiaoxia

2017-12-01

Early death (ED) is one of the most critical issues involved in the current care of patients with acute promyelocytic leukemia (APL). Factors identified as independent predictors of ED varied among published studies. We retrospectively analyzed the incidence, causes, and prognostic factors of ED in a series of 216 patients with newly diagnosed APL who received arsenic trioxide (ATO) as induction therapy. Multivariate logistic regression analysis was used to determine the association of clinical factors with overall ED, hemorrhagic ED, death within 7 days, and death within 8-30 days. In total, 35 EDs (16.2%) occurred that were caused by hemorrhage, differentiation syndrome (DS), infection, and other causes, in order of prevalence. The independent prognostic factors for overall ED and death within 8-30 days were the same and included serum creatinine level, Eastern Cooperative Oncology Group (ECOG) score, sex, and fibrinogen level. The risk factors for hemorrhagic ED and death within 7 days were similar and included serum creatinine level, ECOG score, and white blood cell count, while hemorrhagic ED was also associated with D-dimer. Our findings revealed a high rate of ED, and the causes of ED were similar to those among patients who received ATRA-based therapy. Increased creatinine level was the most powerful predictor, and an ECOG score greater than 2 was another strong prognostic factor for all four types of ED.

All-transretinoic acid (ATRA) treatment-related pancarditis and severe pulmonary edema in a child with acute promyelocytic leukemia.

PubMed

Işık, Pamir; Çetin, Ilker; Tavil, Betul; Azik, Fatih; Kara, Abdurrahman; Yarali, Nese; Tunc, Bahattin

2010-11-01

Use of all-transretinoic acid (ATRA) with other chemotherapeutic agents in the treatment of acute promyelocytic leukemia (APL) has been shown to cause the differentiation of abnormally granulated specific blast cells into mature granulocytes by acting on the t(15; 17) fusion gene product. The complete remission rate is increased and survival time is prolonged in APL patients who receive chemotherapy plus ATRA, whereas ATRA syndrome and other ATRA-related adverse effects including pseudo tumor cerebri, headache, severe bone pain, mucosal and skin dryness, hypercholesterolemia, and cheilitis may be observed especially during induction phase of the treatment. In this paper, we report a 9-year-old girl with APL who developed pancarditis while receiving the APL-93 treatment protocol. In our patient, endocarditis and myocarditis were initially determined after ATRA treatment during the induction part of the protocol. All findings disappeared after ATRA was discontinued. When ATRA was readministered in the maintenance part of the treatment protocol, she developed pancarditis and severe pulmonary edema. As her symptoms decreased dramatically with the discontinuation of ATRA and the initiation of steroid treatment, the clinical picture strongly suggested the ATRA treatment as the causative factor. To the best of our knowledge, this clinical picture of pancarditis secondary to ATRA treatment has not been reported earlier in the English literature.

The role of ADP-ribosylation in regulating DNA interstrand crosslink repair

PubMed Central

Gunn, Alasdair R.; Banos-Pinero, Benito; Paschke, Peggy; Sanchez-Pulido, Luis; Ariza, Antonio; Day, Joseph; Emrich, Mehera; Leys, David; Ponting, Chris P.

2016-01-01

ABSTRACT ADP-ribosylation by ADP-ribosyltransferases (ARTs) has a well-established role in DNA strand break repair by promoting enrichment of repair factors at damage sites through ADP-ribose interaction domains. Here, we exploit the simple eukaryote Dictyostelium to uncover a role for ADP-ribosylation in regulating DNA interstrand crosslink repair and redundancy of this pathway with non-homologous end-joining (NHEJ). In silico searches were used to identify a protein that contains a permutated macrodomain (which we call aprataxin/APLF-and-PNKP-like protein; APL). Structural analysis reveals that this permutated macrodomain retains features associated with ADP-ribose interactions and that APL is capable of binding poly(ADP-ribose) through this macrodomain. APL is enriched in chromatin in response to cisplatin treatment, an agent that induces DNA interstrand crosslinks (ICLs). This is dependent on the macrodomain of APL and the ART Adprt2, indicating a role for ADP-ribosylation in the cellular response to cisplatin. Although adprt2− cells are sensitive to cisplatin, ADP-ribosylation is evident in these cells owing to redundant signalling by the double-strand break (DSB)-responsive ART Adprt1a, promoting NHEJ-mediated repair. These data implicate ADP-ribosylation in DNA ICL repair and identify that NHEJ can function to resolve this form of DNA damage in the absence of Adprt2. PMID:27587838

Gangrenous cheilitis associated with all-trans retinoic acid therapy for acute promyelocytic leukemia.

PubMed

Tanaka, Mariko; Fukushima, Noriyasu; Itamura, Hidekazu; Urata, Chisako; Yokoo, Masako; Ide, Masaru; Hisatomi, Takashi; Tomimasu, Rika; Sueoka, Eisaburo; Kimura, Shinya

2010-01-01

A 67-year-old Japanese woman who presented with erythema on the abdomen and pancytopenia was found to have acute promyelocytic leukemia (APL). A skin biopsy revealed invasion of APL cells. She was started on induction treatment with all-trans retinoic acid (ATRA) at 45 mg/m(2). On day 4, the leukemic cell number had increased to over 1.0 x 10(9)/L. Consequently, chemotherapy with idarubicin and cytarabine was initiated. On day 10, dryness of the lips appeared. The lower lip swelled and developed painful black eschars. A high fever was also present. Despite discontinuing ATRA on day 20 and administering antibiotics, an anti-fungal agent and valaciclovir, these signs did not improve. Histopathologically, the biopsied lip revealed infiltration of neutrophils and vasculitis. The patient was given ATRA on days 29 and 30 due to an increase in APL cell numbers, after which the gangrenous cheilitis extended over the whole lip. On day 49, the patient was started on re-induction treatment with arsenic trioxide. She achieved complete remission and the gangrenous cheilitis slowly healed over the following 8 weeks. Since the clinical features of the gangrenous cheilitis in this case were similar to those of ATRA-associated scrotal ulcers, it appears that activated neutrophils derived from differentiated APL cells may have caused the gangrenous cheilitis. Physicians should be alert to the development of gangrenous cheilitis during treatment with ATRA.

Antiphospholipid antibodies and non-thrombotic manifestations of systemic lupus erythematosus.

PubMed

İlgen, U; Yayla, M E; Ateş, A; Okatan, İ E; Yurteri, E U; Torgutalp, M; Keleşoğlu, A B D; Turgay, T M; Kınıklı, G

2018-04-01

Objectives The aim of this study was to investigate the association between antiphospholipid antibodies and non-thrombotic and non-gestational manifestations of systemic lupus erythematosus. Methods Systemic lupus erythematosus patients with persistently positive antiphospholipid antibodies or lupus anticoagulant were identified and grouped as systemic lupus erythematosus with antiphospholipid syndrome (SLE-APS), systemic lupus erythematosus with positive antiphospholipid antibodies/lupus anticoagulant without antiphospholipid syndrome (SLE-aPL), and systemic lupus erythematosus with negative aPLs (SLE-No aPL). Groups were compared in terms of non-thrombotic systemic lupus erythematosus manifestations and laboratory features retrospectively. Results A total of 150 systemic lupus erythematosus patients, 26 with SLE-APS, 25 with SLE-aPL, and 99 with SLE-No aPL, were identified. Livedo reticularis, neurologic involvement, and thrombocytopenia were more common in antiphospholipid antibody positive systemic lupus erythematosus cases. Malar rash, arthritis, and pleuritis were more common in the SLE-No aPL, SLE-APS, and SLE-aPL groups, respectively. Positivity rates and titers of specific antiphospholipid antibodies did not differ between the SLE-APS and SLE-aPL groups. Conclusions Presence of antiphospholipid syndrome or persistent antiphospholipid antibodies may be related to non-thrombotic and non-gestational systemic lupus erythematosus manifestations. Patients with systemic lupus erythematosus plus antiphospholipid syndrome and persistent antiphospholipid antibodies without antiphospholipid syndrome also differ in terms of systemic lupus erythematosus manifestations.

New Horizons Launch Contingency Effort

NASA Astrophysics Data System (ADS)

Chang, Yale; Lear, Matthew H.; McGrath, Brian E.; Heyler, Gene A.; Takashima, Naruhisa; Owings, W. Donald

2007-01-01

On 19 January 2006 at 2:00 PM EST, the NASA New Horizons spacecraft (SC) was launched from the Cape Canaveral Air Force Station (CCAFS), FL, onboard an Atlas V 551/Centaur/STAR™ 48B launch vehicle (LV) on a mission to explore the Pluto Charon planetary system and possibly other Kuiper Belt Objects. It carried a single Radioisotope Thermoelectric Generator (RTG). As part of the joint NASA/US Department of Energy (DOE) safety effort, contingency plans were prepared to address the unlikely events of launch accidents leading to a near-pad impact, a suborbital reentry, an orbital reentry, or a heliocentric orbit. As the implementing organization. The Johns Hopkins University Applied Physics Laboratory (JHU/APL) had expanded roles in the New Horizons launch contingency effort over those for the Cassini mission and Mars Exploration Rovers missions. The expanded tasks included participation in the Radiological Control Center (RADCC) at the Kennedy Space Center (KSC), preparation of contingency plans, coordination of space tracking assets, improved aerodynamics characterization of the RTG's 18 General Purpose Heat Source (GPHS) modules, and development of spacecraft and RTG reentry breakup analysis tools. Other JHU/APL tasks were prediction of the Earth impact footprints (ElFs) for the GPHS modules released during the atmospheric reentry (for purposes of notification and recovery), prediction of the time of SC reentry from a potential orbital decay, pre-launch dissemination of ballistic coefficients of various possible reentry configurations, and launch support of an Emergency Operations Center (EOC) on the JHU/APL campus. For the New Horizons launch, JHU/APL personnel at the RADCC and at the EOC were ready to implement any real-time launch contingency activities. A successful New Horizons launch and interplanetary injection precluded any further contingency actions. The New Horizons launch contingency was an interagency effort by several organizations. This paper describes JHU/APL's roles and responsibilities in the launch contingency effort, and the specific tasks to fulfill those responsibilities. The overall effort contributed to mission safety and demonstrated successful cooperation between several agencies.

Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis.

PubMed

Opatrny, Lucie; David, Michéle; Kahn, Susan R; Shrier, Ian; Rey, Evelyne

2006-11-01

To assess the strength of association between recurrent fetal loss (RFL) and presence of antiphospholipid antibodies (aPL) in women without autoimmune disease, and to examine whether magnitude of association varies according to type or titer of antibody and timing of fetal loss. We searched Medline and Current Contents for articles published between 1975 and 2003 with terms denoting early (less than 13 weeks) and late (less than 24 weeks) RFL associated with various aPL. Published case-control, cohort, and cross-sectional studies rated moderate or strong were included in our metaanalysis. Pooled odds ratios with 95% CI were generated using the random-effects models with Cochrane Review Manager software. Our analysis included 25 studies. Lupus anticoagulant (LAC) was associated with late RFL (OR 7.79, 95% CI 2.30-26.45); the association of LAC was stronger than that of any other aPL. IgG anticardiolipin antibodies (aCL), when combining all titers, were associated with both early (OR 3.56, 95% CI 1.48-8.59) and late RFL (OR 3.57, 95% CI 2.26-5.65). Restricting analysis to include only women with moderate to high titers increased the strength of association (OR 4.68, 95% CI 2.96-7.40). It was not possible to extract data on isolated low IgG aCL positivity. IgM aCL were associated with late RFL (OR 5.61, 95% CI 1.26-25.03). There was no association found between early RFL and anti-Beta2-glycoprotein I antibodies (OR 2.12, 95% CI 0.69-6.53). The magnitude of the association between aPL and RFL varies according to type of aPL. More data on the relationship between recurrent fetal loss and isolated IgM aCL as well as with low titer IgG aCL would be useful. The place of testing for anti-Beta2-glycoprotein I antibodies remains to be determined.

Retinoids in pediatric onco-hematology: the model of acute promyelocytic leukemia and neuroblastoma.

PubMed

Masetti, Riccardo; Biagi, Carlotta; Zama, Daniele; Vendemini, Francesca; Martoni, Anna; Morello, William; Gasperini, Pietro; Pession, Andrea

2012-09-01

Retinoids are lipophilic compounds derived from vitamin A, which have been extensively studied in cancer prevention and therapy. In pediatric oncology, they are successfully used for the treatment of acute promyelocytic leukemia (APL) and high-risk neuroblastoma (HR-NBL). APL is a subtype of acute myeloid leukemia (AML) clinically characterized by a severe bleeding tendency with a highrisk of fatal hemorrhage. The molecular hallmark of this disease is the presence of the promyelocytic leukemia (PML)-retinoic acid receptor-α (RAR α) gene fusion that plays a critical role in promyelocytic leukemogenesis and represents the target of retinoid therapy. The introduction in the late 1980s of all-trans retinoic acid (ATRA) into the therapy of APL radically changed the management and the outcome of this disease. Presently, the standard front-line therapeutic approach for pediatric APL includes anthracycline-based chemotherapy and ATRA, leading to a complete remission in almost 90% of the patients. Neuroblastoma (NBL) is an aggressive childhood tumor derived from the peripheral neural crest. More than half of patients have a high-risk disease, with a poor outcome despite intensive multimodal treatment. Although the exact mechanism of action remains unclear, the introduction of 13-cis-retinoic acid (13-cis-RA) in the therapy of NBL has improved the prognosis of this disease. Currently, the standard treatment for HR-NBL consists of myeloablative therapy followed by autologous hematopoietic stem cell transplantation (HSCT) and maintenance with 13-cis-RA for the treatment of minimal residual disease, leading to a 3-year disease-free survival rate (DFS) of about 50%. In this paper the authors provide a review of the peer-reviewed literature on the role of retinoids in the treatment of pediatric APL and HR-NBL, summarizing the most relevant clinical trial results of the last decades, analyzing the ongoing trials, and investigating future therapeutic perspectives of children affected by these diseases.

Mice with experimental antiphospholipid syndrome display hippocampal dysfunction and a reduction of dendritic complexity in hippocampal CA1 neurones.

PubMed

Frauenknecht, Katrin; Katzav, Aviva; Weiss Lavi, Ronen; Sabag, Avishag; Otten, Susanne; Chapman, Joab; Sommer, Clemens J

2015-08-01

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by high titres of auto-antibodies (aPL) leading to thrombosis and consequent infarcts. However, many affected patients develop neurological symptoms in the absence of stroke. Similarly, in a mouse model of this disease (eAPS), animals consistently develop behavioural abnormalities despite lack of ischemic brain injury. Therefore, the present study was designed to identify structural alterations of hippocampal neurones underlying the neurological symptoms in eAPS. Adult female Balb/C mice were subjected to either induction of eAPS by immunization with β2-Glycoprotein 1 or to a control group. After sixteen weeks animals underwent behavioural and cognitive testing using Staircase test (experiment 1 and 2) and Y-maze alternation test (experiment 1) and were tested for serum aPL levels (both experiments). Animals of experiment 1 (n = 7/group) were used for hippocampal neurone analysis using Golgi-Cox staining. Animals of experiment 2 (n = 7/group) were used to analyse molecular markers of total dendritic integrity (MAP2), presynaptic plasticity (synaptobrevin 2/VAMP2) and dendritic spines (synaptopodin) using immunohistochemistry. eAPS mice developed increased aPL titres and presented with abnormal behaviour and impaired short term memory. Further, they revealed a reduction of dendritic complexity of hippocampal CA1 neurones as reflected by decreased dendritic length, arborization and spine density, respectively. Additional decrease of the spine-associated protein expression of Synaptopodin points to dendritic spines as major targets in the pathological process. Reduction of hippocampal dendritic complexity may represent the structural basis for the behavioural and cognitive abnormalities of eAPS mice. © 2014 British Neuropathological Society.

Complement inhibition by hydroxychloroquine prevents placental and fetal brain abnormalities in antiphospholipid syndrome.

PubMed

Bertolaccini, Maria Laura; Contento, Gregorio; Lennen, Ross; Sanna, Giovanni; Blower, Philip J; Ma, Michelle T; Sunassee, Kavitha; Girardi, Guillermina

2016-12-01

Placental ischemic disease and adverse pregnancy outcomes are frequently observed in patients with antiphospholipid syndrome (APS). Despite the administration of conventional antithrombotic treatment a significant number of women continue to experience adverse pregnancy outcomes, with uncertain prevention and management. Efforts to develop effective pharmacological strategies for refractory obstetric APS cases will be of significant clinical benefit for both mothers and fetuses. Although the antimalarial drug, hydroxychloroquine (HCQ) is increasingly used to treat pregnant women with APS, little is known about its efficacy and mechanism of action of HCQ. Because complement activation plays a crucial and causative role in placental ischemia and abnormal fetal brain development in APS we hypothesised that HCQ prevents these pregnancy complications through inhibition of complement activation. Using a mouse model of obstetric APS that closely resembles the clinical condition, we found that HCQ prevented fetal death and the placental metabolic changes -measured by proton magnetic resonance spectroscopy in APS-mice. Using 111 In labelled antiphospholipid antibodies (aPL) we identified the placenta and the fetal brain as the main organ targets in APS-mice. Using this same method, we found that HCQ does not inhibit aPL binding to tissues as was previously suggested from in vitro studies. While HCQ did not affect aPL binding to fetal brain it prevented fetal brain abnormal cortical development. HCQ prevented complement activation in vivo and in vitro. Complement C5a levels in serum samples from APS patients and APS-mice were lower after treatment with HCQ while the antibodies titres remained unchanged. HCQ prevented not only placental insufficiency but also abnormal fetal brain development in APS. By inhibiting complement activation, HCQ might also be an effective antithrombotic therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

The APL-UW Multiport Acoustic Projector System

DTIC Science & Technology

2009-12-01

delivered are shown in Figs. 18 and 19 . Concern regarding heat build-up in the device led APL-UW to provide two thermistors to Coiltron during the...winding process to be inserted deep inside the windings, near the core, for monitoring during operation. Leads from these thermistors can be seen in...using a chain bridle attached to the bolt eyes fixed into the top of the main tube. A tentative plan was devised to lift from a hard point welded onto

Developments in Science and Technology

DTIC Science & Technology

1979-01-01

Testing of the APL OTEC Heat Exchanger as an Evaporator 74 P. P. Pandolfini, J. L. Keirsey, antd J. A. Funk Geothermal Energy Market Study on the Atlantic...Wozniak I. J. J. Wozniak, Follow- on Study of the Towed Underwater Launch Platforn (TULP) Concept for Trident It Testing, APL/JIIU PM. 8342, Oct 1978... studies . MAGSAT was shipped to Vandenberg AB, REFERENCES California, on 5 October 1979. Field operations coim- 1 51,(,i1 1srujtl.’ tiim. APt Jil L Sl) 114b

KSC-04pd1470

NASA Image and Video Library

2004-07-14

KENNEDY SPACE CENTER, FLA. - The MESSENGER (Mercury Surface, Space Environment, Geochemistry and Ranging) spacecraft, mated to the Delta II third stage Payload Assist Module, is ready for presentation to the media at Astrotech Space Operations in Titusville, Fla. Spokespersons for the event are Dr. Robert Gold, MESSENGER payload manager with The Johns Hopkins University Applied Physics Laboratory (APL); and Ted Hartka, MESSENGER lead mechanical engineer, APL. MESSENGER is scheduled to launch Aug. 2 aboard a Boeing Delta II rocket from Pad 17-B, Cape Canaveral Air Force Station, Fla.

KSC-04pd1471

NASA Image and Video Library

2004-07-14

KENNEDY SPACE CENTER, FLA. - The MESSENGER (Mercury Surface, Space Environment, Geochemistry and Ranging) spacecraft, mated to the Delta II third stage Payload Assist Module, is on display at Astrotech Space Operations in Titusville, Fla., for the media. Spokespersons for the event are Dr. Robert Gold, MESSENGER payload manager with The Johns Hopkins University Applied Physics Laboratory (APL); and Ted Hartka, MESSENGER lead mechanical engineer, APL. MESSENGER is scheduled to launch Aug. 2 aboard a Boeing Delta II rocket from Pad 17-B, Cape Canaveral Air Force Station, Fla.

Tumor SHB gene expression affects disease characteristics in human acute myeloid leukemia.

PubMed

Jamalpour, Maria; Li, Xiujuan; Cavelier, Lucia; Gustafsson, Karin; Mostoslavsky, Gustavo; Höglund, Martin; Welsh, Michael

2017-10-01

The mouse Shb gene coding for the Src Homology 2-domain containing adapter protein B has recently been placed in context of BCRABL1-induced myeloid leukemia in mice and the current study was performed in order to relate SHB to human acute myeloid leukemia (AML). Publicly available AML databases were mined for SHB gene expression and patient survival. SHB gene expression was determined in the Uppsala cohort of AML patients by qPCR. Cell proliferation was determined after SHB gene knockdown in leukemic cell lines. Despite a low frequency of SHB gene mutations, many tumors overexpressed SHB mRNA compared with normal myeloid blood cells. AML patients with tumors expressing low SHB mRNA displayed longer survival times. A subgroup of AML exhibiting a favorable prognosis, acute promyelocytic leukemia (APL) with a PMLRARA translocation, expressed less SHB mRNA than AML tumors in general. When examining genes co-expressed with SHB in AML tumors, four other genes ( PAX5, HDAC7, BCORL1, TET1) related to leukemia were identified. A network consisting of these genes plus SHB was identified that relates to certain phenotypic characteristics, such as immune cell, vascular and apoptotic features. SHB knockdown in the APL PMLRARA cell line NB4 and the monocyte/macrophage cell line MM6 adversely affected proliferation, linking SHB gene expression to tumor cell expansion and consequently to patient survival. It is concluded that tumor SHB gene expression relates to AML survival and its subgroup APL. Moreover, this gene is included in a network of genes that plays a role for an AML phenotype exhibiting certain immune cell, vascular and apoptotic characteristics.

WT - WIND TUNNEL PERFORMANCE ANALYSIS

NASA Technical Reports Server (NTRS)

Viterna, L. A.

1994-01-01

WT was developed to calculate fan rotor power requirements and output thrust for a closed loop wind tunnel. The program uses blade element theory to calculate aerodynamic forces along the blade using airfoil lift and drag characteristics at an appropriate blade aspect ratio. A tip loss model is also used which reduces the lift coefficient to zero for the outer three percent of the blade radius. The application of momentum theory is not used to determine the axial velocity at the rotor plane. Unlike a propeller, the wind tunnel rotor is prevented from producing an increase in velocity in the slipstream. Instead, velocities at the rotor plane are used as input. Other input for WT includes rotational speed, rotor geometry, and airfoil characteristics. Inputs for rotor blade geometry include blade radius, hub radius, number of blades, and pitch angle. Airfoil aerodynamic inputs include angle at zero lift coefficient, positive stall angle, drag coefficient at zero lift coefficient, and drag coefficient at stall. WT is written in APL2 using IBM's APL2 interpreter for IBM PC series and compatible computers running MS-DOS. WT requires a CGA or better color monitor for display. It also requires 640K of RAM and MS-DOS v3.1 or later for execution. Both an MS-DOS executable and the source code are provided on the distribution medium. The standard distribution medium for WT is a 5.25 inch 360K MS-DOS format diskette in PKZIP format. The utility to unarchive the files, PKUNZIP, is also included. WT was developed in 1991. APL2 and IBM PC are registered trademarks of International Business Machines Corporation. MS-DOS is a registered trademark of Microsoft Corporation. PKUNZIP is a registered trademark of PKWare, Inc.

Molecular dynamics simulation studies and in vitro site directed mutagenesis of avian beta-defensin Apl_AvBD2

PubMed Central

2010-01-01

Background Defensins comprise a group of antimicrobial peptides, widely recognized as important elements of the innate immune system in both animals and plants. Cationicity, rather than the secondary structure, is believed to be the major factor defining the antimicrobial activity of defensins. To test this hypothesis and to improve the activity of the newly identified avian β-defensin Apl_AvBD2 by enhancing the cationicity, we performed in silico site directed mutagenesis, keeping the predicted secondary structure intact. Molecular dynamics (MD) simulation studies were done to predict the activity. Mutant proteins were made by in vitro site directed mutagenesis and recombinant protein expression, and tested for antimicrobial activity to confirm the results obtained in MD simulation analysis. Results MD simulation revealed subtle, but critical, structural variations between the wild type Apl_AvBD2 and the more cationic in silico mutants, which were not detected in the initial structural prediction by homology modelling. The C-terminal cationic 'claw' region, important in antimicrobial activity, which was intact in the wild type, showed changes in shape and orientation in all the mutant peptides. Mutant peptides also showed increased solvent accessible surface area and more number of hydrogen bonds with the surrounding water molecules. In functional studies, the Escherichia coli expressed, purified recombinant mutant proteins showed total loss of antimicrobial activity compared to the wild type protein. Conclusion The study revealed that cationicity alone is not the determining factor in the microbicidal activity of antimicrobial peptides. Factors affecting the molecular dynamics such as hydrophobicity, electrostatic interactions and the potential for oligomerization may also play fundamental roles. It points to the usefulness of MD simulation studies in successful engineering of antimicrobial peptides for improved activity and other desirable functions. PMID:20122244

PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3.

PubMed

Jeanne, Marion; Lallemand-Breitenbach, Valérie; Ferhi, Omar; Koken, Marcel; Le Bras, Morgane; Duffort, Stéphanie; Peres, Laurent; Berthier, Caroline; Soilihi, Hassane; Raught, Brian; de Thé, Hugues

2010-07-13

As(2)O(3) cures acute promyelocytic leukemia (APL) by initiating PML/RARA oncoprotein degradation, through sumoylation of its PML moiety. However, how As(2)O(3) initiates PML sumoylation has remained largely unexplained. As(2)O(3) binds vicinal cysteines and increases reactive oxygen species (ROS) production. We demonstrate that upon As(2)O(3) exposure, PML undergoes ROS-initiated intermolecular disulfide formation and binds arsenic directly. Disulfide-linked PML or PML/RARA multimers form nuclear matrix-associated nuclear bodies (NBs), become sumoylated and are degraded. Hematopoietic progenitors transformed by an As(2)O(3)-binding PML/RARA mutant exhibit defective As(2)O(3) response. Conversely, nonarsenical oxidants elicit PML/RARA multimerization, NB-association, degradation, and leukemia response in vivo, but do not affect PLZF/RARA-driven APLs. Thus, PML oxidation regulates NB-biogenesis, while oxidation-enforced PML/RARA multimerization and direct arsenic-binding cooperate to enforce APL's exquisite As(2)O(3) sensitivity. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Collaborative Research and Development (CR&D). Task Order 0036: Physical and Chemical Processes of Operating Electronic Devices

DTIC Science & Technology

2006-09-01

actually seen. A. Hierro , … S. A. Ringel et al., Phys. Stat. Sol (b) 228, 937 (2001). Ohio State U. Use DLTS and DLOS (Deep Level Optical Spectroscopy...to threading dislocations. Also see A. Hierro et al., APL 76, 3064 (2000), where traps at EC-ET=0.58-0.62, 1.35, 2.57-2.64, 3.22eV are seen in GaN

DOD Weapon Systems Software Management Study, Appendix B. Shipborne Systems

DTIC Science & Technology

1975-06-01

program management, from Inception to development maintenance, 2. Detailed documentation requirements, 3. Standard high -level language development (CS-1...the Guided Missile School (GMS) at Dam Neck. The APL Land-Based Test Site (LETS) consisted of a Mk 152 digital fire control computer, SPG-55B radar...instruction and data segments are respectively placed in low and high core addresses to take advantage of UYK-7 memory accessing time savings. UYK-7

Architecture Study on Telemetry Coverage for Immediate Post-Separation Phase

NASA Technical Reports Server (NTRS)

Cheung, Kar-Ming; Lee, Charles H.; Kellogg, Kent H.; Stocklin, Frank J.; Zillig, David J.; Fielhauer, Karl B.

2008-01-01

This paper presents the preliminary results of an architecture study that provides continuous telemetry coverage for NASA missions for immediate post-separation phase. This study is a collaboration effort between Jet Propulsion Laboratory (JPL), Goddard Space Flight Center (GSFC), and Applied Physics Laboratory (APL). After launch when the spacecraft separated from the upper stage, the spacecraft typically executes a number of mission-critical operations prior to the deployment of solar panels and the activation of the primary communication subsystem. JPL, GSFC, and APL have similar design principle statements that require continuous coverage of mission-critical telemetry during the immediate post-separation phase. To conform to these design principles, an architecture that consists of a separate spacecraft transmitter and a robust communication network capable of tracking the spacecraft signals is needed.This paper presents the preliminary results of an architecture study that provides continuous telemetry coverage for NASA missions for immediate post-separation phase. This study is a collaboration effort between Jet Propulsion Laboratory (JPL), Goddard Space Flight Center (GSFC), and Applied Physics Laboratory (APL). After launch when the spacecraft separated from the upper stage, the spacecraft typically executes a number of mission-critical operations prior to the deployment of solar panels and the activation of the primary communication subsystem. JPL, GSFC, and APL have similar design principle statements that require continuous coverage of mission-critical telemetry during the immediate post-separation phase. To conform to these design principles, an architecture that consists of a separate spacecraft transmitter and a robust communication network capable of tracking the spacecraft signals is needed. The main results of this study are as follows: 1) At low altitude (< 10000 km) when most post-separation critical operations are executed, Earth-based network (e.g. Deep Space Network (DSN)) can only provide limited coverage, whereas space-based network (e.g. Space Network (SN)) can provide continuous coverage. 2) Commercial-off-the-shelf SN compatible transmitters are available for small satellite applications. In this paper we present the detailed coverage analysis of Earth-based and Space-based networks. We identify the key functional and performance requirements of the architecture, and describe the proposed selection criteria of the spacecraft transmitter. We conclude the paper with a proposed forward plan.

Early mortality in acute promyelocytic leukemia: Potential predictors

PubMed Central

Chen, Can; Huang, Xilian; Wang, Kaile; Chen, Kuang; Gao, Danquan; Qian, Shenxian

2018-01-01

Acute promyelocytic leukemia (APL) is a rare leukemia characterized by the balanced reciprocal translocation between the promyelocytic leukemia gene on chromosome 15 and the retinoic acid receptor α (RARα) gene on chromosome 17, and accounts for 10–15% of newly diagnosed acute myeloid leukemia each year. The combined use of all-trans retinoic acid and arsenic trioxide (ATO) as primary therapy has markedly improved the survival rate of patients with APL. Mortality in the first 30 days following therapy remains a major contribution to treatment failure. In the present study, published data was reviewed with a focus on the factors associated with early mortality. When treated with ATO as a primary treatment, the fms-like tyrosine kinase-internal tandem deletion has no impact on early mortality. Low lymphoid enhancer binding factor-1 expression may be a reliable marker for early mortality and the target of therapy if it could be proven by further studies. Cluster of differentiation (CD)56+ and CD34+/CD2+ may be candidates to select high-risk patients. The risk of early mortality in APL still cannot be predicted via the cell surface makers, despite multiple studies on their prognostic significance. Typically, a complex translocation did not alter the survival rate in patients with APL; however, if an abnormal karyotype [e.g., Ide(17), ZBTB16/RARα and STAT5B/RARα] appeared singularly or as part of a complex mutation, there is a high possibility of early mortality if clinicians are unable to identify or monitor it. PMID:29541170

Antagonism between granulocytic maturation and deacetylase inhibitor-induced apoptosis in acute promyelocytic leukaemia cells.

PubMed

Hennig, D; Müller, S; Wichmann, C; Drube, S; Pietschmann, K; Pelzl, L; Grez, M; Bug, G; Heinzel, T; Krämer, O H

2015-01-20

Transcriptional repression is a key mechanism driving leukaemogenesis. In acute promyelocytic leukaemia (APL), the fusion protein promyelocytic leukaemia-retinoic acid receptor-α fusion (PML-RARα) recruits transcriptional repressors to myeloid differentiation genes. All-trans-retinoic acid (ATRA) induces the proteasomal degradation of PML-RARα and granulocytic differentiation. Histone deacetylases (HDACs) fall into four classes (I-IV) and contribute to the transcription block caused by PML-RARα. Immunoblot, flow cytometry, and May-Grünwald-Giemsa staining were used to analyze differentiation and induction of apoptosis. A PML-RARα- and ATRA-dependent differentiation programme induces granulocytic maturation associated with an accumulation of the myeloid transcription factor CCAAT/enhancer binding protein (C/EBP)ɛ and of the surface protein CD11b. While this process protects APL cells from inhibitors of class I HDAC activity, inhibition of all Zinc-dependent HDACs (classes I, II, and IV) with the pan-HDACi (histone deacetylase inhibitor(s)) LBH589 induces apoptosis of immature and differentiated APL cells. LBH589 can eliminate C/EBPɛ and the mitochondrial apoptosis regulator B-cell lymphoma (BCL)-xL in immature and differentiated NB4 cells. Thus, BCL-xL and C/EBPɛ are newly identified molecular markers for the efficacy of HDACi against APL cells. Our results could explain the therapeutic limitations occurring with ATRA and class I HDACi combinations. Pro-apoptotic effects caused by pan-HDAC inhibition are not blunted by ATRA-induced differentiation and may provide a clinically interesting alternative.

Antiphospholipid antibodies promote tissue factor-dependent angiogenic switch and tumor progression.

PubMed

Wu, Yuan-Yuan; V Nguyen, Andrew; Wu, Xiao-Xuan; Loh, Mingyu; Vu, Michelle; Zou, Yiyu; Liu, Qiang; Guo, Peng; Wang, Yanhua; Montgomery, Leslie L; Orlofsky, Amos; Rand, Jacob H; Lin, Elaine Y

2014-12-01

Progression to an angiogenic state is a critical event in tumor development, yet few patient characteristics have been identified that can be mechanistically linked to this transition. Antiphospholipid autoantibodies (aPLs) are prevalent in many human cancers and can elicit proangiogenic expression in several cell types, but their role in tumor biology is unknown. Herein, we observed that the elevation of circulating aPLs among breast cancer patients is specifically associated with invasive-stage tumors. By using multiple in vivo models of breast cancer, we demonstrated that aPL-positive IgG from patients with autoimmune disease rapidly accelerates tumor angiogenesis and consequent tumor progression, particularly in slow-growing avascular tumors. The action of aPLs was local to the tumor site and elicited leukocytic infiltration and tumor invasion. Tumor cells treated with aPL-positive IgG expressed multiple proangiogenic genes, including vascular endothelial growth factor, tissue factor (TF), and colony-stimulating factor 1. Knockdown and neutralization studies demonstrated that the effects of aPLs on tumor angiogenesis and growth were dependent on tumor cell-derived TF. Tumor-derived TF was essential for the development of pericyte coverage of tumor microvessels and aPL-induced tumor cell expression of chemokine ligand 2, a mediator of pericyte recruitment. These findings identify antiphospholipid autoantibodies as a potential patient-specific host factor promoting the transition of indolent tumors to an angiogenic malignant state through a TF-mediated pathogenic mechanism. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

The contribution of antiphospholipid antibodies to organ damage in systemic lupus erythematosus.

PubMed

Taraborelli, M; Leuenberger, L; Lazzaroni, M G; Martinazzi, N; Zhang, W; Franceschini, F; Salmon, J; Tincani, A; Erkan, D

2016-10-01

The objective of this study was to assess the contribution of clinically significant antiphospholipid antibodies (aPL) to organ damage in systemic lupus erythematosus (SLE). Patients with disease duration of less than 10 years and at least 5 years of follow-up were identified from two SLE registries. A clinically significant antiphospholipid antibody (aPL) profile was defined as: positive lupus anticoagulant, anticardiolipin IgG/M ≥ 40 G phospholipid units (GPL)/M phospholipid units (MPL), and/or anti-β2-glycoprotein-I IgG/M ≥ 99th percentile on two or more occasions, at least 12 weeks apart. Organ damage was assessed by the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Univariate and multivariate analysis compared SLE patients with and without SDI increase during a 15-year follow-up. Among 262 SLE patients, 33% had a clinically significant aPL profile, which was associated with an increased risk of organ damage accrual during a 5-year follow-up in univariate analysis, and during a 15-year follow-up in the multivariate analysis adjusting for age, gender, race, disease duration at registry entry, and time. In the multivariate analysis, older age at diagnosis and male gender were also associated with SDI increase at each time point. A clinically significant aPL profile is associated with an increased risk of organ damage accrual during a 15-year follow-up in SLE patients. © The Author(s) 2016.

Comparison of acid-detergent lignin, alkaline-peroxide lignin, and acid-detergent insoluble ash as internal markers for predicting fecal output and digestibility by cattle offered bermudagrass hays of varying nutrient composition.

PubMed

Kanani, Juvenal; Philipp, Dirk; Coffey, Kenneth P; Kegley, Elizabeth B; West, Charles P; Gadberry, Shane; Jennings, John; Young, Ashley N; Rhein, Robert T

2014-01-13

The potential for acid-detergent insoluble ash (ADIA), alkaline-peroxide lignin (APL), and acid-detergent lignin (ADL) to predict fecal output (FO) and dry matter digestibility (DMD) by cattle offered bermudagrass [Cynodon dactylon (L.) Pers.] hays of different qualities was evaluated. Eight ruminally cannulated cows (594 ± 35.5 kg) were allocated randomly to 4 hay diets: low (L), medium low (ML), medium high (MH), and high (H) crude protein (CP) concentration (79, 111, 131, and 164 g CP/kg on a DM basis, respectively). Diets were offered in 3 periods with 2 diet replicates per period and were rotated across cows between periods. Cows were individually fed 20 g DM/kg of body weight in equal feedings at 08:00 and 16:00 h for a 10-d adaptation followed by a 5-d total fecal collection. Actual DM intake (DMI), DMD, and FO were determined based on hay offered, ort, and feces excreted. These components were then analyzed for ADL, APL, and ADIA concentration to determine marker recovery and marker-based estimates of FO and DMD. Forage DMI was affected by diet (P = 0.02), and DMI from MH and H was greater (P < 0.05) than from L. Apparent DMD tended (P = 0.08) to differ among diets while FO (P = 0.20) was not affected by diet treatments. Average ADL recovery (1.16) was greater (P < 0.05) than that of ADIA (1.03) and APL (1.06), but ADIA and APL did not differ (P = 0.42). Estimates of FO and DMD derived using APL and ADIA were not different (P ≥ 0.05) from total fecal collection while those using ADL differed (P < 0.05). There was no diet by marker interaction (P ≥ 0.22) for either FO or DMD. Acid-detergent insoluble ash and APL accurately predicted FO and DMD of cattle fed bermudagrass hay of varying nutrient composition. These internal markers may facilitate studies involving large numbers of animals and forages. Results from such studies may be used to develop improved equations to predict energy values of forages based on the relationship of dietary components to digestibility across a wide range of forages.

High-performance, event-driven, low-cost, and SWaP imaging sensor for hostile fire detection, homeland protection, and border security

NASA Astrophysics Data System (ADS)

Rizk, Charbel G.; Lin, Joseph H.; Kennerly, Stephen W.; Pouliquen, Philippe; Goldberg, Arnold C.; Andreou, Andreas G.

2012-06-01

The advanced imagers team at JHU APL and ECE has been advocating and developing a new class of sensor systems that address key system level performance bottlenecks but are sufficiently flexible to allow optimization of associated cost and size, weight, and power (SWaP) for different applications and missions. A primary component of this approach is the innovative system-on-chip architecture: Flexible Readout and Integration Sensors (FRIS). This paper reports on the development and testing of a prototype based on the FRIS concept. It will include the architecture, a summary of test results to date relevant to the hostile fire detection challenge. For this application, this prototype demonstrates the potential for this concept to yield the smallest SWaP and lowest cost imaging solution with a low false alarm rate. In addition, a specific solution based on the visible band is proposed. Similar performance and SWaP gains are expected for other wavebands such as SWIR, MWIR, and LWIR and/or other applications like persistent surveillance for critical infrastructure and border control in addition to unattended sensors.

Initial test of MITA/DIMM with an operational CBP system

NASA Astrophysics Data System (ADS)

Baldwin, Kevin; Hanna, Randall; Brown, Andrea; Brown, David; Moyer, Steven; Hixson, Jonathan G.

2018-05-01

The MITA (Motion Imagery Task Analyzer) project was conceived by CBP OA (Customs and Border Protection - Office of Acquisition) and executed by JHU/APL (Johns Hopkins University/Applied Physics Laboratory) and CERDEC NVESD MSD (Communications and Electronics Research Development Engineering Command Night Vision and Electronic Sensors Directorate Modeling and Simulation Division). The intent was to develop an efficient methodology whereby imaging system performance could be quickly and objectively characterized in a field setting. The initial design, development, and testing spanned a period of approximately 18 months with the initial project coming to a conclusion after testing of the MITA system in June 2017 with a fielded CBP system. The NVESD contribution to MITA was thermally heated target resolution boards deployed to support a range close to the sensor and, when possible, at range with the targets of interest. JHU/APL developed a laser DIMM (Differential Image Motion Monitor) system designed to measure the optical turbulence present along the line of sight of the imaging system during the time of image collection. The imagery collected of the target board was processed to calculate the in situ system resolution. This in situ imaging system resolution and the time-correlated turbulence measured by the DIMM system were used in NV-IPM (Night Vision Integrated Performance Model) to calculate the theoretical imaging system performance. Overall, this proves the MITA concept feasible. However, MITA is still in the initial phases of development and requires further verification and validation to ensure accuracy and reliability of both the instrument and the imaging system performance predictions.

Retinoic acid plus arsenic trioxide, the ultimate panacea for acute promyelocytic leukemia?

PubMed

Lallemand-Breitenbach, Valérie; de Thé, Hugues

2013-09-19

Rarely in the field of cancer treatment did we experience as many surprises as with acute promyelocytic leukemia (APL). Yet, the latest clinical trial reported by Lo-Coco et al in the New England Journal of Medicine is a practice-changing study, as it reports a very favorable outcome of virtually all enrolled low-intermediate risk patients with APL without any DNA-damaging chemotherapy. Although predicted from previous small pilot studies, these elegant and stringently controlled results open a new era in leukemia therapy.

Developing Optimized Trajectories Derived from Mission and Thermo-Structural Constraints

NASA Technical Reports Server (NTRS)

Lear, Matthew H.; McGrath, Brian E.; Anderson, Michael P.; Green, Peter W.

2008-01-01

In conjunction with NASA and the Department of Defense, the Johns Hopkins University Applied Physics Laboratory (JHU/APL) has been investigating analytical techniques to address many of the fundamental issues associated with solar exploration spacecraft and high-speed atmospheric vehicle systems. These issues include: thermo-structural response including the effects of thermal management via the use of surface optical properties for high-temperature composite structures; aerodynamics with the effects of non-equilibrium chemistry and gas radiation; and aero-thermodynamics with the effects of material ablation for a wide range of thermal protection system (TPS) materials. The need exists to integrate these discrete tools into a common framework that enables the investigation of interdisciplinary interactions (including analysis tool, applied load, and environment uncertainties) to provide high fidelity solutions. In addition to developing robust tools for the coupling of aerodynamically induced thermal and mechanical loads, JHU/APL has been studying the optimal design of high-speed vehicles as a function of their trajectory. Under traditional design methodology the optimization of system level mission parameters such as range and time of flight is performed independently of the optimization for thermal and mechanical constraints such as stress and temperature. A truly optimal trajectory should optimize over the entire range of mission and thermo-mechanical constraints. Under this research, a framework for the robust analysis of high-speed spacecraft and atmospheric vehicle systems has been developed. It has been built around a generic, loosely coupled framework such that a variety of readily available analysis tools can be used. The methodology immediately addresses many of the current analysis inadequacies and allows for future extension in order to handle more complex problems.

The Effects of Sand Sediment Volume Heterogeneities on Sound Propagation and Scattering

DTIC Science & Technology

2012-09-30

modulus of a poroelastic medium,” J. Acoust . Soc. Am. 127, 3372–3384 (2010). 3. K. L. Williams, “An effective density fluid model for acoustic ...previously developed at APL- UW for the study of high-frequency acoustics . These models include perturbation models applied to scattering from the...scattering levels that may mask target detection. RELATED PROJECTS 1. “ Acoustic Color of mines and mine-like objects: Finite Element modeling (FEM

Clinical features and treatment outcomes of pediatric acute promyelocytic leukemia in a Mexican pediatric hospital.

PubMed

Dorantes-Acosta, Elisa; Medina-Sanson, Aurora; Jaimes-García, Yanet; López-Martínez, Briceida

2013-01-01

Acute promyelocytic leukemia (APL) is a distinct type of acute myeloid leukemia (AML) characterized by chromosomal translocations involving the retinoid acid receptor α (RARA) gene on chromosome 17. APL is a relatively rare blood disease that is highly curable with current treatment strategies; however, patient outcomes are heterogeneous in countries with limited resources. Promyelocytic leukemia accounts for 20-25% of all AML cases in Latin American countries. We conducted a study from July 2007 to July 2012 and applied the IC-APL2006 protocol. This case study reports the results from eleven patients with AML M3 (five males and six females). In all cases, the diagnoses were made by aspirating bone marrow and evaluating the t(15:17) or t(11:17) transcript. In eight cases, the molecular biology-based diagnostics for the PLM-RARa transcript were positive, and they were negative in two cases. One patient was positive for the PLZF-RARa transcript. The mean WBC at the time of diagnosis was 10.1 x 10(9)/L, and the mean platelet count was 17.1 x 10(9)/L. The mean percentage of abnormal promyelocytes in the bone marrow aspirates was 68%. Of the eleven patients, four presented with disseminated intravascular coagulation. All of the patients began treatment with transretinoic acid (ATRA) (45 mg/m(2)/day), which led to 4 cases of ATRA syndrome. There were 2 relapses, and the patient died in one case. The remaining ten patients were alive after the median follow-up period of 33.6 months (range from 11 to 60 months). The authors report on a series of cases involving pediatric patients with AML M3 seen at a single institution; the patients were stratified and treated with a standard protocol to obtain satisfactory results. Although the number of patients is limited, the health outcomes are relevant. To our knowledge, this is the first series of pediatric APL patients in Mexico who were treated with the IC-APL2006 protocol.

Biomedical Research, Development, and Engineering at the Johns Hopkins University Applied Physics Laboratory Annual Report, October 1, 1975-September 30, 1976

DTIC Science & Technology

1976-09-01

Holographic Stress Testing of the surgicai. cornea, B. F. Hochheimer (APL) and J. .. Calkins (JHMI) §37 Constant Pressure Tonography, L. J. Viernatein...September 1976 HOLOGRAPHIC STRESS TESTING OF SUMMARY AND DISCUSSION THE SURGICAL CORNEA We have successfully demonstrated that holographic interferometry is...recording me- stress testing of corneal wounds in several thodology suitable for performing do sle-pulsed postoperative patients. The only stress used

acn-1, a C. elegans homologue of ACE, genetically interacts with the let-7 microRNA and other heterochronic genes.

PubMed

Metheetrairut, Chanatip; Ahuja, Yuri; Slack, Frank J

2017-10-02

The heterochronic pathway in C. elegans controls the relative timing of cell fate decisions during post-embryonic development. It includes a network of microRNAs (miRNAs), such as let-7, and protein-coding genes, such as the stemness factors, LIN-28 and LIN-41. Here we identified the acn-1 gene, a homologue of mammalian angiotensin-converting enzyme (ACE), as a new suppressor of the stem cell developmental defects of let-7 mutants. Since acn-1 null mutants die during early larval development, we used RNAi to characterize the role of acn-1 in C. elegans seam cell development, and determined its interaction with heterochronic factors, including let-7 and its downstream interactors - lin-41, hbl-1, and apl-1. We demonstrate that although RNAi knockdown of acn-1 is insufficient to cause heterochronic defects on its own, loss of acn-1 suppresses the retarded phenotypes of let-7 mutants and enhances the precocious phenotypes of hbl-1, though not lin-41, mutants. Conversely, the pattern of acn-1 expression, which oscillates during larval development, is disrupted by lin-41 mutants but not by hbl-1 mutants. Finally, we show that acn-1(RNAi) enhances the let-7-suppressing phenotypes caused by loss of apl-1, a homologue of the Alzheimer's disease-causing amyloid precursor protein (APP), while significantly disrupting the expression of apl-1 during the L4 larval stage. In conclusion, acn-1 interacts with heterochronic genes and appears to function downstream of let-7 and its target genes, including lin-41 and apl-1.

Fluxes of 13 selected pharmaceuticals in the water cycle of Stockholm, Sweden.

PubMed

Wahlberg, C; Björlenius, B; Paxéus, N

2011-01-01

Mass flows of 13 pharmaceutical active ingredients (APIS) found in drinking water were studied in the water cycle of Stockholm. Data were collected by analyzing samples of surface water, raw water and drinking water as well as influents, effluents and sludges from waste water treatment plants (WWTPs) in Stockholm area. A mass balance was performed, based on sold amounts of pharmaceuticals and the measured concentrations in water and sludge. The selected APls were all present in WWTP effluents and the removal rates for many of them were poor. Mass balance calculations showed that the three studied WWTPs in Stockholm release considerable amounts of the selected APIs into the Baltic Sea while the portions ending up in WWTP sludge were significantly lower. The levels of APIs found in drinking water are low at present, but may increase in the future unless the releases from WWTPs in the catchment of Lake Mälären are mitigated.

Induction treatments for acute promyelocytic leukemia: a network meta-analysis

PubMed Central

Zhang, Qiaoxia; Lou, Jin; Cai, Yun; Chen, Weihong; Du, Xin

2016-01-01

Background 9 treatments for acute promyelocytic leukemia (APL) have been compared in many randomized controlled trials (RCT). The conclusions have been inconsistent and the purpose of this study is to conduct a network meta-analysis. Results Rankings of event-free survival are ATRA+RIF (81.2%), ATRA+ATO (69.6%), ATO (50.6%). Rankings of complete remission are ATRA+RIF (79.3%), ATRA+ATO (64.8%), RIF (60.3%), ATO (55.9%). Rankings of avoiding differentiation syndromes are CT (84.3%), ATO (80.3%), RIF (71.6%), ATRA+RIF (49%), ATRA+ATO (40.8%). Methods A total of 1,666 patients from 12 RCTs were enrolled. The frequentist method was used. Relative risks with 95% confidence intervals were calculated. We produced a network plot, a contribution plot, and a forest plot predictive intervals. The inconsistency factor, the surface under the cumulative ranking curve and the publication bias were evaluated. Conclusions ATRA+ATO is eligible to be the first-line treatment for APL. ATRA+RIF is a prospective alternative to the first-line treatment. RIF or ATO should be reconsidered as another option for de novo APL. PMID:27713127

[Studies on red orpiment induction of NB4 and HL-60 cell apoptosis].

PubMed

Bai, Y; Huang, S

1998-09-01

To study the possible mechanism of red orpiment, which is main component of composite indigo naturalis tablets, in the treatment of acute promyelocytic leukemia(APL). The effect of red orpiment on induction of APL cell line NB4 and HL-60 apoptosis were studied by cell morphology, DNA gel electrophoresis and flow cytometry assay. Red orpiment induced NB4 and HL-60 cell apoptosis. When treated with different concentration of red orpiment(25-200 micrograms/ml) for 16 hours, both NB4 and HL-60 cells showed typical apoptosis features. If decreased the concentration of red orpiment to 12.5 micrograms/ml, the NB4 cell still showed apoptosis features while the HL-60 cell did not when cultured for 72 hours. Arsenic disulfide(As2S2) had the same effect as red orpiment did under the same experiment condition. It is the main component, As2S2 of the red orpiment that can induces NB4 and HL-60 cell apoptosis. and the red orpiment is responsible for the high CR rate of APL induced by the composite indigo naturalis tablets.

PML nuclear bodies in the pathogenesis of acute promyelocytic leukemia: active players or innocent bystanders?

PubMed

Brown, Nicola J M; Ramalho, Michal; Pedersen, Eva W; Moravcsik, Eva; Solomon, Ellen; Grimwade, David

2009-01-01

The promyelocytic leukemia gene (PML) encodes a protein which localizes to PML-nuclear bodies (NBs), sub-nuclear multi-protein structures, which have been implicated in diverse biological functions such as apoptosis, cell proliferation and senescence. However, the exact biochemical and molecular basis of PML function up until now has not been defined. Strikingly, over a decade ago, PML-NBs were found to be disrupted in acute promyelocytic leukemia (APL) in which PML is fused to the gene encoding retinoic acid receptor alpha (RARA) due to the t(15;17) chromosomal translocation, generating the PML-RARA chimeric protein. The treatment of APL patients with all-transretinoic acid (ATRA) and arsenic trioxide which target the PML-RARA oncoprotein results in clinical remission, associated with blast cell differentiation and reformation of the PML NBs, thus linking NB integrity with disease status. This review focuses on the current theories for molecular and biochemical functions of the PML-NBs, which would imply a role in the pathogenesis of APL, whilst also discussing the intriguing possibility that their disruption may not be in itself a significant oncogenic event.

Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML.

PubMed

Zhang, Xiao-Wei; Yan, Xiao-Jing; Zhou, Zi-Ren; Yang, Fei-Fei; Wu, Zi-Yu; Sun, Hong-Bin; Liang, Wen-Xue; Song, Ai-Xin; Lallemand-Breitenbach, Valérie; Jeanne, Marion; Zhang, Qun-Ye; Yang, Huai-Yu; Huang, Qiu-Hua; Zhou, Guang-Biao; Tong, Jian-Hua; Zhang, Yan; Wu, Ji-Hui; Hu, Hong-Yu; de Thé, Hugues; Chen, Sai-Juan; Chen, Zhu

2010-04-09

Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide (As2O3) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells, PML-RARalpha (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RARalpha degradation is triggered by their SUMOylation, but the mechanism by which As2O3 induces this posttranslational modification is unclear. Here we show that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RARalpha and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation. The identification of PML as a direct target of As2O3 provides new insights into the drug's mechanism of action and its specificity for APL.

'Non-criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010.

PubMed

Bertolaccini, M L; Amengual, O; Atsumi, T; Binder, W L; de Laat, B; Forastiero, R; Kutteh, W H; Lambert, M; Matsubayashi, H; Murthy, V; Petri, M; Rand, J H; Sanmarco, M; Tebo, A E; Pierangeli, S S

2011-02-01

Abstract: Current classification criteria for definite APS recommend the use of one or more of three positive standardized laboratory assays, including anticardiolipin antibodies (aCL), lupus anticoagulant (LA), and antibodies directed to β(2)glycoprotein I (anti-β(2)GPI) to detect antiphospholipid antibodies (aPL) in the presence of at least one of the two major clinical manifestations (i.e., thrombosis or pregnancy morbidity) of the syndrome. Several other autoantibodies shown to be directed to phospholipids and/or their complexes with phospholipids and/or to proteins of the coagulation cascade, as well as a mechanistic test for resistance to annexin A5 anticoagulant activity, have been proposed to be relevant to APS. A task force of worldwide scientists in the field discussed and analyzed critical questions related to 'non-criteria' aPL tests in an evidence-based manner during the 13th International Congress on Antiphospholipid Antibodies (APLA 2010, 13-16 April 2010, Galveston, Texas, USA). This report summarizes the findings, conclusions, and recommendations of this task force.

Minimal Residual Disease in Acute Myeloid Leukemia

PubMed Central

Hourigan, Christopher S.; Karp, Judith E.

2014-01-01

Technological advances in the laboratory have lead to substantial improvements in clinical decision-making by the use of pre-treatment prognostic risk stratification factors in acute myeloid leukemia (AML). Unfortunately similar progress has not been made in treatment response criteria, with the definition of “complete remission” in AML largely unchanged for over half a century. Several recent clinical trials have demonstrated that higher sensitivity measurements of residual disease burden during or after treatment can be performed, that results are predictive for clinical outcome and can be used to improve outcomes by guiding additional therapeutic intervention to patients in clinical complete remission but at increased relapse risk. We review here these recent trials, the characteristics and challenges of the modalities currently used to detect minimal residual disease (MRD), and outline opportunities to both refine detection and better clinically utilize MRD measurements. MRD measurement is already the standard of care in other myeloid malignancies such as chronic myelogenous leukemia (CML) and acute promyelocytic leukemia (APL). It is our belief that response criteria for non-APL AML should be updated to include assessment for molecular complete remission (mCR) and that recommendations for post-consolidation surveillance should include regular monitoring for molecular relapse as a standard of care. PMID:23799371

Baseline design of an OTEC pilot plantship. Volume A. Detailed report. [Performance analysis of OTEC power plant

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

George, J. F.; Richards, D.; Perini, L. L.

1979-05-01

The Applied Physics Laboratory (APL) of the Johns Hopkins University has engineered a baseline design of an Ocean Thermal Energy Conversion (OTEC) pilot plantship. The work was sponsored jointly by the Department of Energy and the US Maritime Administration of the Department of Commerce. The design, drawings, specifications, supporting calculations, and narrative documentation are available through APL for use by the Government and industry for the acquisition of a pilot OTEC system. The baseline design features a platform that is configured to produce up to 20 MW(e) (net) power, using low-cost folded-tube aluminum heat exchangers, while it grazes slowly inmore » tropical waters where the thermal gradient is greatest and the ocean environment is least severe. The design was developed by a team of contractors whose capabilities provided a systems approach to the design process. The work is documented in three volumes. Volume A is the Detailed report, which develops the design rationale, summarizes important calculations, outlines areas for future work, and presents a study of system costs. Volumes B and C, respectively, contain the engineering drawings and specifications.« less

Acute promyelocytic leukaemia: novel insights into the mechanisms of cure.

PubMed

de Thé, Hugues; Chen, Zhu

2010-11-01

The fusion oncogene, promyelocytic leukaemia (PML)-retinoic acid receptor-α (RARA), initiates acute promyelocytic leukaemia (APL) through both a block to differentiation and increased self-renewal of leukaemic progenitor cells. The current standard of care is retinoic acid (RA) and chemotherapy, but arsenic trioxide also cures many patients with APL, and an RA plus arsenic trioxide combination cures most patients. This Review discusses the recent evidence that reveals surprising new insights into how RA and arsenic trioxide cure this leukaemia, by targeting PML-RARα for degradation. Drug-triggered oncoprotein degradation may be a strategy that is applicable to many cancers.

Cumulative and Synergistic Effects of Physical, Biological, and Acoustic Signals on Marine Mammal Habitat Use

DTIC Science & Technology

2013-10-28

apl.washington.edu Award Number: N00014-08-1-0394 Physical Oceanography Component Soundscapes Under Sea Ice: Can we listen for open water? LONG-TERM GOALS...as “ soundscapes ”, and graphically represented by comparing two or more features of the sound field, such as SPL levels at different frequencies or...spectral slopes between selected frequencies (Figure 1). Soundscapes are persistent on the time scale of hours to days, but can change rapidly if

RSM 1.0 - A RESUPPLY SCHEDULER USING INTEGER OPTIMIZATION

NASA Technical Reports Server (NTRS)

Viterna, L. A.

1994-01-01

RSM, Resupply Scheduling Modeler, is a fully menu-driven program that uses integer programming techniques to determine an optimum schedule for replacing components on or before the end of a fixed replacement period. Although written to analyze the electrical power system on the Space Station Freedom, RSM is quite general and can be used to model the resupply of almost any system subject to user-defined resource constraints. RSM is based on a specific form of the general linear programming problem in which all variables in the objective function and all variables in the constraints are integers. While more computationally intensive, integer programming was required for accuracy when modeling systems with small quantities of components. Input values for component life cane be real numbers, RSM converts them to integers by dividing the lifetime by the period duration, then reducing the result to the next lowest integer. For each component, there is a set of constraints that insure that it is replaced before its lifetime expires. RSM includes user-defined constraints such as transportation mass and volume limits, as well as component life, available repair crew time and assembly sequences. A weighting factor allows the program to minimize factors such as cost. The program then performs an iterative analysis, which is displayed during the processing. A message gives the first period in which resources are being exceeded on each iteration. If the scheduling problem is unfeasible, the final message will also indicate the first period in which resources were exceeded. RSM is written in APL2 for IBM PC series computers and compatibles. A stand-alone executable version of RSM is provided; however, this is a "packed" version of RSM which can only utilize the memory within the 640K DOS limit. This executable requires at least 640K of memory and DOS 3.1 or higher. Source code for an APL2/PC workspace version is also provided. This version of RSM can make full use of any installed extended memory but must be run with the APL2 interpreter; and it requires an 80486 based microcomputer or an 80386 based microcomputer with an 80387 math coprocessor, at least 2Mb of extended memory, and DOS 3.3 or higher. The standard distribution medium for this package is one 5.25 inch 360K MS-DOS format diskette. RSM was developed in 1991. APL2 and IBM PC are registered trademarks of International Business Machines Corporation. MS-DOS is a registered trademark of Microsoft Corporation.

ETARA - EVENT TIME AVAILABILITY, RELIABILITY ANALYSIS

NASA Technical Reports Server (NTRS)

Viterna, L. A.

1994-01-01

The ETARA system was written to evaluate the performance of the Space Station Freedom Electrical Power System, but the methodology and software can be modified to simulate any system that can be represented by a block diagram. ETARA is an interactive, menu-driven reliability, availability, and maintainability (RAM) simulation program. Given a Reliability Block Diagram representation of a system, the program simulates the behavior of the system over a specified period of time using Monte Carlo methods to generate block failure and repair times as a function of exponential and/or Weibull distributions. ETARA can calculate availability parameters such as equivalent availability, state availability (percentage of time at a particular output state capability), continuous state duration and number of state occurrences. The program can simulate initial spares allotment and spares replenishment for a resupply cycle. The number of block failures are tabulated both individually and by block type. ETARA also records total downtime, repair time, and time waiting for spares. Maintenance man-hours per year and system reliability, with or without repair, at or above a particular output capability can also be calculated. The key to using ETARA is the development of a reliability or availability block diagram. The block diagram is a logical graphical illustration depicting the block configuration necessary for a function to be successfully accomplished. Each block can represent a component, a subsystem, or a system. The function attributed to each block is considered for modeling purposes to be either available or unavailable; there are no degraded modes of block performance. A block does not have to represent physically connected hardware in the actual system to be connected in the block diagram. The block needs only to have a role in contributing to an available system function. ETARA can model the RAM characteristics of systems represented by multilayered, nesting block diagrams. There are no restrictions on the number of total blocks or on the number of blocks in a series, parallel, or M-of-N parallel subsystem. In addition, the same block can appear in more than one subsystem if such an arrangement is necessary for an accurate model. ETARA 3.3 is written in APL2 for IBM PC series computers or compatibles running MS-DOS and the APL2 interpreter. Hardware requirements for the APL2 system include 640K of RAM, 2Mb of extended memory, and an 80386 or 80486 processor with an 80x87 math co-processor. The standard distribution medium for this package is a set of two 5.25 inch 360K MS-DOS format diskettes. A sample executable is included. The executable contains licensed material from the APL2 for the IBM PC product which is program property of IBM; Copyright IBM Corporation 1988 - All rights reserved. It is distributed with IBM's permission. The contents of the diskettes are compressed using the PKWARE archiving tools. The utility to unarchive the files, PKUNZIP.EXE, is included. ETARA was developed in 1990 and last updated in 1991.

Evaluation of three paediatric weight estimation methods in Singapore.

PubMed

Loo, Pei Ying; Chong, Shu-Ling; Lek, Ngee; Bautista, Dianne; Ng, Kee Chong

2013-04-01

Rapid paediatric weight estimation methods in the emergency setting have not been evaluated for South East Asian children. This study aims to assess the accuracy and precision of three such methods in Singapore children: Broselow-Luten (BL) tape, Advanced Paediatric Life Support (APLS) (estimated weight (kg) = 2 (age + 4)) and Luscombe (estimated weight (kg) = 3 (age) + 7) formulae. We recruited 875 patients aged 1-10 years in a Paediatric Emergency Department in Singapore over a 2-month period. For each patient, true weight and height were determined. True height was cross-referenced to the BL tape markings and used to derive estimated weight (virtual BL tape method), while patient's round-down age (in years) was used to derive estimated weights using APLS and Luscombe formulae, respectively. The percentage difference between the true and estimated weights was calculated. For each method, the bias and extent of agreement were quantified using Bland-Altman method (mean percentage difference (MPD) and 95% limits of agreement (LOA)). The proportion of weight estimates within 10% of true weight (p₁₀) was determined. The BL tape method marginally underestimated weights (MPD +0.6%; 95% LOA -26.8% to +28.1%; p₁₀ 58.9%). The APLS formula underestimated weights (MPD +7.6%; 95% LOA -26.5% to +41.7%; p₁₀ 45.7%). The Luscombe formula overestimated weights (MPD -7.4%; 95% LOA -51.0% to +36.2%; p₁₀ 37.7%). Of the three methods we evaluated, the BL tape method provided the most accurate and precise weight estimation for Singapore children. The APLS and Luscombe formulae underestimated and overestimated the children's weights, respectively, and were considerably less precise. © 2013 The Authors. Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Monitoring anticoagulant therapy with vitamin K antagonists in patients with antiphospholipid syndrome.

PubMed

Isert, Mecki; Miesbach, Wolfgang; Schüttfort, Gundolf; Weil, Yvonne; Tirneci, Vanessa; Kasper, Alexander; Weber, Adele; Lindhoff-Last, Edelgard; Herrmann, Eva; Linnemann, Birgit

2015-08-01

Because of the possible interference of antiphospholipid antibodies (APL) with the phospholipid component of thromboplastin reagents, concerns have been raised about the validity of international normalized ratio (INR) testing to monitor anticoagulant therapy with vitamin K antagonists in patients with antiphospholipid syndrome (APS). To investigate the reliability of the INR, we determined the INR using various prothrombin time (PT) assays and compared the results with those of a chromogenic factor X (CFX) assay. The study cohort consisted of 40 APS patients and 100 APL-negative patients who were on anticoagulant therapy for reasons other than APS. The agreement (i.e. the percentage of patients with a difference ≤0.5 INR units) between the PT-derived INR and CFX-derived INR equivalents was only moderate in both patient groups. The best agreement with CFX-derived INR equivalents was observed for the Thromborel S reagent in APS patients (69.1 %) and for Neoplastin Plus in APL-negative patients (72.0 %). Regarding the results for the point-of-care system CoaguChek XS, an agreement between the INR and the CFX-derived INR equivalent was less frequently observed in the APS patients (55.6 vs. 67.8 %; p = 0.050). When considering all 3058 pairs of INR tests within the international sensitivity index (ISI)-calibrated range of 1.5 to 4.5 s, we did not observe a higher variability of INR values in either the APS patient group or the subgroup of APS patients positive for lupus coagulants compared with the APL-negative controls. In conclusion, monitoring vitamin K antagonists (VKA) therapy with laboratory INR measurements seems to be suitable for the majority of APS patients.

Significance of AZD1152 as a potential treatment against Aurora B overexpression in acute promyelocytic leukemia.

PubMed

Ghanizadeh-Vesali, Samad; Zekri, Ali; Zaker, Farhad; Zaghal, Azam; Yousefi, Meysam; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir; Ghaffari, Seyed H

2016-06-01

Aurora B kinase as a chromosomal passenger protein plays multiple roles in regulating mitosis and cytokinesis. The function of Aurora B in leukemic cells has made it an important treatment target. In this study, we explored the expressions of Aurora (A, B, and C) kinases in newly diagnosed acute promyelocytic leukemia (APL) patients. In addition, we investigated the effects of AZD1152 as a specific inhibitor of Aurora B on cell survival, DNA synthesis, nuclear morphology, apoptosis induction, cell cycle distribution, and gene expression in an APL-derived NB4 cell line. Our results showed that Aurora B was overexpressed in 88 % of APL patients. AZD1152 treatment of NB4 cells led to viability reduction and G2/M arrest followed by an increase in cell size and polyploidy induction. These giant cells showed morphological evidence of mitotic catastrophe. AZD1152 treatment induced activation of G2/M checkpoint which in turn led to transient G2/M arrest in a p21-independent manner. Lack of functional p53 in NB4 cells might provide an opportunity to escape from G2/M block and to endure repeated rounds of replication and polyploidy. Treated cells were probably eliminated via p73-mediated overexpression of BAX, PUMA, and APAF1 and downregulation of survivin and MCL-1. In summary, AZD1152 treatment led to endomitosis and polyploidy in TP53-mutated NB4 cells. These giant polyploid cells might undergo mitotic catastrophe and p73-mediated apoptosis. It seems that induction of polyploidy via AZD1152 could be a novel form of anti-cancer therapy for APL that may be clinically accessible in the near future.

CORKSCREW 2013 CORK study of children's realistic estimation of weight.

PubMed

Skrobo, Darko; Kelleher, Gemma

2015-01-01

In a resuscitation situation involving a child (age 1-15 years) it is crucial to obtain a weight as most interventions and management depend on it. The APLS formula, '2×(age+4)', is taught via the APLS course and is widely used in Irish hospitals. As the prevalence of obesity is increasing the accuracy of the formula has been questioned and a newer formula has been suggested, the Luscombe and Owens (LO) formula, '(3×age)+7'. To gather data on the weights and ages of the Cork paediatric population (ages 1-15 years) attending services at the Cork University Hospital (CUH), and to identify which of the two age-based weight estimation formulae has best diagnostic accuracy. CUH, Ireland's only level one trauma centre. Retrospective data collection from charts in the Emergency Department, Paediatric Assessment Unit and the Paediatric wards of CUH. 3155 children aged 1-15 years were included in the study. There were 1344 girls and 1811 boys. The formula weight='2×(age+4)' underestimated children's weights by a mean of 20.3% (95% CI 19.7% to 20.9%) for the ages of 1-15 years. The LO formula weight='(3×age)+7' showed a mean underestimation of 4.0% (95% CI 3.3% to 4.6%) for the same age range. The LO formula has been validated in several studies and proven to be a superior age-based weight estimation formula in many western emergency departments. This study shows that the LO formula leads to less underestimation of weights in Irish children than the APLS formula. It is a simple, safe and more accurate age-based estimation formula that can be used over a large age range (1-15 years). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

ABO blood group in primary antiphospholipid syndrome: influence in the site of thrombosis?

PubMed

Nascimento, Natália Mastantuono; Bydlowski, Sergio Paulo; Soares, Rosangela Paula Silva; de Andrade, Danieli Castro Oliveira; Bonfá, Eloísa; Seguro, Luciana Parente Costa; Borba, Eduardo Ferreira

2015-10-01

Antiphospholipid syndrome (APS) is characterized by vascular thrombosis and/or obstetric complications associated with presence of antiphospholipid antibodies (aPL) but additional factors would also induce thrombosis. ABO (H) blood groups are known to be closely related to thrombosis, especially non-O blood type with venous events. The aim of this study was to investigate possible role of ABO (H) blood types in the thrombotic events in primary APS (PAPS). Seventy PAPS patients were selected for the study and were divided according to ABO blood group in: O PAPS (n = 26) and non-O PAPS (n = 44). ABO blood group phenotyping was performed by indirect technique. aPL anticardiolipin (aCL) and anti-βeta2 glycoprotein-1 (aβ2GPI) and the concentrations and activities of von Willebrand factor (VWF) were measured with ELISA. Lupus anticoagulant (LA) was detected by coagulation assays. A significant higher frequency of venous events was observed in non-O PAPS group (72.7 vs. 46.2 %, p = 0.040). In contrast, the frequency of arterial events was significantly higher in the O PAPS compared to the non-O PAPS group (69.2 vs. 36.4 %, respectively; p = 0.013). Frequencies of aCL, LA, aβ2GPI and triple aPL positivity were similar in both groups (p > 0.05). VWF antigen (75.54 ± 8.68 vs. 79.51 ± 7.07 IU/dl, p = 0.041) and activity (70.23 ± 11.96 vs. 77.92 ± 13.67 %, p = 0.020) were decreased in O PAPS compared to non-O blood group. VWF:CB/VWF:Ag ratio was similar among groups (p > 0.05). This is the first report that confirms the role of ABO blood system in thrombosis of PAPS and suggests that non-O blood group was related with venous events and O blood group with arterial thrombosis.

KSC-97PC1013

NASA Image and Video Library

1997-07-02

Workers from the Johns Hopkins University’s Applied Physics Laboratory (APL) install the Cosmic Ray Isotope Spectrometer (CRIS) on the Advanced Composition Explorer (ACE) spacecraft in KSC’s Spacecraft Assembly and Encapsulation Facility-2 (SAEF-2). From left, are Al Sadilek, Marcos Gonzalez and Cliff Willey. CRIS is one of nine instruments on ACE, which will investigate the origin and evolution of solar phenomenon, the formation of the solar corona, solar flares and the acceleration of the solar wind. ACE was developed for NASA by the APL. The spacecraft is scheduled to be launched Aug. 21 aboard a two-stage Delta II 7920-8 rocket from Space Launch Complex 17, Pad A

Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer.

PubMed

Wei, Shuo; Kozono, Shingo; Kats, Lev; Nechama, Morris; Li, Wenzong; Guarnerio, Jlenia; Luo, Manli; You, Mi-Hyeon; Yao, Yandan; Kondo, Asami; Hu, Hai; Bozkurt, Gunes; Moerke, Nathan J; Cao, Shugeng; Reschke, Markus; Chen, Chun-Hau; Rego, Eduardo M; Lo-Coco, Francesco; Cantley, Lewis C; Lee, Tae Ho; Wu, Hao; Zhang, Yan; Pandolfi, Pier Paolo; Zhou, Xiao Zhen; Lu, Kun Ping

2015-05-01

A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency for inhibiting Pin1 function in vivo. By using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but whose drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the protein encoded by the fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human patients. ATRA-induced Pin1 ablation also potently inhibits triple-negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors.

Autologous platelet lysates local injections for treatment of tibia non-union with breakage of the nickelclad: a case report.

PubMed

Jiang, Hong-Jiang; Tan, Xun-Xiang; Ju, Hai-Yang; Su, Jin-Ping; Yan, Wei; Song, Xiu-Gang; Qin, Li-Wu; Ju, Chang-Jun; Wang, Ling-Shuang; Zou, De-Bao

2016-01-01

Nonunions of the tibia represent challenging orthopedic problems, which require the surgeon to analyze numerous factors and choose an appropriate treatment. This article presents a case report of tibia and fibula fracture patient who failed the internal fixation surgery and successfully recovered after one course of percutaneous autologous platelet lysates injection. The patient received an internal nickelclad breakage at 9 months post-surgery but reluctant to accept a second surgery, then autologous platelet lysates (APL) injection which is a less invasive method was recommended. The injections were carried once a week for three times. Radiologic evaluation was conducted every month until recovery. To the best of our knowledge, this is the first reported case of tibia delayed union with breakage of the plate resolved with APL injection. Improved clinical evidence was observed at 4 and 6 months after injection. The patient got good bony union at 8 months post-injection. The patient didn't feel any discomfort postinjection, no complications such as infection, refracture etc. were observed. APL percutaneous injection could be a new therapeutic option for the treatment of nonunion or delayed healing fractures.

Glucosidase inhibitory activity and antioxidant activity of flavonoid compound and triterpenoid compound from Agrimonia Pilosa Ledeb.

PubMed

Liu, Xi; Zhu, Liancai; Tan, Jun; Zhou, Xuemei; Xiao, Ling; Yang, Xian; Wang, Bochu

2014-01-10

In Chinese traditional medicine, Agrimonia pilosa Ledeb (APL) exhibits great effect on treatment of type 2 diabetes mellitus (T2DM), however its mechanism is still unknown. Considering that T2DM are correlated with postprandial hyperglycemia and oxidative stress, we investigated the α-glucosidase inhibitory activity and the antioxidant activity of flavonoid compound (FC) and triterpenoid compound (TC) from APL. Entire plants of APL were extracted using 95% ethanol and 50% ethanol successively. The resulting extracts were partitioned and isolated by applying liquid chromatography using silica gel column and Sephadex LH 20 column to give FC and TC. The content of total flavonoids in FC and the content of total triterpenoids in TC were determined by using UV spectrophotometry. HPLC analysis was used to identify and quantify the monomeric compound in FC and TC. The α-glucosidase inhibitory activities were determined using the chromogenic method with p-nitrophenyl-α-D-glucopyranoside as substrate. Antioxidant activities were assessed through three kinds of radical scavenging assays (DPPH radical, ABTS radical and hydroxyl radical) & β-carotene-linoleic acid assay. The results indicate FC is abundant of quercitrin, and hyperoside, and TC is abundant of 1β, 2β, 3β, 19α-tetrahydroxy-12-en-28-oic acid (265.2 mg/g) and corosolic acid (100.9 mg/g). The FC & the TC have strong α-glucosidase inhibitory activities with IC50 of 8.72 μg/mL and 3.67 μg/mL, respectively. We find that FC show competitive inhibition against α-glucosidase, while the TC exhibits noncompetitive inhibition. Furthermore, The FC exhibits significant radical scavenging activity with the EC50 values of 7.73 μg/mL, 3.64 μg/mL and 5.90 μg/mL on DPPH radical, hydroxyl radical and ABTS radical, respectively. The FC also shows moderate anti-lipid peroxidation activity with the IC50 values of 41.77 μg/mL on inhibiting β-carotene bleaching. These results imply that the FC and the TC could be responsible for the good clinical effects of APL on T2MD through targeting oxidative stress and postprandial hyperglycaemia. So APL may be good sources of natural antioxidants and α-glucosidase inhibitors exhibiting remarkable potential value for the therapy of T2DM.

Quality of cardio-pulmonary resuscitation (CPR) during paediatric resuscitation training: time to stop the blind leading the blind.

PubMed

Arshid, Muhammad; Lo, Tsz-Yan Milly; Reynolds, Fiona

2009-05-01

Recent evidence suggested that the quality of cardio-pulmonary resuscitation (CPR) during adult advanced life support training was suboptimal. This study aimed to assess the CPR quality of a paediatric resuscitation training programme, and to determine whether it was sufficiently addressed by the trainee team leaders during training. CPR quality of 20 consecutive resuscitation scenario training sessions was audited prospectively using a pre-designed proforma. A consultant intensivist and a senior nurse who were also Advanced Paediatric Life Support (APLS) instructors assessed the CPR quality which included ventilation frequency, chest compression rate and depth, and any unnecessary interruption in chest compressions. Team leaders' response to CPR quality and elective change of compression rescuer during training were also recorded. Airway patency was not assessed in 13 sessions while ventilation rate was too fast in 18 sessions. Target compression rate was not achieved in only 1 session. The median chest compression rate was 115 beats/min. Chest compressions were too shallow in 10 sessions and were interrupted unnecessarily in 13 sessions. More than 50% of training sessions did not have elective change of the compression rescuer. 19 team leaders failed to address CPR quality during training despite all team leaders being certified APLS providers. The quality of CPR performance was suboptimal during paediatric resuscitation training and team leaders-in-training had little awareness of this inadequacy. Detailed CPR quality assessment and feedback should be integrated into paediatric resuscitation training to ensure optimal performance in real life resuscitations.

Van Allen Probes Mission Space Academy: Educating middle school students about Earth's mysterious radiation belts

NASA Astrophysics Data System (ADS)

Butler, L.; Turney, D.; Matiella Novak, A.; Smith, D.; Simon, M.

2013-12-01

How's the weather in space? Why on Earth did NASA send two satellites above Earth to study radiation belts and space weather? To learn the answer to questions about NASA's Van Allen Probes mission, 450 students and their teachers from Maryland middle schools attended Space Academy events highlighting the Van Allen Probes mission. Sponsored by the Applied Physics Laboratory (APL) and Discovery Education, the events are held at the APL campus in Laurel, MD. Space Academies take students and teachers on behind-the-scenes exploration of how spacecraft are built, what they are designed to study, and introduces them to the many professionals that work together to create some of NASA's most exciting projects. Moderated by a public relations representative in the format of an official NASA press conference, the daylong event includes a student press conference with students as reporters and mission experts as panelists. Lunch with mission team members gives students a chance to ask more questions. After lunch, students don souvenir clean room suits, enjoy interactive science demonstrations, and tour APL facilities where the Van Allen Probes were built and tested before launch. Students may even have an opportunity to peek inside a clean room to view spacecraft being assembled. Prior to the event, teachers are provided with classroom activities, lesson plans, and videos developed by APL and Discovery Education to help prepare students for the featured mission. The activities are aligned to National Science Education Standards and appropriate for use in the classroom. Following their visit, student journalists are encouraged to write a short article about their field trip; selections are posted on the Space Academy web site. Designed to engage, inspire, and influence attitudes about space science and STEM careers, Space Academies provide an opportunity to attract underserved populations and emphasize that space science is for everyone. Exposing students to a diverse group of scientists and engineers may alleviate some common stereotypes about these careers. When students engage with the scientists and engineers at APL, they see first-hand that successful science and engineering requires a diverse team with multi-disciplinary backgrounds. Activities throughout the day develop student understanding about science and technology, and address the fundamental concepts that fall under the National Science Education Content Standards. Students are immersed in a hands-on experience designed to facilitate understanding of the History and Nature of Science. Throughout the day students interact with people of diverse backgrounds and interests while hearing about the specific ways various individuals and teams of people contribute to the science and technology of the mission, addressing the concepts which fall under the headings of Science as a Human Endeavor, Nature of Science, and History of Science. Getting students outside the classroom to visit APL is an exclusive opportunity; evaluations have indicated that students became interested in learning more about space science and STEM careers after attending a Space Academy event.

A Large Hemi-Anechoic Enclosure for Community-Compatible Aeroacoustic Testing of Aircraft Propulsion Systems

NASA Technical Reports Server (NTRS)

Cooper, Beth A.

1993-01-01

A large hemi-anechoic (absorptive walls and acoustically hard floor) noise control enclosure has been erected around a complex of test stands at the NASA Lewis Research Center in Cleveland, Ohio. This new state-of-the-art Aeroacoustic Propulsion Laboratory (APL) provides an all-weather, semisecure test environment while limiting noise to acceptable levels in surrounding residential neighborhoods. The 39.6 m (130 ft) diameter geodesic dome structure houses the new Nozzle Aeroacoustic Test Rig (NATR), an ejector-powered M = 0.3 free jet facility for acoustic testing of supersonic aircraft exhaust nozzles and turbomachinery. A multi-axis, force-measuring Powered Lift Facility (PLF) stand for testing of Short Takeoff Vertical Landing (STOVL) vehicles is also located within the dome. The design of the Aeroacoustic Propulsion Laboratory efficiently accomodates the research functions of two separate test rigs, one of which (NATR) requires a specialized environment for taking acoustic measurements. Absorptive fiberglass wedge treatment on the interior surface of the dome provides a hemi-anechoic interior environment for obtaining the accurate acoustic measurements required to meet research program goals. The APL is the first known geodesic dome structure to incorporate transmission-loss properties as well as interior absorption into a free-standing, community-compatible, hemi-anechoic test facility.

Authentication of digital video evidence

NASA Astrophysics Data System (ADS)

Beser, Nicholas D.; Duerr, Thomas E.; Staisiunas, Gregory P.

2003-11-01

In response to a requirement from the United States Postal Inspection Service, the Technical Support Working Group tasked The Johns Hopkins University Applied Physics Laboratory (JHU/APL) to develop a technique tha will ensure the authenticity, or integrity, of digital video (DV). Verifiable integrity is needed if DV evidence is to withstand a challenge to its admissibility in court on the grounds that it can be easily edited. Specifically, the verification technique must detect additions, deletions, or modifications to DV and satisfy the two-part criteria pertaining to scientific evidence as articulated in Daubert et al. v. Merrell Dow Pharmaceuticals Inc., 43 F3d (9th Circuit, 1995). JHU/APL has developed a prototype digital video authenticator (DVA) that generates digital signatures based on public key cryptography at the frame level of the DV. Signature generation and recording is accomplished at the same time as DV is recorded by the camcorder. Throughput supports the consumer-grade camcorder data rate of 25 Mbps. The DVA software is implemented on a commercial laptop computer, which is connected to a commercial digital camcorder via the IEEE-1394 serial interface. A security token provides agent identification and the interface to the public key infrastructure (PKI) that is needed for management of the public keys central to DV integrity verification.

Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis

PubMed Central

Masuya, Masahiro; Ishii, Satomi; Katayama, Naoyuki

2017-01-01

ABSTRACT PLZF is a transcription factor that confers aberrant self-renewal in leukemogenesis, and the PLZF-RARA fusion gene causes acute promyelocytic leukemia (APL) through differentiation block. However, the molecular mechanisms of aberrant self-renewal underlying PLZF-mediated leukemogenesis are poorly understood. To investigate these mechanisms, comprehensive expression profiling of mouse hematopoietic stem/progenitor cells transduced with Plzf was performed, which revealed the involvement of a key transcriptional coactivator, Eya2, a target molecule shared by Plzf and PLZF-RARA, in the aberrant self-renewal. Indeed, PLZF-RARA as well as Plzf rendered those cells immortalized through upregulation of Eya2. Eya2 also led to immortalization without differentiation block, while depletion of Eya2 suppressed clonogenicity in cells immortalized by PLZF-RARA without influence on differentiation and apoptosis. Interestingly, cancer outlier profile analysis of human samples of acute myeloid leukemia (AML) in The Cancer Genome Atlas (TCGA) revealed a subtype of AML that strongly expressed EYA2. In addition, gene set enrichment analysis of human AML samples, including TCGA data, showed that this subtype of AML was more closely associated with the properties of leukemic stem cells in its gene expression signature than other AMLs. Therefore, EYA2 may be a target for molecular therapy in this subtype of AML, including PLZF-RARA APL. PMID:28416638

Experience with custom processors in space flight applications

NASA Technical Reports Server (NTRS)

Fraeman, M. E.; Hayes, J. R.; Lohr, D. A.; Ballard, B. W.; Williams, R. L.; Henshaw, R. M.

1991-01-01

The Applied Physics Laboratory (APL) has developed a magnetometer instrument for a swedish satellite named Freja with launch scheduled for August 1992 on a Chinese Long March rocket. The magnetometer controller utilized a custom microprocessor designed at APL with the Genesil silicon compiler. The processor evolved from our experience with an older bit-slice design and two prior single chip efforts. The architecture of our microprocessor greatly lowered software development costs because it was optimized to provide an interactive and extensible programming environment hosted by the target hardware. Radiation tolerance of the microprocessor was also tested and was adequate for Freja's mission -- 20 kRad(Si) total dose and very infrequent latch-up and single event upset events.

Non-stroke neurological syndromes associated with antiphospholipid antibodies: evaluation of clinical and experimental studies.

PubMed

Chapman, J; Rand, J H; Brey, R L; Levine, S R; Blatt, I; Khamashta, M A; Shoenfeld, Y

2003-01-01

Although many types of neurological disorders and events have been described in association with antiphospholipid antibodies (aPL) and the antiphospholipid syndrome (APS), only ischaemic stroke is reasonably well established and accepted as a diagnostic criterion for the syndrome. We propose to evaluate, classify and rank the association of other neurological manifestations as possible, probable, or definite according to the data available from clinical studies and animal models. By these criteria, none of the neurological disorders or events such as epilepsy, psychiatric disease, dementia, transverse myelitis, multiple sclerosis-like disease, chorea, migraine, Guillian-Barrè syndrome, and sensory-neural hearing loss, can be definitely associated with aPL or APS.

Rocket-Based Combined Cycle Flowpath Testing for Modes 1 and 4

NASA Technical Reports Server (NTRS)

Rice, Tharen

2002-01-01

Under sponsorship of the NASA Glenn Research Center (NASA GRC), the Johns Hopkins University Applied Physics Laboratory (JHU/APL) designed and built a five-inch diameter, Rocket-Based Combined Cycle (RBCC) engine to investigate mode 1 and mode 4 engine performance as well as Mach 4 inlet performance. This engine was designed so that engine area and length ratios were similar to the NASA GRC GTX engine is shown. Unlike the GTX semi-circular engine design, the APL engine is completely axisymmetric. For this design, a traditional rocket thruster was installed inside of the scramjet flowpath, along the engine centerline. A three part test series was conducted to determine Mode I and Mode 4 engine performance. In part one, testing of the rocket thruster alone was accomplished and its performance determined (average Isp efficiency = 90%). In part two, Mode 1 (air-augmented rocket) testing was conducted at a nominal chamber pressure-to-ambient pressure ratio of 100 with the engine inlet fully open. Results showed that there was neither a thrust increment nor decrement over rocket-only thrust during Mode 1 operation. In part three, Mode 4 testing was conducted with chamber pressure-to-ambient pressure ratios lower than desired (80 instead of 600) with the inlet fully closed. Results for this testing showed a performance decrease of 20% as compared to the rocket-only testing. It is felt that these results are directly related to the low pressure ratio tested and not the engine design. During this program, Mach 4 inlet testing was also conducted. For these tests, a moveable centerbody was tested to determine the maximum contraction ratio for the engine design. The experimental results agreed with CFD results conducted by NASA GRC, showing a maximum geometric contraction ratio of approximately 10.5. This report details the hardware design, test setup, experimental results and data analysis associated with the aforementioned tests.

Flight Test of Weather Data Exchange Using the 1090 Extended Squitter (1090ES) and VDL Mode 3 Data Links

NASA Technical Reports Server (NTRS)

Griner, James H., Jr.

2004-01-01

This report describes preliminary results of work done by JHU/APL under contract to the NASA Glenn Research Center to support flight testing of the Universal Access Transceiver (UAT) data link as a medium for weather data exchange. It presents a high level architectural description of the use of UAT to meet the program objectives with an identification of issues associated with the use of this data link, including a high level definition of the changes required to UAT avionics and ground-based receivers and supporting ground infrastructure to support implementation of the recommended architecture with focus on the issues associated with these changes.

The Effect of Autologous Platelet Lysate Eye Drops: An In Vivo Confocal Microscopy Study

PubMed Central

Fea, Antonio M.; Testa, Valeria; Machetta, Federica; Parisi, Simone; D'Antico, Sergio; Spinetta, Roberta; Fusaro, Enrico; Grignolo, Federico M.

2016-01-01

Purpose. To determine the effectiveness of autologous platelet lysate (APL) eye drops in patients with primary Sjögren syndrome (SS) dry eye, refractory to standard therapy, in comparison with patients treated with artificial tears. We focused on the effect of APL on cornea morphology with the in vivo confocal microscopy (IVCM). Methods. Patients were assigned to two groups: group A used autologous platelet lysate QID, and group B used preservative-free artificial tears QID, for 90 days. Ophthalmological assessments included ocular surface disease index (OSDI), best corrected visual acuity (BCVA), Schirmer test, fluorescein score, and breakup time (BUT). A subgroup of patients in group A underwent IVCM: corneal basal epithelium, subbasal nerves, Langerhans cells, anterior stroma activated keratocytes, and reflectivity were evaluated. Results. 60 eyes of 30 patients were enrolled; in group A (n = 20 patients) mean OSDI, fluorescein score, and BUT showed significant improvement compared with group B (n = 10 patients). The IVCM showed a significant increase in basal epithelium cells density and subbasal nerve plexus density and number and a decrease in Langerhans cells density (p < 0.05). Conclusion. APL was found effective in the treatment of SS dry eye. IVCM seems to be a useful tool to visualize cornea morphologic modifications. PMID:27200376

The Effect of Autologous Platelet Lysate Eye Drops: An In Vivo Confocal Microscopy Study.

PubMed

Fea, Antonio M; Aragno, Vittoria; Testa, Valeria; Machetta, Federica; Parisi, Simone; D'Antico, Sergio; Spinetta, Roberta; Fusaro, Enrico; Grignolo, Federico M

2016-01-01

Purpose. To determine the effectiveness of autologous platelet lysate (APL) eye drops in patients with primary Sjögren syndrome (SS) dry eye, refractory to standard therapy, in comparison with patients treated with artificial tears. We focused on the effect of APL on cornea morphology with the in vivo confocal microscopy (IVCM). Methods. Patients were assigned to two groups: group A used autologous platelet lysate QID, and group B used preservative-free artificial tears QID, for 90 days. Ophthalmological assessments included ocular surface disease index (OSDI), best corrected visual acuity (BCVA), Schirmer test, fluorescein score, and breakup time (BUT). A subgroup of patients in group A underwent IVCM: corneal basal epithelium, subbasal nerves, Langerhans cells, anterior stroma activated keratocytes, and reflectivity were evaluated. Results. 60 eyes of 30 patients were enrolled; in group A (n = 20 patients) mean OSDI, fluorescein score, and BUT showed significant improvement compared with group B (n = 10 patients). The IVCM showed a significant increase in basal epithelium cells density and subbasal nerve plexus density and number and a decrease in Langerhans cells density (p < 0.05). Conclusion. APL was found effective in the treatment of SS dry eye. IVCM seems to be a useful tool to visualize cornea morphologic modifications.

Lupus and pregnancy--15 years of experience in a tertiary center.

PubMed

Ambrósio, Paula; Lermann, Rita; Cordeiro, Alexandra; Borges, Augusta; Nogueira, Isabel; Serrano, Fátima

2010-04-01

This retrospective study was designed to evaluate the outcome of pregnancies in women diagnosed with systemic lupus erythematosus (SLE) followed in a tertiary fetal-maternal center. Data were collected from clinical charts between January 1993 and December 2007, with a total of 136 pregnancies (107 patients). Mean maternal age was 29 years, with the vast majority of patients being Caucasian. Most patients were in remission 6 months prior to pregnancy (93%) and the most frequently affected organs were the skin and joints. Renal lupus accounted for 14% of all cases. Twenty-nine percent of patients were positive for at least one antiphospholid antibody (aPL) and nearly 50% had positive SSa/SSb antibodies. All patients with positive aPL received low-dosage aspirin and low-molecular-weight heparin (LMWH). There were no pregnancy complications in more than 50% of cases and hypertensive disease and intrauterine growth restriction were the most common adverse events. There were 125 live births, one neonatal death, eight miscarriages, and three medical terminations of pregnancy. Preterm delivery occurred in 25% of pregnancies. Our results are probably the conjoined result of a multidisciplinary approach together with a systematic management of SLE pregnancies, with most patients keeping their prior SLE medication combined with low-dosage aspirin and LMWH in the presence of aPL.

Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias?

PubMed

Minucci, S; Nervi, C; Lo Coco, F; Pelicci, P G

2001-05-28

Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias.

Integrating microRNA and mRNA expression profiles of acute promyelocytic leukemia cells to explore the occurrence mechanisms of differentiation syndrome

PubMed Central

Ge, Fei; Cao, Fenglin; Li, Haitao; Wang, Ping; Xu, Mengyuan; Song, Peng; Li, Xiaoxia; Wang, Shuye; Li, Jinmei; Han, Xueying; Zhao, Yanhong; Su, Yanhua; Li, Yinghua; Fan, Shengjin; Li, Limin; Zhou, Jin

2016-01-01

The pathogenesis of therapy-induced differentiation syndrome (DS) in patients with acute promyelocytic leukemia (APL) remains unclear. In this study, mRNA and microRNA (miRNA) expression profiling of peripheral blood APL cells from patients complicated with vs. without DS were integratively analyzed to explore the mechanisms underlying arsenic trioxide treatment-associated DS. By integrating the differentially expressed data with the data of differentially expressed microRNAs and their computationally predicted target genes, as well as the data of transcription factors and differentially expressed target microRNAs obtained from a literature search, a DS-related genetic regulatory network was constructed. Then using an EAGLE algorithm in clusterViz, the network was subdivided into 10 modules. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database the modules were annotated functionally, and three functionally active modules were recognized. The further in-depth analyses on the annotated functions of the three modules and the expression and roles of the related genes revealed that proliferation, differentiation, apoptosis and infiltration capability of APL cells might play important roles in the DS pathogenesis. The results could improve our understanding of DS pathogenesis from a more overall perspective, and could provide new clues for future research. PMID:27634874

Treatment of Thrombotic Antiphospholipid Syndrome: The Rationale of Current Management—An Insight into Future Approaches

PubMed Central

Ubiali, Tania; Meroni, Pier Luigi

2015-01-01

Vascular thrombosis and pregnancy morbidity represent the clinical manifestations of antiphospholipid syndrome (APS), which is serologically characterized by the persistent positivity of antiphospholipid antibodies (aPL). Antiplatelet and anticoagulant agents currently provide the mainstay of APS treatment. However, the debate is still open: controversies involve the intensity and the duration of anticoagulation and the treatment of stroke and refractory cases. Unfortunately, the literature cannot provide definite answers to these controversial issues as it is flawed by many limitations, mainly due to the recruitment of patients not fulfilling laboratory and clinical criteria for APS. The recommended therapeutic management of different aPL-related clinical manifestations is hereby presented, with a critical appraisal of the evidence supporting such approaches. Cutting edge therapeutic strategies are also discussed, presenting the pioneer reports about the efficacy of novel pharmacological agents in APS. Thanks to a better understanding of aPL pathogenic mechanisms, new therapeutic targets will soon be explored. Much work is still to be done to unravel the most controversial issues about APS management: future studies are warranted to define the optimal management according to aPL risk profile and to assess the impact of a strict control of cardiovascular risk factors on disease control. PMID:26075289

Disruption of PLZP in mice leads to increased T-lymphocyte proliferation, cytokine production, and altered hematopoietic stem cell homeostasis.

PubMed

Piazza, Francesco; Costoya, José A; Merghoub, Taha; Hobbs, Robin M; Pandolfi, Pier Paolo

2004-12-01

Deregulated function of members of the POK (POZ and Kruppel) family of transcriptional repressors, such as promyelocytic leukemia zinc finger (PLZF) and B-cell lymphoma 6 (BCL-6), plays a critical role in the pathogenesis of acute promyelocytic leukemia (APL) and non-Hodgkin's lymphoma, respectively. PLZP, also known as TZFP, FAZF, or ROG, is a novel POK protein that displays strong homology with PLZF and has been implicated in the pathogenesis of the cancer-predisposing syndrome, Fanconi's anemia, and of APL, in view of its ability to heterodimerize with the FANC-C and PLZF proteins, respectively. Here we report the generation and characterization of mice in which we have specifically inactivated the PLZP gene through in-frame insertion of a lacZ reporter and without perturbing the expression of the neighboring MLL2 gene. We show that PLZP-deficient mice display defects in cell cycle control and cytokine production in the T-cell compartment. Importantly, PLZP inactivation perturbs the homeostasis of the hematopoietic stem and/or progenitor cell. On the basis of our data, a deregulation of PLZP function in Fanconi's anemia and APL may affect the biology of the hematopoietic stem cell, in turn contributing to the pathogenesis of these disorders.

HIGH-AFFINITY T CELL RECEPTOR DIFFERENTIATES COGNATE PEPTIDE-MHC AND ALTERED PEPTIDE LIGANDS WITH DISTINCT KINETICS AND THERMODYNAMICS

PubMed Central

Persaud, Stephen P.; Donermeyer, David L.; Weber, K. Scott; Kranz, David M.; Allen, Paul M.

2010-01-01

Interactions between the T cell receptor and cognate peptide-MHC are crucial initiating events in the adaptive immune response. These binding events are highly specific yet occur with micromolar affinity. Even weaker interactions between TCR and self-pMHC complexes play critical regulatory roles in T cell development, maintenance and coagonist activity. Due to their low affinity, the kinetics and thermodynamics of such weak interactions are difficult to study. In this work, we used M15, a high-affinity TCR engineered from the 3.L2 TCR system, to study the binding properties, thermodynamics, and specificity of two altered peptide ligands (APLs). Our affinity measurements of the high-affinity TCR support the view that the wild type TCR binds these APLs in the millimolar affinity range, and hence very low affinities can still elicit biological functions. Finally, single methylene differences among the APLs gave rise to strikingly different binding thermodynamics. These minor changes in the pMHC antigen were associated with significant and unpredictable changes in both the entropy and enthalpy of the reaction. As the identical TCR was analyzed with several structurally similar ligands, the distinct thermodynamic binding profiles provide a mechanistic perspective on how exquisite antigen specificity is achieved by the T cell receptor. PMID:20334923

Association between antiphospholipid antibodies and all-cause mortality among end-stage renal disease patients with and without SLE: a retrospective cohort study

PubMed Central

Mowrey, Wenzhu B.; Kim, Mimi; Murakhovskaya, Irina; Billett, Henny; Neugarten, Joel; Costenbader, Karen H.; Putterman, Chaim

2016-01-01

Objective. To investigate the association between the presence of aPL and/or LA and all-cause mortality among end-stage renal disease (ESRD) patients with and without SLE. Methods. We included ESRD patients >18 years old followed at an urban tertiary care centre between 1 January 2006 and 31 January 2014 who had aPL measured at least once after initiating haemodialysis. All SLE patients met ACR/SLICC criteria. APL/LA+ was defined as aCL IgG or IgM >40 IU, anti-β2glycoprotein1 IgG or IgM >40 IU or LA+. Deaths as at 31 January 2014 were captured in the linked National Death Index data. Time to death was defined from the first aPL measurement. Results. We included 34 SLE ESRD and 64 non-SLE ESRD patients; 30 patients died during the study period. SLE ESRD patients were younger [40.4 (12.5) vs 51.9 (18.1) years, P = 0.001] and more were women (88.2% vs 54.7%, P < 0.001) vs non-SLE ESRD patients. The frequency of aPL/LA+ was 24% in SLE and 13% in non-SLE ESRD (P = 0.16). Median (inter-quartile range) follow-up time was 1.6 (0.3–3.5) years in SLE and 1.4 (0.4–3.2) years in non-SLE, P = 0.74. The adjusted hazard ratio (HR) for all-cause mortality for SLE patients who were aPL/LA+ vs aPL/LA− was 9.93 (95% CI 1.33, 74.19); the adjusted HR for non-SLE aPL/LA+ vs aPL/LA− was 0.77 (95% CI 0.14, 4.29). Conclusion. SLE ESRD patients with aPL/LA+ had higher all-cause mortality risk than SLE ESRD patients without these antibodies, while the effects of aPL/LA on mortality were comparable among non-SLE ESRD patients. PMID:26705328

Value of Isolated IgA anti-β2GPI Positivity in the Diagnosis of the Antiphospholipid Syndrome

PubMed Central

Murthy, Vijaya; Willis, Rohan; Romay-Penabad, Zurina; Ruiz-Limón, Patricia; Martínez-Martínez, Laura A.; Jatwani, Shraddha; Jajoria, Praveen; Seif, Alan; Alarcón, Graciela S.; Papalardo, Elizabeth; Liu, Jigna; Vilá, Luis M.; McGwin, Gerald; McNearney, Terry A.; Maganti, Rashmi; Sunkureddi, Prashanth; Parekh, Trisha; Tarantino, Michael; Akhter, Ehtisham; Fang, Hong; Gonzalez, Emilio B.; Binder, Walter R.; Norman, Gary L.; Shums, Zakera; Teodorescu, Marius; Reveille, John D.; Petri, Michelle; Pierangeli, Silvia S.

2014-01-01

Purpose To examine the prevalence of isolated IgA anti-β2Glycoprotein I (anti-β2GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of β2GPI, with clinical manifestations of the Antiphospholipid Syndrome (APS) in three patients groups. The pathogenicity of IgA anti-β2GPI was also evaluated in a mouse model of thrombosis. Methods Patients with systemic lupus erythematosus (SLE) from a multiethnic, multicenter cohort (LUpus in MInorities, NAture versus nurture [LUMINA]) (n=558), patients with SLE from the Hopkins Lupus Cohort (n=215), and serum samples referred to the Antiphospholipid Standardization Laboratory (APLS) (n=5,098) were evaluated. IgA anti-β2GPI titers and binding to domain IV/V of β2GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti- β2GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity. Results A total of 198 patients were found to be positive for IgA anti-β2GPI isotype, and 57 patients were positive exclusively for IgA anti-β2GPI antibodies. Of these, 13 of 23 patients (56.5%) in the LUMINA cohort, 17 of 17 patients (100%) in the Hopkins cohort, and 10 of 17 patients (58.9%) referred to APLS had at least one APS-related clinical manifestation. Fifty-four percent of all the IgA anti-β2GPI positive serum samples reacted with domain IV/V of anti-β2GPI, and 77% of those had clinical features of APS. Isolated IgA anti-β2GPI positivity was associated with an increased risk for arterial thrombosis (p<0.001), venous thrombosis (p=0.015) and all thrombosis (p<0.001). The association between isolated IgA anti-β2GPI and arterial thrombosis (p=0.0003) and all thrombosis (p=0.0003) remained significant after adjusting for other risk factors for thrombosis. In vivo mouse studies demonstrated that IgA anti-β2GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls. Conclusion Isolated IgA anti-β2GPI positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid (aPL) tests are negative and APS is suspected is recommended. IgA anti-β2GPI antibodies directed to domain IV/V of β2GPI represent an important subgroup of clinically relevant antiphospholipids. PMID:23983008

Glucosidase inhibitory activity and antioxidant activity of flavonoid compound and triterpenoid compound from Agrimonia Pilosa Ledeb

PubMed Central

2014-01-01

Background In Chinese traditional medicine, Agrimonia pilosa Ledeb (APL) exhibits great effect on treatment of type 2 diabetes mellitus (T2DM), however its mechanism is still unknown. Considering that T2DM are correlated with postprandial hyperglycemia and oxidative stress, we investigated the α-glucosidase inhibitory activity and the antioxidant activity of flavonoid compound (FC) and triterpenoid compound (TC) from APL. Methods Entire plants of APL were extracted using 95% ethanol and 50% ethanol successively. The resulting extracts were partitioned and isolated by applying liquid chromatography using silica gel column and Sephadex LH 20 column to give FC and TC. The content of total flavonoids in FC and the content of total triterpenoids in TC were determined by using UV spectrophotometry. HPLC analysis was used to identify and quantify the monomeric compound in FC and TC. The α-glucosidase inhibitory activities were determined using the chromogenic method with p-nitrophenyl-α-D-glucopyranoside as substrate. Antioxidant activities were assessed through three kinds of radical scavenging assays (DPPH radical, ABTS radical and hydroxyl radical) & β-carotene-linoleic acid assay. Results The results indicate FC is abundant of quercitrin, and hyperoside, and TC is abundant of 1β, 2β, 3β, 19α-tetrahydroxy-12-en-28-oic acid (265.2 mg/g) and corosolic acid (100.9 mg/g). The FC & the TC have strong α-glucosidase inhibitory activities with IC50 of 8.72 μg/mL and 3.67 μg/mL, respectively. We find that FC show competitive inhibition against α-glucosidase, while the TC exhibits noncompetitive inhibition. Furthermore, The FC exhibits significant radical scavenging activity with the EC50 values of 7.73 μg/mL, 3.64 μg/mL and 5.90 μg/mL on DPPH radical, hydroxyl radical and ABTS radical, respectively. The FC also shows moderate anti-lipid peroxidation activity with the IC50 values of 41.77 μg/mL on inhibiting β-carotene bleaching. Conclusion These results imply that the FC and the TC could be responsible for the good clinical effects of APL on T2MD through targeting oxidative stress and postprandial hyperglycaemia. So APL may be good sources of natural antioxidants and α-glucosidase inhibitors exhibiting remarkable potential value for the therapy of T2DM. PMID:24410924

A Repeated Power Training Enhances Fatigue Resistance While Reducing Intraset Fluctuations.

PubMed

Gonzalo-Skok, Oliver; Tous-Fajardo, Julio; Moras, Gerard; Arjol-Serrano, José Luis; Mendez-Villanueva, Alberto

2018-04-04

Oliver, GS, Julio, TF, Moras, G, José Luis, AS, and Alberto, MV. A repeated power training enhances fatigue resistance while reducing intraset fluctuations. J Strength Cond Res XX(X): 000-000, 2018-The present study analyzed the effects of adding an upper-body repeated power ability (RPA) training to habitual strength training sessions. Twenty young elite male basketball players were randomly allocated into a control group (CON, n = 10) or repeated power group (RPG, n = 10) and evaluated by 1 repetition maximum (1RM), incremental load, and RPA tests in the bench press exercise before and after a 7-week period and a 4-week cessation period. Repeated power group performed 1-3 blocks of 5 sets of 5 repetitions using the load that maximized power output with 30 seconds and 3 minute of passive recovery between sets and blocks, respectively. Between-group analysis showed substantial greater improvements in RPG compared with CON in: best set (APB), last set (APL), mean power over 5 sets (APM), percentage of decrement, fluctuation decrease during APL and RPA index (APLpost/APBpre) during the RPA test (effect size [ES] = 0.64-1.86), and 1RM (ES = 0.48) and average power at 80% of 1RM (ES = 1.11) in the incremental load test. The improvements of APB and APM were almost perfectly correlated. In conclusion, RPA training represents an effective method to mainly improve fatigue resistance together with the novel finding of a better consistency in performance (measured as reduced intraset power fluctuations) at the end of a dynamic repeated effort.

Differentiation therapy revisited.

PubMed

de Thé, Hugues

2018-02-01

The concept of differentiation therapy emerged from the fact that hormones or cytokines may promote differentiation ex vivo, thereby irreversibly changing the phenotype of cancer cells. Its hallmark success has been the treatment of acute promyelocytic leukaemia (APL), a condition that is now highly curable by the combination of retinoic acid (RA) and arsenic. Recently, drugs that trigger differentiation in a variety of primary tumour cells have been identified, suggesting that they are clinically useful. This Opinion article analyses the basis for the clinical successes of RA or arsenic in APL by assessing the respective roles of terminal maturation and loss of self-renewal. By reviewing other successful examples of drug-induced tumour cell differentiation, novel approaches to transform differentiating drugs into more efficient therapies are proposed.

The Stabilising Effect of the Anterior Oblique Ligament to Prevent Directional Subluxation at the Trapeziometacarpal Joint of the Thumb: A Biomechanical Cadaveric Study

PubMed Central

McCann, Mark R.; Rust, Philippa A.; Wallace, Robert

2018-01-01

Background: The trapeziometacarpal joint (TMCJ) is inherently unstable, relying on ligament restraint to prevent subluxation. Subluxation of the thumb in a dorsoradial direction is often observed in clinical practice, either after acute ligament injury or more commonly with osteoarthritis (OA). This subluxation follows loss of function of trapeziometacarpal ligaments that stabilise this joint, resisting the deforming force of abductor pollicis longus (APL). The exact ligaments that stabilise and prevent the thumb from the pull of APL causing dorsoradial subluxation remain unknown, although the anterior oblique ligament (AOL) has been implicated. The aim of this study was to measure the direction of subluxation resisted by the AOL. Methods: In this study we used cadaveric limbs and custom made biomechanical testing to measure the influence AOL has in stabilising the thumb against subluxation in three planes: radial, dorsal and dorsoradial. Three fresh frozen hands were dissected to expose the TMCJ, leaving all ligaments, capsule and APL attachment in place. The force required to create a displacement of 5mm between the first metacarpal and the trapezium in these three planes was measured before and after AOL division. Results: The average force to displace in the dorsoradial plane prior to division was 6.68N, and a statistically significant reduction to 1.15N (P<0.001) was found after division of the AOL. A statistically significant increase in force (P<0.001) from 2.89N to 4.04N was seen in the radial plane, while no change was seen dorsally (P=0.98), with average forces of 2.74N and 2.62N found pre and post division. Conclusion: There is clinical significance in reporting quantifiable data in this field, as subluxation of the thumb is often seen with OA. The results of our study provide support for surgical reconstruction of the AOL as the primary surgical stabilizer against dorsoradial subluxation of the thumb. Level of evidence: III PMID:29600262

Lupus anticoagulants and antiphospholipid antibodies

MedlinePlus

Blood clots - lupus anticoagulants; DVT - anticoagulants ... Most often, lupus anticoagulants and aPL are found in people with diseases such as systemic lupus erythematosus (SLE). Lupus anticoagulants and ...

Dual excitation acoustic paramagnetic logging tool

DOEpatents

Vail, W.B. III.

1989-02-14

New methods and apparatus are disclosed which allow measurement of the presence of oil and water in geological formations using a new physical effect called the Acoustic Paramagnetic Logging Effect (APLE). The presence of petroleum in formation causes a slight increase in the earth's magnetic field in the vicinity of the reservoir. This is the phenomena of paramagnetism. Application of an acoustic source to a geological formation at the Larmor frequency of the nucleons present causes the paramagnetism of the formation to disappear. This results in a decrease in the earth's magnetic field in the vicinity of the oil bearing formation. Repetitively frequency sweeping the acoustic source through the Larmor frequency of the nucleons present (approx. 2 kHz) causes an amplitude modulation of the earth's magnetic field which is a consequence of the APLE. The amplitude modulation of the earth's magnetic field is measured with an induction coil gradiometer and provides a direct measure of the amount of oil and water in the excitation zone of the formation. The phase of the signal is used to infer the longitudinal relaxation times of the fluids present, which results in the ability in general to separate oil and water and to measure the viscosity of the oil present. Such measurements may be performed in open boreholes and in cased well bores. The Dual Excitation Acoustic Paramagnetic Logging Tool employing two acoustic sources is also described. 6 figs.

8-CPT-cAMP/all-trans retinoic acid targets t(11;17) acute promyelocytic leukemia through enhanced cell differentiation and PLZF/RARα degradation

PubMed Central

Jiao, Bo; Ren, Zhi-Hong; Liu, Ping; Chen, Li-Juan; Shi, Jing-Yi; Dong, Ying; Ablain, Julien; Shi, Lin; Gao, Li; Hu, Jun-Pei; Ren, Rui-Bao; de Thé, Hugues; Chen, Zhu; Chen, Sai-Juan

2013-01-01

The refractoriness of acute promyelocytic leukemia (APL) with t(11;17)(q23;q21) to all-trans retinoic acid (ATRA)-based therapy concerns clinicians and intrigues basic researchers. By using a murine leukemic model carrying both promyelocytic leukemia zinc finger/retinoic acid receptor-α (PLZF/RARα) and RARα/PLZF fusion genes, we discovered that 8-chlorophenylthio adenosine-3′, 5′-cyclic monophosphate (8-CPT-cAMP) enhances cellular differentiation and improves gene trans-activation by ATRA in leukemic blasts. Mechanistically, in combination with ATRA, 8-CPT-cAMP activates PKA, causing phosphorylation of PLZF/RARα at Ser765 and resulting in increased dissociation of the silencing mediator for retinoic acid and thyroid hormone receptors/nuclear receptor corepressor from PLZF/RARα. This process results in changes of local chromatin and transcriptional reactivation of the retinoic acid pathway in leukemic cells. Meanwhile, 8-CPT-cAMP also potentiated ATRA-induced degradation of PLZF/RARα through its Ser765 phosphorylation. In vivo treatment of the t(11;17) APL mouse model demonstrated that 8-CPT-cAMP could significantly improve the therapeutic effect of ATRA by targeting a leukemia-initiating cell activity. This combined therapy, which induces enhanced differentiation and oncoprotein degradation, may benefit t(11;17) APL patients. PMID:23382200

Clinical Study on Prospective Efficacy of All-Trans Acid, Realgar-Indigo Naturalis Formula Combined with Chemotherapy as Maintenance Treatment of Acute Promyelocytic Leukemia

PubMed Central

Lu-Qun, Wang; Hao, Li; Xiao-Peng, He; Fang-Lin, Li; Ling-Ling, Wang; Xue-Liang, Chen; Ming, Hou

2014-01-01

Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA), Realgar-Indigo naturalis formula (RIF) and chemotherapy (CT) were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL). Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen), while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX) plus 6-mercaptopurine (6-MP) alternately (ATRA/CTlow regimen). The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity. PMID:24963332

Clinical study on prospective efficacy of all-trans Acid, realgar-indigo naturalis formula combined with chemotherapy as maintenance treatment of acute promyelocytic leukemia.

PubMed

Xiang-Xin, Li; Lu-Qun, Wang; Hao, Li; Xiao-Peng, He; Fang-Lin, Li; Ling-Ling, Wang; Xue-Liang, Chen; Ming, Hou

2014-01-01

Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA), Realgar-Indigo naturalis formula (RIF) and chemotherapy (CT) were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL). Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen), while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX) plus 6-mercaptopurine (6-MP) alternately (ATRA/CTlow regimen). The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity.

The AGPase Family Proteins in Banana: Genome-Wide Identification, Phylogeny, and Expression Analyses Reveal Their Involvement in the Development, Ripening, and Abiotic/Biotic Stress Responses.

PubMed

Miao, Hongxia; Sun, Peiguang; Liu, Qing; Liu, Juhua; Xu, Biyu; Jin, Zhiqiang

2017-07-25

ADP-glucose pyrophosphorylase (AGPase) is the first rate-limiting enzyme in starch biosynthesis and plays crucial roles in multiple biological processes. Despite its importance, AGPase is poorly studied in starchy fruit crop banana ( Musa acuminata L.). In this study, eight MaAGPase genes have been identified genome-wide in M. acuminata , which could be clustered into the large (APL) and small (APS) subunits. Comprehensive transcriptomic analysis revealed temporal and spatial expression variations of MaAPLs and MaAPSs and their differential responses to abiotic/biotic stresses in two banana genotypes, Fen Jiao (FJ) and BaXi Jiao (BX). MaAPS1 showed generally high expression at various developmental and ripening stages and in response to abiotic/biotic stresses in both genotypes. MaAPL-3 and -2a were specifically induced by abiotic stresses including cold, salt, and drought, as well as by fungal infection in FJ, but not in BX. The presence of hormone-related and stress-relevant cis -acting elements in the promoters of MaAGPase genes suggests that MaAGPases may play an important role in multiple biological processes. Taken together, this study provides new insights into the complex transcriptional regulation of AGPases , underlying their key roles in promoting starch biosynthesis and enhancing stress tolerance in banana.

Exclusion of assembled MreB by anionic phospholipids at cell poles confers cell polarity for bidirectional growth.

PubMed

Kawazura, Takuma; Matsumoto, Kanon; Kojima, Koki; Kato, Fumiya; Kanai, Tomomi; Niki, Hironori; Shiomi, Daisuke

2017-05-01

Cell polarity determines the direction of cell growth in bacteria. MreB actin spatially regulates peptidoglycan synthesis to enable cells to elongate bidirectionally. MreB densely localizes in the cylindrical part of the rod cell and not in polar regions in Escherichia coli. When treated with A22, which inhibits MreB polymerization, rod-shaped cells became round and MreB was diffusely distributed throughout the cytoplasmic membrane. A22 removal resulted in restoration of the rod shape. Initially, diffuse MreB started to re-assemble, and MreB-free zones were subsequently observed in the cytoplasmic membrane. These MreB-free zones finally became cell poles, allowing the cells to elongate bidirectionally. When MreB was artificially located at the cell poles, an additional pole was created, indicating that artificial localization of MreB at the cell pole induced local peptidoglycan synthesis. It was found that the anionic phospholipids (aPLs), phosphatidylglycerol and cardiolipin, which were enriched in cell poles preferentially interact with monomeric MreB compared with assembled MreB in vitro. MreB tended to localize to cell poles in cells lacking both aPLs, resulting in production of Y-shaped cells. Their findings indicated that aPLs exclude assembled MreB from cell poles to establish cell polarity, thereby allowing cells to elongate in a particular direction. © 2017 John Wiley & Sons Ltd.

The AGPase Family Proteins in Banana: Genome-Wide Identification, Phylogeny, and Expression Analyses Reveal Their Involvement in the Development, Ripening, and Abiotic/Biotic Stress Responses

PubMed Central

Miao, Hongxia; Sun, Peiguang; Liu, Qing; Liu, Juhua; Xu, Biyu; Jin, Zhiqiang

2017-01-01

ADP-glucose pyrophosphorylase (AGPase) is the first rate-limiting enzyme in starch biosynthesis and plays crucial roles in multiple biological processes. Despite its importance, AGPase is poorly studied in starchy fruit crop banana (Musa acuminata L.). In this study, eight MaAGPase genes have been identified genome-wide in M. acuminata, which could be clustered into the large (APL) and small (APS) subunits. Comprehensive transcriptomic analysis revealed temporal and spatial expression variations of MaAPLs and MaAPSs and their differential responses to abiotic/biotic stresses in two banana genotypes, Fen Jiao (FJ) and BaXi Jiao (BX). MaAPS1 showed generally high expression at various developmental and ripening stages and in response to abiotic/biotic stresses in both genotypes. MaAPL-3 and -2a were specifically induced by abiotic stresses including cold, salt, and drought, as well as by fungal infection in FJ, but not in BX. The presence of hormone-related and stress-relevant cis-acting elements in the promoters of MaAGPase genes suggests that MaAGPases may play an important role in multiple biological processes. Taken together, this study provides new insights into the complex transcriptional regulation of AGPases, underlying their key roles in promoting starch biosynthesis and enhancing stress tolerance in banana. PMID:28757545

Teaching Mathematical Biology in High School Using Adapted Primary Literature

NASA Astrophysics Data System (ADS)

Norris, Stephen P.; Stelnicki, Nathan; de Vries, Gerda

2012-08-01

The study compared the effect of two adaptations of a scientific article on students' comprehension and use of scientific inquiry skills. One adaptation preserved as much as possible the canonical form of the original article (APL, Adapted Primary Literature) and the other was written in a more narrative mode typical of secondary literature (SL). Both adaptations contained the same content. Two hundred and eleven senior high school students in a Western Canadian school district participated. The numbers of males and females were approximately equal, and all students were registered in an introductory calculus course. All students were given a 90 min class by their teachers that introduced them to the basic mathematical concepts needed to read the articles. Students were randomly assigned to read either the APL or the SL and afterwards to complete a questionnaire, which was common to both groups. Major findings showed that the SL students better understood the article, that the APL students thought more critically about the article, that females understood the article better than males, and that students' attitudes towards reading the articles, regardless of group, were positively associated with their comprehension and use of inquiry skills. The results coincide in important ways with those of similar studies in Israel, and show that asking students to read text that resembles scientific writing increases their use of critical thinking skills when reading.

Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries.

PubMed

Wennström, Lovisa; Edslev, Pernille Wendtland; Abrahamsson, Jonas; Nørgaard, Jan Maxwell; Fløisand, Yngvar; Forestier, Erik; Gustafsson, Göran; Heldrup, Jesper; Hovi, Liisa; Jahnukainen, Kirsi; Jonsson, Olafur Gisli; Lausen, Birgitte; Palle, Josefine; Zeller, Bernward; Holmberg, Erik; Juliusson, Gunnar; Stockelberg, Dick; Hasle, Henrik

2016-01-01

Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited. We investigated disease characteristics and outcome for de novo AML patients 10-30 years old treated in pediatric or adult departments. We included 166 patients 10-18 years of age with AML treated according to the pediatric NOPHO-protocols (1993-2009) compared with 253 patients aged 15-30 years treated in hematology departments (1996-2009) in the Nordic countries. The incidence of AML was 4.9/million/year for the age group 10-14 years, 6.5 for 15-18 years, and 6.9 for 19-30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients without APL. Overall survival at 5 years was 60% (52-68%) for pediatric patients compared to 65% (58-70%) for adult patients. Cytogenetics and presenting white blood cell count were the only independent prognostic factors for overall survival. Age was not an independent prognostic factor. No difference was found in outcome for AML patients age 10-30 years treated according to pediatric as compared to adult protocols. © 2015 Wiley Periodicals, Inc.

Tretinoin

MedlinePlus

Tretinoin is used to treat acute promyelocytic leukemia (APL; a type of cancer in which there are ... worsened following treatment with other types of chemotherapy. Tretinoin is used to produce remission (a decrease or ...

75 FR 20849 - Notice of Agreements Filed

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-21

... Cross Space Charter, Sailing and Cooperative Working Agreement. Parties: APL Co. Pte Ltd; American...., Ltd. and United Abaco Shipping Company Limited Slot Charter and Sailing Agreement. Parties: Tropical...

Pacific Fleet Regional Inventory Stocking Model (PRISM)

DTIC Science & Technology

2003-06-01

Fleet Inventory Management Form ..........................................................................99 19. Master Parts List Input Form...100 20. Master Parts List Update Form...107 26. Master Parts List by APL Report..............................................................................109 27. Master

[Systemic lupus erythematosus presenting with a choreo-athetosic syndrome associated with antiphospholipid antibodies].

PubMed

Rafai, M A; El Moutawakil, B; Gam, I; Hakim, K; Fadel, H; Kissani, N; Slassi, I

2005-10-01

Chorea is a rare manifestation of systemic lupus erythematosus (1-4 percent), commonly affecting young woman. Chorea is revealing lupic disease in 50 percent, in the other cases it occurs early in the course of the disease. A 33-year-old woman was hospitalized for choreo-athetosic movements prevailing on the left leg and arm accompanied by behavioral and general state deterioration. The biological assessment consolidated the diagnosis of lupic disease associated antiphospholipides antibody (aPL). Cerebral magnetic resonance imaging (MRI) was normal except for cortical and subcortical atrophy. The patient was treated by corticosteroids (1mg/kg/day) and then was lost to follow-up. We review data in the literature on the pathophysiological mechanisms of lupic chorea focusing particularly on role of aPL.

RXR is an essential component of the oncogenic PML/RARA complex in vivo.

PubMed

Zhu, Jun; Nasr, Rihab; Pérès, Laurent; Riaucoux-Lormière, Florence; Honoré, Nicole; Berthier, Caroline; Kamashev, Dmitrii; Zhou, Jun; Vitoux, Dominique; Lavau, Catherine; de Thé, Hugues

2007-07-01

Although PML-enforced RARA homodimerization allows PML/RARA to bind DNA independently of its coreceptor RXR, the latter was identified within the PML/RARA complex. We demonstrate that a PML/RARA mutant defective for RXR binding fails to trigger APL development in transgenic mice, although it still transforms primary hematopoietic progenitors ex vivo. RXR enhances PML/RARA binding to DNA and is required for rexinoid-induced APL differentiation. In RA-treated PML/RARA-transformed cells, the absence of RXR binding results in monocytic, rather than granulocytic, differentiation. PML/RARA enhances posttranslational modifications of RXRA, including its sumoylation, suggesting that PML-bound sumoylation enzymes target RXRA and possibly other PML/RARA-bound chromatin proteins, further contributing to deregulated transcription. Thus, unexpectedly, RXR contributes to several critical aspects of in vivo transformation.

Autophagy maturation associated with CD38-mediated regulation of lysosome function in mouse glomerular podocytes

PubMed Central

Xiong, Jing; Xia, Min; Xu, Ming; Zhang, Yang; Abais, Justine M; Li, Guangbi; Riebling, Christopher R; Ritter, Joseph K; Boini, Krishna M; Li, Pin-Lan

2013-01-01

Podocytes are highly differentiated glomerular epithelial cells that contribute to the glomerular barrier function of kidney. A role for autophagy has been proposed in maintenance of their cellular integrity, but the mechanisms controlling autophagy in podocytes are not clear. The present study tested whether CD38-mediated regulation of lysosome function contributes to autophagic flux or autophagy maturation in podocytes. Podocytes were found to exhibit a high constitutive level of LC3-II, a robust marker of autophagosomes (APs), suggesting a high basal level of autophagic activity. Treatment with the mTOR inhibitor, rapamycin, increased LC3-II and the content of both APs detected by Cyto-ID Green staining and autophagolysosomes (APLs) measured by acridine orange staining and colocalization of LC3 and Lamp1. Lysosome function inhibitor bafilomycin A1 increased APs, but decreased APLs content under both basal and rapamycin-induced conditions. Inhibition of CD38 activity by nicotinamide or silencing of CD38 gene produced the similar effects to that bafilomycin A1 did in podocytes. To explore the possibility that CD38 may control podocyte autophagy through its regulation of lysosome function, the fusion of APs with lysosomes in living podocytes was observed by co-transfection of GFP-LC3B and RFP-Lamp1 expression vectors. A colocalization of GFP-LC3B and RFP-Lamp1 upon stimulation of rapamycin became obvious in transfected podocytes, which could be substantially blocked by nicotinamide, CD38 shRNA, and bafilomycin. Moreover, blockade of the CD38-mediated regulation by PPADS completely abolished rapamycin-induced fusion of APs with lysosomes. These results indicate that CD38 importantly control lysosomal function and influence autophagy at the maturation step in podocytes. PMID:24238063

Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome.

PubMed

Nuri, Entela; Taraborelli, Mara; Andreoli, Laura; Tonello, Marta; Gerosa, Maria; Calligaro, Antonia; Argolini, Lorenza Maria; Kumar, Rajesh; Pengo, Vittorio; Meroni, Pier Luigi; Ruffatti, Amelia; Tincani, Angela

2017-02-01

Hydroxychloroquine (HCQ) was suggested to play a role in lowering antiphospholipid antibody titers and preventing thrombotic recurrences in patients with systemic lupus erythematosus, but few data are available in patients with primary antiphospholipid syndrome (PAPS). In this retrospective, propensity score-matched cohort study, we evaluated the impact of HCQ on aPL titers and the incidence of thrombotic events in 57 exposed patients compared to 57 not exposed patients. These were matched for sex/type of disease onset/follow-up duration, age at the beginning of the follow-up ±10 years and initial date of the follow-up ±5 years. At baseline, no significant differences in demographical, clinical and serological features were observed between the two groups except for positive anti-extractable nuclear antigen antibodies (21 % in HCQ exposed vs 0 % in HCQ not exposed, P = 0.001). Both the levels of IgG anti-cardiolipin and IgG/IgM anti-β2-glycoprotein I (anti-β2GPI) were significantly reduced at end of follow-up compared to the baseline in HCQ-exposed patients, while there were no differences in the other group. Moreover, anti-β2GPI IgG titers were significantly decreased when the end of follow-up was compared between the two groups (P < 0.002). Among patients with a history of thrombosis, the annual incidence of recurrence was 1.16 % in HCQ exposed and 1.71 % in not exposed patients, with a significant reduction in the incidence of arterial events (0 vs 1.14 %). This study shows a strong reduction in aPL titers together with an apparent decrease in the incidence of arterial thrombosis recurrence in PAPS patients treated with HCQ.

Neuropsychiatric lupus: the prevalence and autoantibody associations depend on the definition: results from the 1000 faces of lupus cohort.

PubMed

Borowoy, Alan M; Pope, Janet E; Silverman, Earl; Fortin, Paul R; Pineau, Christian; Smith, C Douglas; Arbillaga, Hector; Gladman, Dafna; Urowitz, Murray; Zummer, Michel; Hudson, Marie; Tucker, Lori; Peschken, Christine

2012-10-01

The (ever) prevalence of neuropsychiatric systemic lupus erythematosus (NPSLE) can vary widely depending on the definition used. We determined the prevalence of NPSLE in 1000 Faces of Lupus, a large multicenter Canadian cohort. Adults enrolled at 10 sites who satisfied the American College of Rheumatology (ACR) classification for systemic lupus erythematosus (SLE) were included. NPSLE was defined as (i) NPSLE by ACR classification criteria (seizures or psychosis), (ii) ACR, SLEDAI (seizure, psychosis, organic brain syndrome, cranial nerve disorder, headache, and cerebrovascular accident (CVA)), SLAM (CVA, seizure, cortical dysfunction, and headache), and SLICC (cognitive impairment, psychosis, seizures, CVA, cranial or peripheral neuropathy, and transverse myelitis) with and (iii) without minor nonspecific NPSLE manifestations (including mild depression, mild cognitive impairment, and electromyogram-negative neuropathies), and (iv) by ACR and SLEDAI neuropsychiatric (NP) indexes alone. Factors associated with NPSLE were explored using regression models. Cohort size was 1253, with mean disease 12 ± 10 years, mean age 41 ± 16 years, and 86% female. Subgroup size was dependent on the specific definition of NPSLE. Prevalence of NPSLE was 6.4% in group (i), n = 1253 (n = 80); 38.6% in group (ii), n = 681(n = 263); 28.7% in group (iii), n = 586 (n = 168); and 10.2% in group (iv), n = 1125 (n = 115). In univariate analysis, Aboriginals had a nearly 2-fold increase in frequency of NPSLE in all groups. Education level and income were not associated with NPSLE (P = 0.32 and 0.03, respectively). As well, number of ACR criteria, SLAM, age at diagnosis, disease duration, and gender were not associated with NPSLE. Anti-Ro was significantly associated in groups (i) and (iv) and antiphospholipid antibodies (aPL) were increased in groups (i), (ii), and (iii); however, this lost significance when thromboembolic events were excluded from SLICC, SLEDAI, and SLAM indexes. In group (iv), absence of anti-Sm was significant. In multivariate analysis, anti-Ro and aPL (i) and anti-Ro+ and lack of anti-Sm (iv) were significant. NPSLE was not increased in those with +anti-DNA, La, or ribonucleoprotein (RNP), lupus anticoagulant (LAC), or anticardiolipin (aCL) antibody. The prevalence and factors associated with NPSLE varied depending on the definition used, was highest in Aboriginals, and may be higher if +anti-Ro or aPL are present. SLAM and SLICC include mild subjective disease manifestations, which contributed to a 10% higher prevalence of NPSLE compared to a more strict definition. NPSLE may be less in this database than other publications as its overall prevalence may be decreasing, or because of selection bias inherent to those who enter an observational cohort. NPSLE was associated with aPL and often anti-Ro and varied by ethnicity. Copyright © 2012 Elsevier Inc. All rights reserved.

Arsenic Trioxide Injection

MedlinePlus

Arsenic trioxide is used to treat acute promyelocytic leukemia (APL; a type of cancer in which there ... worsened following treatment with other types of chemotherapy. Arsenic trioxide is in a class of medications called ...

Small Radioisotope Power System at NASA Glenn Research Center

NASA Technical Reports Server (NTRS)

Dugala, Gina M.; Fraeman, Martin; Frankford, David P.; Duven, Dennis; Shamkovich, Andrei; Ambrose, Hollis; Meer, David W.

2012-01-01

In April 2009, NASA Glenn Research Center (GRC) formed an integrated product team (IPT) to develop a Small Radioisotope Power System (SRPS) utilizing a single Advanced Stirling Convertor (ASC) with passive balancer for possible use by the International Lunar Network (ILN) program. The ILN program is studying the feasibility of implementing a multiple node seismometer network to investigate the internal lunar structure. A single ASC produces approximately 80 W(sub e) and could potentially supply sufficient power for that application. The IPT consists of Sunpower, Inc., to provide the single ASC with balancer, The Johns Hopkins University Applied Physics Laboratory (JHU/APL) to design an engineering model Single Convertor Controller (SCC) for an ASC with balancer, and NASA GRC to provide technical support to these tasks and to develop a simulated lunar lander test stand. A controller maintains stable operation of an ASC. It regulates the alternating current produced by the linear alternator of the convertor, provides a specified output voltage, and maintains operation at a steady piston amplitude and hot end temperature. JHU/APL also designed an ASC dynamic engine/alternator simulator to aid in the testing and troubleshooting of the SCC. This paper describes the requirements, design, and development of the SCC, including some of the key challenges and the solutions chosen to overcome those issues. In addition, it describes the plans to analyze the effectiveness of a passive balancer to minimize vibration from the ASC, characterize the effect of ASC vibration on a lunar lander, characterize the performance of the SCC, and integrate the single ASC, SCC, and lunar lander test stand to characterize performance of the overall system.

All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia

PubMed Central

Shen, Zhi-Xiang; Shi, Zhan-Zhong; Fang, Jing; Gu, Bai-Wei; Li, Jun-Min; Zhu, Yong-Mei; Shi, Jing-Yi; Zheng, Pei-Zheng; Yan, Hua; Liu, Yuan-Fang; Chen, Yu; Shen, Yang; Wu, Wen; Tang, Wei; Waxman, Samuel; de Thé, Hugues; Wang, Zhen-Yi; Chen, Sai-Juan; Chen, Zhu

2004-01-01

Both all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) have proven to be very effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL), but they had not been used jointly in an integrated treatment protocol for remission induction or maintenance among newly diagnosed APL patients. In this study, 61 newly diagnosed APL subjects were randomized into three treatment groups, namely by ATRA, As2O3, and the combination of the two drugs. CR was determined by hematological analysis, tumor burden was examined with real-time quantitative RT-PCR of the PML-RARα (promyelocytic leukemia-retinoic acid receptor α) fusion transcripts, and side effects were evaluated by means of clinical examinations. Mechanisms possibly involved were also investigated with cellular and molecular biology methods. Although CR rates in three groups were all high (≥90%), the time to achieve CR differed significantly, with that of the combination group being the shortest one. Earlier recovery of platelet count was also found in this group. The disease burden as reflected by fold change of PML-RARα transcripts at CR decreased more significantly in combined therapy as compared with ATRA or As2O3 mono-therapy (P < 0.01). This difference persisted after consolidation (P < 0.05). Importantly, all 20 cases in the combination group remained in CR whereas 7 of 37 cases treated with mono-therapy relapsed (P < 0.05) after a follow-up of 8–30 months (median: 18 months). Synergism of ATRA and As2O3 on apoptosis and degradation of PML-RARα oncoprotein might provide a plausible explanation for superior efficacy of combinative therapy in clinic. In conclusion, the ATRA/As2O3 combination for remission/maintenance therapy of APL brings much better results than either of the two drugs used alone in terms of the quality of CR and the status of the disease-free survival. PMID:15044693

Insulin Delivery System

NASA Technical Reports Server (NTRS)

1988-01-01

When Programmable Implantable Medication System (PIMS) is implanted in human body, it delivers precise programmed amounts of insulin over long periods of time. Mini-Med Technologies has been refining the Technologies since initial development at APL. The size of a hockey puck, and encased in titanium shell, PIMS holds about 2 1/2 teaspoons of insulin at a programmed basal rate. If a change in measured blood sugar level dictates a different dose, the patient can vary the amount of insulin delivered by holding a small radio transceiver over the implanted system and dialing in a specific program held in the PIMS computer memory. Insulin refills are accomplished approximately 4 times a year by hypodermic needle.

What Is Antiphospholipid Antibody Syndrome?

MedlinePlus

... or rheumatic (ru-MAT-ik) disorders, such as lupus . ("Rheumatic" refers to disorders that affect the joints, ... aCL syndrome Antiphospholipid syndrome aPL syndrome Hughes syndrome Lupus anticoagulant syndrome Causes Antiphospholipid antibody syndrome (APS) occurs ...

Space plasma physics at the Applied Physics Laboratory over the past half-century

NASA Technical Reports Server (NTRS)

Potemra, Thomas A.

1992-01-01

An overview is given of space-plasma experiments conducted at the Applied Physics Laboratory (APL) at Johns Hopkins University including observational campaigns and the instrumentation developed. Specific space-plasma experiments discussed include the study of the radiation environment in the Van Allen radiation belt with solid-state proton detectors. Also described are the 5E-1 satellites which acquired particle and magnetic-field data from earth orbit. The Triad satellite and its magnetometer system were developed for high-resolution studies of the earth's magnetic field, and APL contributions to NASA's Interplanetary Monitoring Platforms are listed. The review mentions the International Ultraviolet Explorer, the Atmosphere Explorer mission, and the Active Magnetic Particle Tracer Explorers mission. Other recent programs reviewed include a high-latitude satellite, contributions to the Voyager mission, and radar studies of space plasmas.

Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells

PubMed Central

Liu, Ting; Men, Qiuxu; Wu, Guixian; Yu, Chunrong; Huang, Zan; Liu, Xin; Li, Wenhua

2015-01-01

All-trans retinoic acid (ATRA) is a differentiating agent for the treatment of acute promyelocytic leukemia (APL). However, the therapeutic efficacy of ATRA has limitations. Tetrandrine is a traditional Chinese medicinal herb extract with antitumor effects. In this study, we investigated the effects of tetrandrine on human PML-RARα-positive acute promyelocytic leukemia cells. Tetrandrine inhibited tumors in vivo. It induced autophagy and differentiation by triggering ROS generation and activating Notch1 signaling. Tetrandrine induced autophagy and differentiation in M5 type patient primary leukemia cells. The in vivo results indicated that low concentrations of tetrandrine inhibited leukemia cells proliferation and induced autophagy and then facilitated their differentiation, by activating ROS and Notch1 signaling. We suggest that tetrandrine is a potential agent for the treatment of APL by inducing differentiation of leukemia cells. PMID:25797266

Time maintenance system for the BMDO MSX spacecraft

NASA Technical Reports Server (NTRS)

Hermes, Martin J.

1994-01-01

The Johns Hopkins University Applied Physics Laboratory (APL) is responsible for designing and implementing a clock maintenance system for the Ballistic Missile Defense Organizations (BMDO) Midcourse Space Experiment (MSX) spacecraft. The MSX spacecraft has an on-board clock that will be used to control execution of time-dependent commands and to time tag all science and housekeeping data received from the spacecraft. MSX mission objectives have dictated that this spacecraft time, UTC(MSX), maintain a required accuracy with respect to UTC(USNO) of +/- 10 ms with a +/- 1 ms desired accuracy. APL's atomic time standards and the downlinked spacecraft time were used to develop a time maintenance system that will estimate the current MSX clock time offset during an APL pass and make estimates of the clock's drift and aging using the offset estimates from many passes. Using this information, the clock's accuracy will be maintained by uplinking periodic clock correction commands. The resulting time maintenance system is a combination of offset measurement, command/telemetry, and mission planning hardware and computing assets. All assets provide necessary inputs for deciding when corrections to the MSX spacecraft clock must be made to maintain its required accuracy without inhibiting other mission objectives. The MSX time maintenance system is described as a whole and the clock offset measurement subsystem, a unique combination of precision time maintenance and measurement hardware controlled by a Macintosh computer, is detailed. Simulations show that the system estimates the MSX clock offset to less than+/- 33 microseconds.

Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen.

PubMed

Thirugnanam, Rajasekar; George, Biju; Chendamarai, Ezhil; Lakshmi, Kavitha M; Balasubramanian, Poonkuzhali; Viswabandya, Auro; Srivastava, Alok; Chandy, Mammen; Mathews, Vikram

2009-11-01

In patients with relapsed acute promyelocytic leukemia (APL), the best consolidation regimen following induction of remission with arsenic trioxide (ATO) remains to be defined. Since January 2000, 37 patients with relapsed APL were treated at our center. The median age was 34 years (range, 6-57 years), and there were 20 males (54.1%). The median duration of first remission was 20.3 months (range, 2.9-81.2 months). Relapse was treated with single-agent ATO in 22 patients (59.5%), ATO+ATRA in 5 patients (13.5%), and ATO+ATRA + anthracycline in 10 patients (27%). Thirty-three patients (89%) achieved molecular remission after induction and a consolidation course. Fourteen patients opted to undergo autologous stem cell transplantation (SCT), and the remaining 19 patients received monthly cycles of ATO as a single agent (n=13) or ATO+ATRA (n=6) for 6 months. At a median follow-up of 32 months, the 5-year Kaplan-Meier estimate of event-free survival (EFS) was 83.33% +/- 15.21% in those who underwent autologous SCT versus 34.45% +/- 11.24% in those who did not (P=.001; log-rank test). Following remission induction with ATO-based regimens in patients with relapsed APL, consolidation with autologous SCT is associated with a significantly superior clinical outcome compared with ATO- and ATO+ATRA-based maintenance regimens.

Long term curative effects of sequential therapy with all-trans retinoic acid, arsenious oxide and chemotherapy on patients with acute promyelocytic leukemia.

PubMed

Pei, Renzhi; Cao, Junjie; Ma, Junxia; Zhang, Pisheng; Liu, Xuhui; Du, Xiaohong; Chen, Dong; Sha, Keya; Chen, Lieguang; Li, Shuangyue; Wu, Jingyi; Fan, Zhen; Lin, Li; Ye, Peipei; Tang, Shanhao; Zhang, Bibo

2012-11-01

Both all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) have proven to be very effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL). In this study, 73 newly diagnosed APL subjects were treated with an ATRA and As(2)O(3) combination treatment in remission induction and post remission therapy. Tumor burden was examined with PCR of the PML-RAR fusion transcripts, and side effects were evaluated by means of clinical examination. The results showed that ATRA/As(2)O(3) combination therapy yielded a CR rate of 94.5% (69/73) with a shorter time to enter CR (median: 27 days; range: 21-43 days). Four cases failed to enter CR; three of these died of cerebral hemorrhage and disseminated intravascular coagulation (DIC) within 72 hours of starting induction therapy, one older patient died of severe pulmonary infection. The early death rate was 5.5% (4/73). All 69 cases that obtained CR remained in good clinical remission after a follow-up of 35-74 months (median: 52 months).The drug toxicity profile with the use of As(2)O(3) showed mainly hepatotoxicity. Liver dysfunction was slight in most cases. There were no severe side effects in long term follow-up. We conclude that APL patients may benefit from the use of the combination of ATRA and As(2)O(3) in either remission induction or consolidation/maintenance.

Constitutive expression of the promyelocytic leukemia-associated oncogene PML-RARalpha in TF1 cells: isoform-specific and retinoic acid-dependent effects on growth, bcl-2 expression, and apoptosis.

PubMed

Slack, J L; Yu, M

1998-05-01

Two major isoforms of PML-RARalpha are associated with (15;17)-positive acute promyelocytic leukemia (APL); however, functional differences between these isoforms have been difficult to define, and the molecular mechanism by which each isoform contributes to the pathogenesis of APL is not fully understood. To address these issues, the 'short' (S) and 'long' (L) isoforms of PML-RARalpha were constitutively expressed in the factor-dependent human erythroleukemia cell line, TF1. Expression of the L, but not the S, isoform inhibited growth of these cells in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). In the absence of GM-CSF, the S isoform partially protected against apoptosis, while the L isoform accelerated cell death. Treatment with all-trans retinoic acid (ATRA) inhibited cell growth and caused apoptosis only in PML-RARalpha-expressing cells, and these effects of ATRA were more marked in cells expressing the L isoform. ATRA treatment also led to downregulation of bcl-2 and endogenous RARalpha in PML-RARalpha-expressing cells, but had little effect on the level of exogenously expressed PML-RARalpha. We conclude that (1) subtle differences exist in the biologic activities of the L and S isoforms of PML-RARalpha, and (2) both isoforms are capable of transducing an ATRA-mediated signal that leads to downregulation of bcl-2 and induction of programmed cell death.

Nuclear space power safety and facility guidelines study

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

Mehlman, W.F.

1995-09-11

This report addresses safety guidelines for space nuclear reactor power missions and was prepared by The Johns Hopkins University Applied Physics Laboratory (JHU/APL) under a Department of Energy grant, DE-FG01-94NE32180 dated 27 September 1994. This grant was based on a proposal submitted by the JHU/APL in response to an {open_quotes}Invitation for Proposals Designed to Support Federal Agencies and Commercial Interests in Meeting Special Power and Propulsion Needs for Future Space Missions{close_quotes}. The United States has not launched a nuclear reactor since SNAP 10A in April 1965 although many Radioisotope Thermoelectric Generators (RTGs) have been launched. An RTG powered system ismore » planned for launch as part of the Cassini mission to Saturn in 1997. Recently the Ballistic Missile Defense Office (BMDO) sponsored the Nuclear Electric Propulsion Space Test Program (NEPSTP) which was to demonstrate and evaluate the Russian-built TOPAZ II nuclear reactor as a power source in space. As of late 1993 the flight portion of this program was canceled but work to investigate the attributes of the reactor were continued but at a reduced level. While the future of space nuclear power systems is uncertain there are potential space missions which would require space nuclear power systems. The differences between space nuclear power systems and RTG devices are sufficient that safety and facility requirements warrant a review in the context of the unique features of a space nuclear reactor power system.« less

User’s Manual for Computer Programs to Perform Oceanographic Vector Time Series Data Analysis and Related Graphics.

DTIC Science & Technology

1980-01-01

IIINDOk.I. IF THE VALUE OF Ni,.INDO IS GREATER THAN 1’.THEN SPECTRAL iINiOl. :SA::LING :THOLILI BE PERFORMED LIIG ’PECTRAL IIIN- DiOW.I NI. I MirO - 1i𔃻...8217321iis C:OMMON UVYi312!i3PPI3MM’G11’’ 322 C INITIA+LIZE VARIARBLES. NUMB=LE NG-20.~NN RAVRG=FLOPT (NAlVRG’l NUMBM1=NUMB-1 SUM 1=0. SUM20. SIJM3=I...1) =sumaRAVG * G11l ) SUM3/PAVRG ’ 322 (I)-SU1M4/RAVRG G12 (I) =SUM5’/RPVRG C DETERMINE SUMS FOR NEXT ESTIMATES. * SUM I -SUM I -Apl +GPP QI .tiMR𔃽

AURORA: The Next Generation Space Weather Sensor for NPOESS

NASA Astrophysics Data System (ADS)

Paxton, L.; Morrison, D.; Santo, A.; Ogorzalek, B.; Goldsten, J.; Boldt, J.; Kil, H.; Zhang, Y.; Demajistre, R.; Wolven, B.; Meng, C.

2005-12-01

The AURORA sensor slated for flight on the NPOESS satellites represents the culmination of over 20 years of experience at JHU/APL in the design, manufacture, flight, operation and analysis of compact, cost-effective far ultraviolet sensors for space weather data collection. The far ultraviolet covers the spectral range from about 115 to 185 nm. This region is ideal for observations of the upper atmosphere because, at these wavelengths, the lower atmosphere and Earth's surface are black. AURORA will observe the mid- and low-latitude F-region ionosphere, the auroral E-region ionosphere, the day thermosphere composition, auroral energy deposition and map ionospheric irregularities. AURORA implements the flight-proven design derived from SSUSI on the DMSP Block 5D spacecraft and GUVI on the NASA TIMED spacecraft. These instruments have provided the instrument and algorithm heritage for NPOESS/AURORA. In this talk the performance capabilities of the AURORA instrument will be summarized along with the design of the instrument and algorithms. Example products will be shown for each of the measurement regimes. We acknowldge support from DMSP and NASA and the collaboration with our science colleagues at the Aerospace Corporation (Paul Straus, Jim Hecht, Dave McKenzie, and Andy Christensen) and Computational Physics (Doug Strickland, Hal Knight, and Scott Evans) and Naval Research Laboratory (Robert Meier, Mike Picone, Stefan Thonnard, Pat Dandenault, and Andy Stefan) and our colleagues at APL (Michele Weiss, Doug Holland, Bill Wood, and Jim Eichert) among others.

Properties of the single Jovian planet population and the pursuit of Solar system analogues

NASA Astrophysics Data System (ADS)

Agnew, Matthew T.; Maddison, Sarah T.; Horner, Jonathan

2018-07-01

While the number of exoplanets discovered continues to increase at a rapid rate, we are still to discover any system that truly resembles the Solar system. Existing and near future surveys will likely continue this trend of rapid discovery. To see if these systems are Solar system analogues, we will need to efficiently allocate resources to carry out intensive follow-up observations. We seek to uncover the properties and trends across systems that indicate how much of the habitable zone is stable in each system to provide focus for planet hunters. We study the dynamics of all known single Jovian planetary systems to assess the dynamical stability of the habitable zone around their host stars. We perform a suite of simulations of all systems where the Jovian planet will interact gravitationally with the habitable zone, and broadly classify these systems. Besides the system's mass ratio (Mpl/Mstar), the Jovian planet's semimajor axis (apl), and eccentricity (epl), we find that there are no underlying system properties which are observable that indicate the potential for planets to survive within the system's habitable zone. We use Mpl/Mstar, apl, and epl to generate a parameter space over which the unstable systems cluster, thus allowing us to predict which systems to exclude from future observational or numerical searches for habitable exoplanets. We also provide a candidate list of 20 systems that have completely stable habitable zones and Jovian planets orbiting beyond the habitable zone as potential first-order Solar system analogues.

Properties of the single Jovian planet population and the pursuit of Solar system analogues

NASA Astrophysics Data System (ADS)

Agnew, Matthew T.; Maddison, Sarah T.; Horner, Jonathan

2018-04-01

While the number of exoplanets discovered continues to increase at a rapid rate, we are still to discover any system that truly resembles the Solar system. Existing and near future surveys will likely continue this trend of rapid discovery. To see if these systems are Solar system analogues, we will need to efficiently allocate resources to carry out intensive follow-up observations. We seek to uncover the properties and trends across systems that indicate how much of the habitable zone is stable in each system to provide focus for planet hunters. We study the dynamics of all known single Jovian planetary systems, to assess the dynamical stability of the habitable zone around their host stars. We perform a suite of simulations of all systems where the Jovian planet will interact gravitationally with the habitable zone, and broadly classify these systems. Besides the system's mass ratio (Mpl/Mstar), and the Jovian planet's semi-major axis (apl) and eccentricity (epl), we find that there are no underlying system properties which are observable that indicate the potential for planets to survive within the system's habitable zone. We use Mpl/Mstar, apl and epl to generate a parameter space over which the unstable systems cluster, thus allowing us to predict which systems to exclude from future observational or numerical searches for habitable exoplanets. We also provide a candidate list of 20 systems that have completely stable habitable zones and Jovian planets orbiting beyond the habitable zone as potential first order Solar system analogues.

78 FR 49596 - Order 1050.1F Environmental Impact: Policies and Procedures

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-14

...: Policies and Procedures is available at http://www.faa.gov/about/office_org/headquarters_ offices/apl... categorical exclusion justification package is available at http://www.faa.gov/about/office_org/headquarters...

Predictors of pregnancy outcome in antiphospholipid syndrome: a review.

PubMed

De Carolis, Sara; Botta, Angela; Santucci, Stefania; Garofalo, Serafina; Martino, Carmelinda; Perrelli, Alessandra; Salvi, Silvia; Ferrazzani, Sergio; Caforio, Leonardo; Scambia, Giovanni

2010-04-01

In pregnant women, antiphospholipid syndrome (APS) is associated with an increased risk of preeclampsia, fetal intrauterine growth restriction, and other complications related to uteroplacental insufficiency. In the last two decades, several studies were performed to identify the predictive role of some parameters in relation to obstetric outcome in APS patients. Among these, the uterine velocimetry Doppler is the most studied. It provides a non-invasive method for the study of uteroplacental blood flow, being able to detect a condition of impaired placental perfusion, due to the presence of circulating antiphospholipid antibodies (aPL). To date, the uterine artery Doppler velocimetry resulted to be a useful tool to identify APS pregnancies at higher risk of adverse pregnancy outcome. False-positive IgM for toxoplasmosis, others, rubella, cytomegalovirus, herpes viruses (TORCH) complex is associated to a worse pregnancy outcome because it reflects a dysregulation of the immune system which may amplify placental autoimmune damage. Moreover low levels of complement components are related to an increased incidence of obstetrical complications, suggesting that placental deposition of immune complexes and activation of complement cascade may contribute to placental failure APS related. The abnormal uterine Doppler velocimetry, false-positive TORCH IgM and low levels of complement components can be considered prognostic indexes of poor pregnancy outcome in APS.

Determining average path length and average trapping time on generalized dual dendrimer

NASA Astrophysics Data System (ADS)

Li, Ling; Guan, Jihong

2015-03-01

Dendrimer has wide number of important applications in various fields. In some cases during transport or diffusion process, it transforms into its dual structure named Husimi cactus. In this paper, we study the structure properties and trapping problem on a family of generalized dual dendrimer with arbitrary coordination numbers. We first calculate exactly the average path length (APL) of the networks. The APL increases logarithmically with the network size, indicating that the networks exhibit a small-world effect. Then we determine the average trapping time (ATT) of the trapping process in two cases, i.e., the trap placed on a central node and the trap is uniformly distributed in all the nodes of the network. In both case, we obtain explicit solutions of ATT and show how they vary with the networks size. Besides, we also discuss the influence of the coordination number on trapping efficiency.

Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor α (RARα) and oncogenic RARα fusion proteins

PubMed Central

Zhu, Jun; Gianni, Maurizio; Kopf, Eliezer; Honoré, Nicole; Chelbi-Alix, Mounira; Koken, Marcel; Quignon, Frédérique; Rochette-Egly, Cécile; de Thé, Hugues

1999-01-01

Analyzing the pathways by which retinoic acid (RA) induces promyelocytic leukemia/retinoic acid receptor α (PML/RARα) catabolism in acute promyelocytic leukemia (APL), we found that, in addition to caspase-mediated PML/RARα cleavage, RA triggers degradation of both PML/RARα and RARα. Similarly, in non-APL cells, RA directly targeted RARα and RARα fusions to the proteasome degradation pathway. Activation of either RARα or RXRα by specific agonists induced degradation of both proteins. Conversely, a mutation in RARα that abolishes heterodimer formation and DNA binding, blocked both RARα and RXRα degradation. Mutations in the RARα DNA-binding domain or AF-2 transcriptional activation region also impaired RARα catabolism. Hence, our results link transcriptional activation to receptor catabolism and suggest that transcriptional up-regulation of nuclear receptors by their ligands may be a feedback mechanism allowing sustained target-gene activation. PMID:10611294

[Multiple organ failure presumably due to alkylating agents used as preconditioning drugs for autologous peripheral blood stem cell transplantation in an acute promyelocytic leukemia].

PubMed

Ida, Tori; Hashimoto, Shigeo; Suzuki, Nobuaki; Ebe, Yusuke; Yano, Toshio; Sato, Naoko; Koike, Tadashi

2016-01-01

A 52-year-old male was diagnosed as having acute promyelocytic leukemia (APL) in 2006. He received induction chemotherapy including all-trans retinoic acid and initially achieved a complete remission (CR). After several courses of consolidation therapy combining anthracyclines and cytarabine, he maintained CR. In 2009, an APL relapse was diagnosed, and he was treated with arsenic trioxide. Since he achieved a second CR, he underwent autologous peripheral blood stem cell transplantation (auto-PBSCT) with a conditioning regimen consisting of busulfan and melphalan. At four months after auto-PBSCT, he developed a pneumothorax and acute respiratory failure. He died despite intensive therapy. Autopsy findings included various atypical and apoptotic cells in his pulmonary tissue. These changes were confirmed in multiple organs throughout the body, suggesting them to be drug-induced. The findings in this case suggested multiple organ failure due to alkylating agents.

Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710

PubMed Central

Moser, Barry; Stock, Wendy; Gallagher, Robert E.; Willman, Cheryl L.; Stone, Richard M.; Rowe, Jacob M.; Coutre, Steven; Feusner, James H.; Gregory, John; Couban, Stephen; Appelbaum, Frederick R.; Tallman, Martin S.; Larson, Richard A.

2010-01-01

Arsenic trioxide (As2O3) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As2O3 consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As2O3 consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As2O3 arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As2O3 arm, 90% compared with 70% at 3 years (P < .0001). The addition of As2O3 consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934). PMID:20705755

Long-term outcome of 31 cases of refractory acute promyelocytic leukemia treated with compound realgar natural indigo tablets administered alternately with chemotherapy

PubMed Central

LIU, YANFENG; HE, PENGCHENG; CHENG, XIAOYAN; ZHANG, MEI

2015-01-01

The aim of the present study was to investigate the long-term survival of patients with refractory acute promyelocytic leukemia (APL) that were administered alternately with compound realgar natural indigo tablet (CRNIT) treatment and chemotherapy. In total, 31 patients with refractory APL were administered with CRNIT treatment alternately with chemotherapy. The complete remission (CR) and relapse rates were estimated by bone marrow (BM) examination. The expression of the promyelocytic leukemia-retinoic acid receptor α (PML-RARα) fusion protein and the apoptosis rate in the retinoic acid (RA)-resistant NB4-R1 cell line administered with CRNIT treatment in vitro were measured by western blot analysis and flow cytometry, respectively. The patients were followed up for 12–60 months, with a median follow-up time of 43 months. The total continuous CR rate was 90.32% (28/31), and the duration of response was between 10.3 and 60 months (median, 42.4 months). The total relapse rate was 9.68% (3/31), and the median time of relapse was 13 months (range, 8–27 months). During the treatment with CRNITs, there was no evident BM depression and only limited side-effects were experienced. Additionally, in vitro cell molecular biology results revealed that CRNIT treatment resulted in a marked induction of apoptosis and degradation of the PML-RARα fusion protein. The present results revealed that CRNIT treatment in combination with chemotherapy is an effective and feasible therapy for the treatment of patients with refractory APL. PMID:26622649

Southern Phosphorus Indices, Water Quality Data, and Modeling (APEX, APLE, and TBET) Results: A Comparison.

PubMed

Osmond, Deanna; Bolster, Carl; Sharpley, Andrew; Cabrera, Miguel; Feagley, Sam; Forsberg, Adam; Mitchell, Charles; Mylavarapu, Rao; Oldham, J Larry; Radcliffe, David E; Ramirez-Avila, John J; Storm, Dan E; Walker, Forbes; Zhang, Hailin

2017-11-01

Phosphorus (P) Indices in the southern United States frequently produce different recommendations for similar conditions. We compared risk ratings from 12 southern states (Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, Mississippi, North Carolina, Oklahoma, South Carolina, Tennessee, and Texas) using data collected from benchmark sites in the South (Arkansas, Georgia, Mississippi, North Carolina, Oklahoma, and Texas). Phosphorus Index ratings were developed using both measured erosion losses from each benchmark site and Revised Universal Soil Loss Equation 2 predictions; mostly, there was no difference in P Index outcome. The derived loss ratings were then compared with measured P loads at the benchmark sites by using equivalent USDA-NRCS P Index ratings and three water quality models (Annual P Loss Estimator [APLE], Agricultural Policy Environmental eXtender [APEX], and Texas Best Management Practice Evaluation Tool [TBET]). Phosphorus indices were finally compared against each other using USDA-NRCS loss ratings model estimate correspondence with USDA-NRCS loss ratings. Correspondence was 61% for APEX, 48% for APLE, and 52% for TBET, with overall P index correspondence at 55%. Additive P Indices (Alabama and Texas) had the lowest USDA-NRCS loss rating correspondence (31%), while the multiplicative (Arkansas, Florida, Louisiana, Mississippi, South Carolina, and Tennessee) and component (Georgia, Kentucky, and North Carolina) indices had similar USDA-NRCS loss rating correspondence-60 and 64%, respectively. Analysis using Kendall's modified Tau suggested that correlations between measured and calculated P-loss ratings were similar or better for most P Indices than the models. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

Long-term outcome of older patients with newly diagnosed de novo acute promyelocytic leukemia treated with ATRA plus anthracycline-based therapy.

PubMed

Martínez-Cuadrón, D; Montesinos, P; Vellenga, E; Bernal, T; Salamero, O; Holowiecka, A; Brunet, S; Gil, C; Benavente, C; Ribera, J M; Pérez-Encinas, M; De la Serna, J; Esteve, J; Rubio, V; González-Campos, J; Escoda, L; Amutio, M E; Arnan, M; Arias, J; Negri, S; Lowënberg, B; Sanz, M A

2018-01-01

Treatment outcome in older patients with acute promyelocytic leukemia (APL) is lower compared with younger patients, mainly because of a higher induction death rate and postremission non-relapse mortality (NRM). This prompted us to design a risk- and age-adapted protocol (Programa Español de Tratamientos en Hematología (PETHEMA)/HOVON LPA2005), with dose reduction of consolidation chemotherapy. Patients aged ⩾60 years reported to the PETHEMA registry and were treated with all-trans retinoic acid (ATRA) plus anthracycline-based regimens according to three consecutive PETHEMA trials that were included. We compared the long-term outcomes of the LPA2005 trial with the preceding PETHEMA trials using non-age-adapted schedules (LPA96&LPA99). From 1996 to 2012, 389 older patients were registered, of whom 268 patients (69%) were eligible. Causes of ineligibility were secondary APL (19%), and unfit for chemotherapy (11%). Median age was 67 years, without relevant differences between LPA2005 and LPA96&LPA99 cohorts. Overall, 216 patients (81%) achieved complete remission with no differences between trials. The 5-year NRM, cumulative incidence of relapse, disease-free survival and overall survival in the LPA2005 vs the LPA96&99 were 5 vs 18% (P=0.15), 7 vs 12% (P=0.23), 87 vs 69% (P=0.04) and 74 vs 60% (P=0.06). A less intensive front-line regimen with ATRA and anthracycline monochemotherapy resulted in improved outcomes in older APL patients.

Cassini launch contingency effort

NASA Astrophysics Data System (ADS)

Chang, Yale; O'Neil, John M.; McGrath, Brian E.; Heyler, Gene A.; Brenza, Pete T.

2002-01-01

On 15 October 1997 at 4:43 AM EDT, the Cassini spacecraft was successfully launched on a Titan IVB/Centaur on a mission to explore the Saturnian system. It carried three Radioisotope Thermoelectric Generators (RTGs) and 117 Light Weight Radioisotope Heater Units (LWRHUs). As part of the joint National Aeronautics and Space Administration (NASA)/U.S. Department of Energy (DoE) safety effort, a contingency plan was prepared to address the unlikely events of an accidental suborbital reentry or out-of-orbital reentry. The objective of the plan was to develop procedures to predict, within hours, the Earth impact footprints (EIFs) for the nuclear heat sources released during the atmospheric reentry. The footprint predictions would be used in subsequent notification and recovery efforts. As part of a multi-agency team, The Johns Hopkins University Applied Physics Laboratory (JHU/APL) had the responsibility to predict the EIFs of the heat sources after a reentry, given the heat sources' release conditions from the main spacecraft. (No ablation burn-through of the heat sources' aeroshells was expected, as a result of earlier testing.) JHU/APL's other role was to predict the time of reentry from a potential orbital decay. The tools used were a three degree-of-freedom trajectory code, a database of aerodynamic coefficients for the heat sources, secure links to obtain tracking data, and a high fidelity special perturbation orbit integrator code to predict time of spacecraft reentry from orbital decay. In the weeks and days prior to launch, all the codes and procedures were exercised. Notional EIFs were derived from hypothetical reentry conditions. EIFs predicted by JHU/APL were compared to those by JPL and US SPACECOM, and were found to be in good agreement. The reentry time from orbital decay for a booster rocket for the Russian Progress M-36 freighter, a cargo ship for the Mir space station, was predicted to within 5 minutes more than two hours before reentry. For the Cassini launch, JHU/APL's on-station real-time launch contingency activities were implemented. Live news from NASA Select TV of a successful Cassini launch and interplanetary injection precluded any further contingency actions. The Cassini launch contingency effort contributed to mission safety and demonstrated successful cooperation between several agencies. .

Design of the optical communication system for the asteroid impact mission

NASA Astrophysics Data System (ADS)

Heese, C.; Sodnik, Z.; Carnelli, I.

2017-09-01

The Asteroid Impact Mission (AIM) is part of the joint Asteroid Impact and Deflection Assessment (AIDA) project of ESA, DLR, Observatoire de la Côte d'Ázur, NASA, and Johns Hopkins University Applied Physics Laboratory (JHU/APL).

Acute Myeloid Leukemia (AML) (For Parents)

MedlinePlus

... an inorganic compound) is also used to treat kids with APL. Stem cell transplant (also called bone marrow transplant). This ... Juvenile Myelomonocytic Leukemia (JMML) Neutropenia Childhood Cancer Chemotherapy Stem Cell ... Kinds of Cancer Kids Get When Cancer Keeps You Home Types of ...

Programming Languages.

ERIC Educational Resources Information Center

Tesler, Lawrence G.

1984-01-01

Discusses the nature of programing languages, considering the features of BASIC, LOGO, PASCAL, COBOL, FORTH, APL, and LISP. Also discusses machine/assembly codes, the operation of a compiler, and trends in the evolution of programing languages (including interest in notational systems called object-oriented languages). (JN)

Inhibition of the NAD-Dependent Protein Deacetylase SIRT2 Induces Granulocytic Differentiation in Human Leukemia Cells

PubMed Central

Sunami, Yoshitaka; Araki, Marito; Hironaka, Yumi; Morishita, Soji; Kobayashi, Masaki; Liew, Ei Leen; Edahiro, Yoko; Tsutsui, Miyuki; Ohsaka, Akimichi; Komatsu, Norio

2013-01-01

Sirtuins, NAD-dependent protein deacetylases, play important roles in cellular functions such as metabolism and differentiation. Whether sirtuins function in tumorigenesis is still controversial, but sirtuins are aberrantly expressed in tumors, which may keep cancerous cells undifferentiated. Therefore, we investigated whether the inhibition of sirtuin family proteins induces cellular differentiation in leukemic cells. The sirtuin inhibitors tenovin-6 and BML-266 induce granulocytic differentiation in the acute promyelocytic leukemia (APL) cell line NB4. This differentiation is likely caused by an inhibition of SIRT2 deacetylase activity, judging from the accumulation of acetylated α-tubulin, a major SIRT2 substrate. Unlike the clinically used differentiation inducer all-trans retinoic acid, tenovin-6 shows limited effects on promyelocytic leukemia–retinoic acid receptor α (PML-RAR-α) stability and promyelocytic leukemia nuclear body formation in NB4 cells, suggesting that tenovin-6 does not directly target PML-RAR-α activity. In agreement with this, tenovin-6 induces cellular differentiation in the non-APL cell line HL-60, where PML-RAR-α does not exist. Knocking down SIRT2 by shRNA induces granulocytic differentiation in NB4 cells, which demonstrates that the inhibition of SIRT2 activity is sufficient to induce cell differentiation in NB4 cells. The overexpression of SIRT2 in NB4 cells decreases the level of granulocytic differentiation induced by tenovin-6, which indicates that tenovin-6 induces granulocytic differentiation by inhibiting SIRT2 activity. Taken together, our data suggest that targeting SIRT2 is a viable strategy to induce leukemic cell differentiation. PMID:23460888

Functional Magnetic Resonance Imaging of Working Memory and Executive Dysfunction in Systemic Lupus Erythematosus and Antiphospholipid Antibody-Positive Patients.

PubMed

Kozora, E; Uluğ, A M; Erkan, D; Vo, A; Filley, C M; Ramon, G; Burleson, A; Zimmerman, R; Lockshin, M D

2016-11-01

Standardized cognitive tests and functional magnetic resonance imaging (fMRI) studies of systemic lupus erythematosus (SLE) patients demonstrate deficits in working memory and executive function. These neurobehavioral abnormalities are not well studied in antiphospholipid syndrome, which may occur independently of or together with SLE. This study compares an fMRI paradigm involving motor skills, working memory, and executive function in SLE patients without antiphospholipid antibody (aPL) (the SLE group), aPL-positive non-SLE patients (the aPL-positive group), and controls. Brain MRI, fMRI, and standardized cognitive assessment results were obtained from 20 SLE, 20 aPL-positive, and 10 healthy female subjects with no history of neuropsychiatric abnormality. Analysis of fMRI data showed no differences in performance across groups on bilateral motor tasks. When analysis of variance was used, significant group differences were found in 2 executive function tasks (word generation and word rhyming) and in a working memory task (N-Back). Patients positive for aPL demonstrated higher activation in bilateral frontal, temporal, and parietal cortices compared to controls during working memory and executive function tasks. SLE patients also demonstrated bilateral frontal and temporal activation during working memory and executive function tasks. Compared to controls, both aPL-positive and SLE patients had elevated cortical activation, primarily in the frontal lobes, during tasks involving working memory and executive function. These findings are consistent with cortical overactivation as a compensatory mechanism for early white matter neuropathology in these disorders. © 2016, American College of Rheumatology.

Cardiovascular disease and cognitive dysfunction in systemic lupus erythematosus.

PubMed

Murray, Sara G; Yazdany, Jinoos; Kaiser, Rachel; Criswell, Lindsey A; Trupin, Laura; Yelin, Edward H; Katz, Patricia P; Julian, Laura J

2012-09-01

Cognitive dysfunction and cardiovascular disease are common and debilitating manifestations of systemic lupus erythematosus (SLE). In this study, we evaluated the relationship between cardiovascular events, traditional cardiovascular risk factors, and SLE-specific risk factors as predictors of cognitive dysfunction in a large cohort of participants with SLE. Subjects included 694 participants from the Lupus Outcomes Study (LOS), a longitudinal study of SLE outcomes based on an annual telephone survey querying demographic and clinical variables. The Hopkins Verbal Learning Test-Revised and the Controlled Oral Word Association Test were administered to assess cognitive function. Multiple logistic regression was used to identify cardiovascular events (myocardial infarction, stroke), traditional cardiovascular risk factors (hypertension, hyperlipidemia, diabetes mellitus, obesity, smoking), and SLE-specific risk factors (antiphospholipid antibodies [aPL], disease activity, disease duration) associated with cognitive impairment in year 7 of the LOS. The prevalence of cognitive impairment as measured by verbal memory and verbal fluency metrics was 15%. In adjusted multiple logistic regression analyses, aPL (odds ratio [OR] 2.10, 95% confidence interval [95% CI] 1.3-3.41), hypertension (OR 2.06, 95% CI 1.19-3.56), and a history of stroke (OR 2.27, 95% CI 1.16-4.43) were significantly associated with cognitive dysfunction. In additional analyses evaluating the association between these predictors and severity of cognitive impairment, stroke was significantly more prevalent in participants with severe impairment when compared to those with mild or moderate impairment (P = 0.036). These results suggest that the presence of aPL, hypertension, and stroke are key variables associated with cognitive impairment, which may aid in identification of patients at greatest risk. Copyright © 2012 by the American College of Rheumatology.

ΔNp73 overexpression promotes resistance to apoptosis but does not cooperate with PML/RARA in the induction of an APL-leukemic phenotype

PubMed Central

Lucena-Araujo, Antonio R.; Coelho-Silva, Juan L.; Pereira-Martins, Diego A.; Thomé, Carolina; Scheucher, Priscila S.; Lange, Ana P.; Paiva, Helder H.; Hemmelgarn, Benjamin T.; Morais-Sobral, Mariana C.; Azevedo, Elisa A.; Franca-Neto, Pedro L.; Franca, Rafael F.; Silva, Cleide L.; Krause, Alexandre; Rego, Eduardo M.

2017-01-01

Here, we evaluated whether the overexpression of transcriptionally inactive ΔNp73 cooperates with PML/RARA fusion protein in the induction of an APL-leukemic phenotype, as well as its role in vitro in proliferation, myeloid differentiation, and drug-induced apoptosis. Using lentiviral gene transfer, we showed in vitro that ΔNp73 overexpression resulted in increased proliferation in murine bone marrow (BM) cells from hCG-PML/RARA transgenic mice and their wild-type (WT) counterpart, with no accumulation of cells at G2/M or S phases; instead, ΔNp73-expressing cells had a lower rate of induced apoptosis. Next, we evaluated the effect of ΔNp73 on stem-cell self-renewal and myeloid differentiation. Primary BM cells lentivirally infected with human ΔNp73 were not immortalized in culture and did not present significant changes in the percentage of CD11b. Finally, we assessed the impact of ΔNp73 on leukemogenesis or its possible cooperation with PML/RARA fusion protein in the induction of an APL-leukemic phenotype. After 120 days of follow-up, all transplanted mice were clinically healthy and, no evidence of leukemia/myelodysplasia was apparent. Taken together, our data suggest that ΔNp73 had no leukemic transformation capacity by itself and apparently did not cooperate with the PML/RARA fusion protein to induce a leukemic phenotype in a murine BM transplantation model. In addition, the forced expression of ΔNp73 in murine BM progenitors did not alter the ATRA-induced differentiation rate in vitro or induce aberrant cell proliferation, but exerted an important role in cell survival, providing resistance to drug-induced apoptosis. PMID:28035072

Tamibarotene as maintenance therapy for acute promyelocytic leukemia: results from a randomized controlled trial.

PubMed

Shinagawa, Katsuji; Yanada, Masamitsu; Sakura, Toru; Ueda, Yasunori; Sawa, Masashi; Miyatake, Junichi; Dobashi, Nobuaki; Kojima, Minoru; Hatta, Yoshihiro; Emi, Nobuhiko; Tamaki, Shigehisa; Gomyo, Hiroshi; Yamazaki, Etsuko; Fujimaki, Katsumichi; Asou, Norio; Matsuo, Keitaro; Ohtake, Shigeki; Miyazaki, Yasushi; Ohnishi, Kazunori; Kobayashi, Yukio; Naoe, Tomoki

2014-11-20

The introduction of all-trans-retinoic acid (ATRA) has significantly improved outcomes for acute promyelocytic leukemia (APL), although a subset of patients still suffer relapse. The purpose of this study was to evaluate the role of maintenance therapy with the synthetic retinoid tamibarotene in APL. Patients with newly diagnosed APL in molecular remission at the end of consolidation therapy were randomly assigned to receive ATRA or tamibarotene, both orally, for 14 days every 3 months for up to 2 years. A total of 347 patients were enrolled. Of the 344 eligible patients, 319 (93%) achieved complete remission. After completing three courses of consolidation therapy, 269 patients underwent maintenance random assignment. The relapse-free survival (RFS) rate at 4 years was 84% for the ATRA arm and 91% for the tamibarotene arm (hazard ratio [HR], 0.54; 95% CI, 0.26 to 1.13). When the analysis was restricted to 52 high-risk patients with an initial WBC count ≥ 10.0 × 10(9)/L, the intergroup difference was statistically significant, with 4-year RFS rates of 58% for the ATRA arm and 87% for the tamibarotene arm (HR, 0.26; 95% CI, 0.07 to 0.95). For patients with non-high-risk disease, the HR was 0.82 (95% CI, 0.32 to 2.01). The test for interaction between treatment effects and these subgroups resulted in P = .075. Both treatments were generally well tolerated. In this trial, no difference was detected between ATRA and tamibarotene for maintenance therapy. In an exploratory analysis, there was a suggestion of improved efficacy of tamibarotene in high-risk patients, but this requires further study. © 2014 by American Society of Clinical Oncology.

A drug from poison: how the therapeutic effect of arsenic trioxide on acute promyelocytic leukemia was discovered.

PubMed

Rao, Yi; Li, Runhong; Zhang, Daqing

2013-06-01

It is surprising that, while arsenic trioxide (ATO) is now considered as "the single most active agent in patients with acute promyelocytic leukemia (APL)", the most important discoverer remains obscure and his original papers have not been cited by a single English paper. The discovery was made during the Cultural Revolution when most Chinese scientists and doctors struggled to survive. Beginning with recipes from a countryside practitioner that were vague in applicable diseases, Zhang TingDong and colleagues proposed in the 1970s that a single chemical in the recipe is most effective and that its target is APL. More than 20 years of work by Zhang and colleagues eliminated the confusions about whether and how ATO can be used effectively. Other researchers, first in China and then in the West, followed his lead. Retrospective analysis of data from his own group proved that APL was indeed the most sensitive target. Removal of a trace amount of mercury chloride from the recipe by another group in his hospital proved that only ATO was required. Publication of Western replication in 1998 made the therapy widely accepted, though neither Western, nor Chinese authors of English papers on ATO cited Zhang's papers in the 1970s. This article focuses on the early papers of Zhang, but also suggests it worth further work to validate Chinese reports of ATO treatment of other cancers, and infers that some findings published in Chinese journals are of considerable value to patients and that doctors from other countries can benefit from the clinical experience of Chinese doctors with the largest population of patients.

APL - North Pacific Acoustic Laboratory

DTIC Science & Technology

2015-03-04

PhilSea10 cruise were spent in a series of upgrades and associated tests of the TCTD system. Electronic upgrades in conjunction with the manufacturers, ADM...amplitude at positions sufficiently removed from caustics . Mr. White computed eigenrays to all tracked upper array hydrophone positions relative to each

Measurements of pile driving noise from control piles and noise-reduced piles at the Vashon Island ferry dock.

DOT National Transportation Integrated Search

2017-04-01

As part of the Washington State Department of Transportation (WSDOT) pile attenuation test program, : researchers from the University of Washington Applied Physics Laboratory (APL-UW) conducted underwater sound : measurements on 7 and 8 December 2015...

Am80 induces neuronal differentiation via increased tropomyosin-related kinase B expression in a human neuroblastoma SH-SY5Y cell line.

PubMed

Shiohira, Hideo; Kitaoka, Akira; Enjoji, Munechika; Uno, Tsukasa; Nakashima, Manabu

2012-01-01

Am80, a synthetic retinoid, has been used in differentiation therapy for acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA) as one of natural retinoid has been also used to treat APL. ATRA treatment causes neuronal differentiation by inducing tropomyosin-related kinase B (TrkB) expression and increasing the sensitivity to brain-derived neurotrophic factor (BDNF), a TrkB ligand. In the present study, we investigated the effects of Am80 on neuronal differentiation, BDNF sensitivity and TrkB expression in human neuroblastoma SH-SY5Y cells. Treatment with Am80 induced morphological differentiation of neurite outgrowth and increased the expression of GAP43 mRNA, a neuronal differentiation marker. Additionally, TrkB protein was also increased, and exogenous BDNF stimulation after treatment with Am80 induced greater neurite outgrowth than without BDNF treatment. These results suggest that Am80 induced neuronal differentiation by increasing TrkB expression and BDNF sensitivity.

Customer Responsiveness

NASA Technical Reports Server (NTRS)

Chiu, Mary

2002-01-01

If you know anyone who's been involved in building a spacecraft, I'm sure you've heard the mantra, 'Test what you fly, and fly what you test.' Listen to a project manager from my institution (The Johns Hopkins Applied Physics Laboratory, a.k.a. APL) talking in his or her sleep, and this is likely what you're going to hear. At APL, we do a lot of testing. We probably do more testing in the initial stages of a project than we could explain to review boards. Perhaps we are conservative in this respect, but our project managers and engineers believe in getting a good night's sleep before a launch, and testing is a good way of ensuring that. So you can imagine my reaction when the NASA project manager, Don Margolies, suggested that on the Advanced Composition Explorer (ACE) mission we pull all the instruments off the spacecraft after we had just completed the full range of environmental testing. This would allow the scientists to do a better job of calibrating their instruments.

Low-Cost Innovation in Spaceflight: The Near Earth Asteroid Rendezvous (NEAR) Shoemaker Mission

NASA Technical Reports Server (NTRS)

McCurdy, Howard E.

2005-01-01

On a spring day in 1996, at their research center in the Maryland countryside, representatives from the Johns Hopkins University Applied Physics Laboratory (APL) presented Administrator Daniel S. Goldin of the National Aeronautics and Space Administration (NASA) with a check for $3.6 million. 1 Two and a half years earlier, APL officials had agreed to develop a spacecraft capable of conducting an asteroid rendezvous and to do so for slightly more than $122 million. This was a remarkably low sum for a spacecraft due to conduct a planetaryclass mission. By contrast, the Mars Observer spacecraft launched in 1992 for an orbital rendezvous with the red planet had cost $479 million to develop, while the upcoming Cassini mission to Saturn required a spacecraft whose total cost was approaching $1.4 billion. In an Agency accustomed to cost overruns on major missions, the promise to build a planetary-class spacecraft for about $100 million seemed excessively optimistic.

Differential Roles of PML Isoforms

PubMed Central

Nisole, Sébastien; Maroui, Mohamed Ali; Mascle, Xavier H.; Aubry, Muriel; Chelbi-Alix, Mounira K.

2013-01-01

The tumor suppressor promyelocytic leukemia (PML) protein is fused to the retinoic acid receptor alpha in patients suffering from acute promyelocytic leukemia (APL). Treatment of APL patients with arsenic trioxide (As2O3) reverses the disease phenotype by a process involving the degradation of the fusion protein via its PML moiety. Several PML isoforms are generated from a single PML gene by alternative splicing. They share the same N-terminal region containing the RBCC/tripartite motif but differ in their C-terminal sequences. Recent studies of all the PML isoforms reveal the specific functions of each. Here, we review the nomenclature and structural organization of the PML isoforms in order to clarify the various designations and classifications found in different databases. The functions of the PML isoforms and their differential roles in antiviral defense also are reviewed. Finally, the key players involved in the degradation of the PML isoforms in response to As2O3 or other inducers are discussed. PMID:23734343

KSC-06pd2381

NASA Image and Video Library

2006-10-19

KENNEDY SPACE CENTER, FLA. - Inside the mobile service tower on Launch Pad 17-B at Cape Canaveral Air Force Station, workers secure the two halves of the fairing that enclose the STEREO spacecraft. The fairing is a molded structure that fits flush with the outside surface of the Delta II upper stage booster and forms an aerodynamically smooth nose cone, protecting the spacecraft during launch and ascent. The STEREO (Solar Terrestrial Relations Observatory) mission is the first to take measurements of the sun and solar wind in 3-dimension. This new view will improve our understanding of space weather and its impact on the Earth. Designed and built by the Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. STEREO is expected to lift off Oct. 25. Photo credit: NASA/George Shelton

KSC-06pd2379

NASA Image and Video Library

2006-10-19

KENNEDY SPACE CENTER, FLA. - Inside the mobile service tower on Launch Pad 17-B at Cape Canaveral Air Force Station, workers maneuver the second half of the fairing into place around the STEREO spacecraft. The fairing is a molded structure that fits flush with the outside surface of the Delta II upper stage booster and forms an aerodynamically smooth nose cone, protecting the spacecraft during launch and ascent. The STEREO (Solar Terrestrial Relations Observatory) mission is the first to take measurements of the sun and solar wind in 3-dimension. This new view will improve our understanding of space weather and its impact on the Earth. Designed and built by the Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. STEREO is expected to lift off Oct. 25. Photo credit: NASA/George Shelton

KSC-06pd2380

NASA Image and Video Library

2006-10-19

KENNEDY SPACE CENTER, FLA. - Inside the mobile service tower on Launch Pad 17-B at Cape Canaveral Air Force Station, the two fairing segments close in around the STEREO spacecraft. The fairing is a molded structure that fits flush with the outside surface of the Delta II upper stage booster and forms an aerodynamically smooth nose cone, protecting the spacecraft during launch and ascent. The STEREO (Solar Terrestrial Relations Observatory) mission is the first to take measurements of the sun and solar wind in 3-dimension. This new view will improve our understanding of space weather and its impact on the Earth. Designed and built by the Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. STEREO is expected to lift off Oct. 25. Photo credit: NASA/George Shelton

KSC-06pd2377

NASA Image and Video Library

2006-10-19

KENNEDY SPACE CENTER, FLA. - Inside the mobile service tower on Launch Pad 17-B at Cape Canaveral Air Force Station, the first half of the fairing is moved into place around the STEREO spacecraft. The fairing is a molded structure that fits flush with the outside surface of the Delta II upper stage booster and forms an aerodynamically smooth nose cone, protecting the spacecraft during launch and ascent. The STEREO (Solar Terrestrial Relations Observatory) mission is the first to take measurements of the sun and solar wind in 3-dimension. This new view will improve our understanding of space weather and its impact on the Earth. Designed and built by the Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. STEREO is expected to lift off Oct. 25. Photo credit: NASA/George Shelton

KSC-06pd2375

NASA Image and Video Library

2006-10-19

KENNEDY SPACE CENTER, FLA. - Inside the mobile service tower on Launch Pad 17-B at Cape Canaveral Air Force Station, workers help maneuver one segment of the fairing around the STEREO spacecraft. The fairing is a molded structure that fits flush with the outside surface of the Delta II upper stage booster and forms an aerodynamically smooth nose cone, protecting the spacecraft during launch and ascent. The STEREO (Solar Terrestrial Relations Observatory) mission is the first to take measurements of the sun and solar wind in 3-dimension. This new view will improve our understanding of space weather and its impact on the Earth. Designed and built by the Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. STEREO is expected to lift off Oct. 25. Photo credit: NASA/George Shelton

KSC-06pd2378

NASA Image and Video Library

2006-10-19

KENNEDY SPACE CENTER, FLA. - Inside the mobile service tower on Launch Pad 17-B at Cape Canaveral Air Force Station, workers check the placement of the first half of the fairing around the STEREO spacecraft. The fairing is a molded structure that fits flush with the outside surface of the Delta II upper stage booster and forms an aerodynamically smooth nose cone, protecting the spacecraft during launch and ascent. The STEREO (Solar Terrestrial Relations Observatory) mission is the first to take measurements of the sun and solar wind in 3-dimension. This new view will improve our understanding of space weather and its impact on the Earth. Designed and built by the Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. STEREO is expected to lift off Oct. 25. Photo credit: NASA/George Shelton

KSC-06pd2373

NASA Image and Video Library

2006-10-19

KENNEDY SPACE CENTER, FLA. - Inside the mobile service tower on Launch Pad 17-B at Cape Canaveral Air Force Station, workers (background) observe the lifting of the two fairing segments that will encapsulate the STEREO spacecraft (foreground). The fairing is a molded structure that fits flush with the outside surface of the Delta II upper stage booster and forms an aerodynamically smooth nose cone, protecting the spacecraft during launch and ascent. The STEREO (Solar Terrestrial Relations Observatory) mission is the first to take measurements of the sun and solar wind in 3-dimension. This new view will improve our understanding of space weather and its impact on the Earth. Designed and built by the Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. STEREO is expected to lift off Oct. 25. Photo credit: NASA/George Shelton

KSC-06pd2370

NASA Image and Video Library

2006-10-19

KENNEDY SPACE CENTER, FLA. - Inside the mobile service tower on Launch Pad 17-B at Cape Canaveral Air Force Station, workers prepare the twin observatories known as STEREO for encapsulation in the fairing. The fairing is a molded structure that fits flush with the outside surface of the Delta II upper stage booster and forms an aerodynamically smooth nose cone, protecting the spacecraft during launch and ascent. The STEREO (Solar Terrestrial Relations Observatory) mission is the first to take measurements of the sun and solar wind in 3-dimension. This new view will improve our understanding of space weather and its impact on the Earth. Designed and built by the Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. STEREO is expected to lift off Oct. 25. Photo credit: NASA/George Shelton

KSC-06pd2372

NASA Image and Video Library

2006-10-19

KENNEDY SPACE CENTER, FLA. - Inside the mobile service tower on Launch Pad 17-B at Cape Canaveral Air Force Station, workers prepare the twin observatories known as STEREO for encapsulation in the fairing. The fairing is a molded structure that fits flush with the outside surface of the Delta II upper stage booster and forms an aerodynamically smooth nose cone, protecting the spacecraft during launch and ascent. The STEREO (Solar Terrestrial Relations Observatory) mission is the first to take measurements of the sun and solar wind in 3-dimension. This new view will improve our understanding of space weather and its impact on the Earth. Designed and built by the Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. STEREO is expected to lift off Oct. 25. Photo credit: NASA/George Shelton

KSC-06pd2374

NASA Image and Video Library

2006-10-19

KENNEDY SPACE CENTER, FLA. - Inside the mobile service tower on Launch Pad 17-B at Cape Canaveral Air Force Station, one segment of the fairing is lifted toward the STEREO spacecraft in the foreground. The fairing is a molded structure that fits flush with the outside surface of the Delta II upper stage booster and forms an aerodynamically smooth nose cone, protecting the spacecraft during launch and ascent. The STEREO (Solar Terrestrial Relations Observatory) mission is the first to take measurements of the sun and solar wind in 3-dimension. This new view will improve our understanding of space weather and its impact on the Earth. Designed and built by the Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. STEREO is expected to lift off Oct. 25. Photo credit: NASA/George Shelton

KSC-06pd2376

NASA Image and Video Library

2006-10-19

KENNEDY SPACE CENTER, FLA. - Inside the mobile service tower on Launch Pad 17-B at Cape Canaveral Air Force Station, workers help maneuver one segment of the fairing around the STEREO spacecraft. The fairing is a molded structure that fits flush with the outside surface of the Delta II upper stage booster and forms an aerodynamically smooth nose cone, protecting the spacecraft during launch and ascent. The STEREO (Solar Terrestrial Relations Observatory) mission is the first to take measurements of the sun and solar wind in 3-dimension. This new view will improve our understanding of space weather and its impact on the Earth. Designed and built by the Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. STEREO is expected to lift off Oct. 25. Photo credit: NASA/George Shelton

KSC-06pd2371

NASA Image and Video Library

2006-10-19

KENNEDY SPACE CENTER, FLA. - Inside the mobile service tower on Launch Pad 17-B at Cape Canaveral Air Force Station, workers prepare the twin observatories known as STEREO for encapsulation in the fairing. The fairing is a molded structure that fits flush with the outside surface of the Delta II upper stage booster and forms an aerodynamically smooth nose cone, protecting the spacecraft during launch and ascent. The STEREO (Solar Terrestrial Relations Observatory) mission is the first to take measurements of the sun and solar wind in 3-dimension. This new view will improve our understanding of space weather and its impact on the Earth. Designed and built by the Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. STEREO is expected to lift off Oct. 25. Photo credit: NASA/George Shelton

Characteristic of leachate at Alor Pongsu Landfill Site, Perak, Malaysia: A comparative study

NASA Astrophysics Data System (ADS)

Nor Farhana Zakaria, Siti; Aziz, Hamidi Abdul

2018-04-01

Leachate is a harmful by product generated from the landfill site. Leachate contains a high concentration of pollutant which can cause serious pollution to environmental. In this study, characteristics of leachate in Alor Pongsu Landfill Site (APLS) were monitored and analyzed according to the Standard Methods for the Examination of Water and Wastewater (2005). Composition in leachate at APLS was monitored for one year starting from January 2015 until January 2016. Nine parameters were monitored including color, chemical oxygen demand (COD), biological oxygen demand (BOD5), ammoniacal nitrogen (NH3-N), biodegradability ratio (BOD5/COD), temperature, dissolved oxygen (DO), total dissolved solid (TDS) and pH. Based on the analysis, Alor Pongsu Landfill leachate was categorized as stabilized landfill leachate by referring to the BOD5/COD < 0.1. Comparison with allowable discharge limits for leachate shows that most of parameters exceeded the standard discharge limitation. Thus, proper treatment is needed before leachate can be discharged to the environment.

[RXR, a key member of the oncogenic complex in acute promyelocytic leukemia].

PubMed

Halftermeyer, Juliane; Le Bras, Morgane; De Thé, Hugues

2011-11-01

Acute promyelocytic leukaemia (APL) is induced by fusion proteins always implying the retinoic acid receptor RARa. Although PML-RARa and other fusion oncoproteins are able to bind DNA as homodimers, in vivo they are always found in association with the nuclear receptor RXRa (Retinoid X Receptor). Thus, RXRa is an essential cofactor of the fusion protein for the transformation. Actually, RXRa contributes to several aspects of in vivo -transformation: RARa fusion:RXRa hetero-oligomeric complexes bind DNA with a much greater affinity than RARa fusion homodimers. Besides, PML-RARa:RXRa recognizes an enlarged repertoire of DNA binding sites. Thus the association between fusion proteins and RXRa regulates more genes than the homodimer alone. Titration of RXRa by the fusion protein may also play a role in the transformation process, as well as post-translational modifications of RXRa in the complex. Finally, RXRa is required for rexinoid-induced APL differentiation. Thus, RXRa is a key member of the oncogenic complex. © 2011 médecine/sciences – Inserm / SRMS.

Southern phosphorus indices, water quality data, and modeling (APEX, APLE, and TBET) results: A comparison

USDA-ARS?s Scientific Manuscript database

Phosphorus (P) indices in the southern United States frequently produce different recommendations for similar conditions. After assembling data from benchmark southern sites (Arkansas, Georgia, Mississippi, North Carolina, Oklahoma, and Texas), land treatment information was used in the 12 southern...

Parameter uncertainty analysis for the annual phosphorus loss estimator (APLE) model

USDA-ARS?s Scientific Manuscript database

Technical abstract: Models are often used to predict phosphorus (P) loss from agricultural fields. While it is commonly recognized that model predictions are inherently uncertain, few studies have addressed prediction uncertainties using P loss models. In this study, we conduct an uncertainty analys...

Mid Course Space Experiment (MSX) Environmental Assessment

DTIC Science & Technology

1992-03-06

8217____ a ~~ACTrv=T _ _ _ _ _ _I wTLL USU/SDL =H/APL OSFC VAPE ITP Fabrication -SBV -SPIRIT ft1 -Satellites -Reference -UVISI ___________ Objects...Vandenberg Air Force Base ( VAPE ) Jobit Hopkins University/Applied Physics Laboratoty MM/UAPL) Kausi Tea Facility (KIT 3 Satellite trussn assucttue, OSDP

Estimating Phosphorus Loss at the Whole-Farm Scale with User-Friendly Models

NASA Astrophysics Data System (ADS)

Vadas, P.; Powell, M.; Brink, G.; Busch, D.; Good, L.

2014-12-01

Phosphorus (P) loss from agricultural fields and delivery to surface waters persists as a water quality impairment issue. For dairy farms, P can be lost from cropland, pastures, barnyards, and open-air cattle lots; and all these sources must be evaluated to determine which ones are a priority for P loss remediation. We used interview surveys to document land use, cattle herd characteristics, and manure management for four grazing-based dairy farms in Wisconsin, USA. We then used the APLE and Snap-Plus models to estimate annual P loss from all areas on these farms and determine their relative contribution to whole-farm P loss. At the whole-farm level, average annual P loss (kg ha-1) from grazing-based dairy farms was low (0.6 to 1.8 kg ha-1), generally because a significant portion of land was in permanently vegetated pastures or hay and had low erosion. However, there were areas on the farms that represented sources of significant P loss. For cropland, the greatest P loss was from areas with exposed soil, typically for corn production, and especially on steeper sloping land. The farm areas with the greatest P loss had concentrated animal housing, including barnyards, and over-wintering and young-stock lots. These areas can represent from about 5% to almost 30% of total farm P loss, depending on lot management and P loss from other land uses. Our project builds on research to show that producer surveys can provide reliable management information to assess whole-farm P loss. It also shows that we can use models like RUSLE2, Snap-Plus, and APLE to rapidly, reliably, and quantitatively estimate P loss in runoff from all areas on a dairy farm and identify areas in greatest need of alternative management to reduce P loss.

New Horizons Pluto Flyby Guest Operations

NASA Astrophysics Data System (ADS)

Simon, M.; Turney, D.; Fisher, S.; Carr, S. S.

2015-12-01

On July 14, 2015, after 9.5 years of cruise, NASA's New Horizons spacecraft flew past the Pluto system to gather first images humankind had ever seen on Pluto and its five moons. While much has been discovered about the Pluto system since New Horizons launch in 2006, the system has never been imaged at high resolution and anticipation of the "First Light" of the Pluto system had been anticipated by planetary enthusiasts for decades. The Johns Hopkins Applied Physics Laboratory (APL), which built and operates New Horizons, was the focal point for gathering three distinct groups: science and engineering team members; media and public affairs representatives; and invited public, including VIP's. Guest operations activities were focused on providing information primarily to the invited public and VIP's. High level objectives for the Guest Operations team was set to entertain and inform the general public, offer media reaction shots, and to deconflict activities for the guests from media activities wherever possible. Over 2000 people arrived at APL in the days surrounding closest approach for guest, science or media operations tracks. Reaction and coverage of the Guest Operations events was universally positive and global in impact: iconic pictures of the auditorium waving flags during the moment of closest approach were published in media outlets on every continent. Media relations activities ensured coverage in all key media publications targeted for release, such as the New York Times, Science, Le Monde, and Nature. Social and traditional media coverage of the events spanned the globe. Guest operations activities are designed to ensure that a guest has a memorable experience and leaves with a lifelong memory of the mission and their partnership in the activity. Results, lessons learned, and other data from the New Horizons guest operations activity will be presented and analyzed.

Human rights violations among economically disadvantaged women with mental illness: An Indian perspective

PubMed Central

Poreddi, Vijayalakshmi; Ramachandra; Thimmaiah, Rohini; Math, Suresh Bada

2015-01-01

Background: Globally women confront manifold violations of human rights and women with poverty and mental illness are doubly disadvantaged. Aim: The aim was to examine the influence of poverty in meeting human rights needs among recovered women with mental illness at family and community level. Materials and Methods: This was a descriptive study carried out among randomly selected (n = 100) recovered women with mental illness at a tertiary care center. Data were collected through face-to-face interview using structured needs assessment questionnaire. Results: Our findings revealed that below poverty line (BPL) participants were not satisfied in meeting their physical needs such as “access to safe drinking water” (χ2 = 8.994, P < 0.02), “served in the same utensils” (χ2 = 13.648, P < 0.00), had adequate food (χ2 = 11.025, P < 0.02), and allowed to use toilet facilities (χ2 = 13.565, P < 0.00). The human rights needs in emotional dimension, that is, afraid of family members (χ2 = 8.233, P < 0.04) and hurt by bad words (χ2 = 9.014, P < 0.02) were rated higher in above poverty line (APL) participants. Similarly, 88.9% of women from APL group expressed that they were discriminated and exploited by the community members (χ2 = 17.490, P < 0.00). More than three-fourths of BPL participants (76.1%) believed that there were wondering homeless mentally ill in their community (χ2 = 11.848, P < 0.01). Conclusion: There is an urgent need to implement social welfare programs to provide employment opportunities, disability allowance, housing and other social security for women with mental illness. Further, mental health professionals play an essential role in educating the family and public regarding human rights of people with mental illness. PMID:26124524

Human rights violations among economically disadvantaged women with mental illness: An Indian perspective.

PubMed

Poreddi, Vijayalakshmi; Ramachandra; Thimmaiah, Rohini; Math, Suresh Bada

2015-01-01

Globally women confront manifold violations of human rights and women with poverty and mental illness are doubly disadvantaged. The aim was to examine the influence of poverty in meeting human rights needs among recovered women with mental illness at family and community level. This was a descriptive study carried out among randomly selected (n = 100) recovered women with mental illness at a tertiary care center. Data were collected through face-to-face interview using structured needs assessment questionnaire. Our findings revealed that below poverty line (BPL) participants were not satisfied in meeting their physical needs such as "access to safe drinking water" (χ(2) = 8.994, P < 0.02), "served in the same utensils" (χ(2) = 13.648, P < 0.00), had adequate food (χ(2) = 11.025, P < 0.02), and allowed to use toilet facilities (χ(2) = 13.565, P < 0.00). The human rights needs in emotional dimension, that is, afraid of family members (χ(2) = 8.233, P < 0.04) and hurt by bad words (χ(2) = 9.014, P < 0.02) were rated higher in above poverty line (APL) participants. Similarly, 88.9% of women from APL group expressed that they were discriminated and exploited by the community members (χ(2) = 17.490, P < 0.00). More than three-fourths of BPL participants (76.1%) believed that there were wondering homeless mentally ill in their community (χ(2) = 11.848, P < 0.01). There is an urgent need to implement social welfare programs to provide employment opportunities, disability allowance, housing and other social security for women with mental illness. Further, mental health professionals play an essential role in educating the family and public regarding human rights of people with mental illness.

Alabama Public Library Service Annual Report.

ERIC Educational Resources Information Center

Alabama Public Library Service, Montgomery.

The Alabama Public Library Service (APLS) lists its duties, goals, and recent accomplishments in this 1988 annual report. Some of these duties and goals are: (1) administering grants for library development and state aid; (2) providing consultation for library automation; (3) researching and answering reference questions; (4) lending books from…

75 FR 62407 - Office of Administration; Single-Source Cooperative Agreement Award; Announcing the Award a...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-08

... Agreement to the Johns Hopkins University, Applied Physics Lab (APL) and School of Public Health, To Support... DEPARTMENT OF HEALTH AND HUMAN SERVICES Administration for Children and Families Office of... a single-source cooperative agreement to the Johns Hopkins University (JHU), Applied Physics Lab...

78 FR 35270 - Notice of Agreements Filed

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-12

...: American President Lines, Ltd. and APL Co. PTE Ltd. (operating as a single carrier); A.P. Moller-Maersk A/S... Container Lines Company, Ltd; Evergreen Line Joint Service Agreement, FMC No. 011982; Hanjin Shipping Co., Ltd.; Hapag-Lloyd A.G.; Hyundai Merchant Marine Co., Ltd.; Kawasaki Kisen Kaisha, Ltd.; Mediterranean...

Federal Public Library Programs in Alabama, 1999.

ERIC Educational Resources Information Center

Alabama Public Library Service, Montgomery.

The Alabama Public Library Service (APLS) is charged with improving library services throughout the state to ensure that all citizens have access to quality library and information services. Part of this charge includes the responsibility for receiving and administering federal funds to the more than 200 public libraries in Alabama. Federal…

Improvement of mathematical models for simulation of vehicle handling : volume 7 : technical manual for the general simulation

DOT National Transportation Integrated Search

1980-03-01

This volume is the technical manual for the general simulation. Mathematical modelling of the vehicle and of the human driver is presented in detail, as are differences between the APL simulation and the current one. Information on model validation a...

Albania’s Road Toward Integrated and Accession into the European Union

DTIC Science & Technology

2014-06-13

50 vii Regional issues and international obligations ........................................................51...88 viii ACRONYMS AI Amnesty International APL Albanian Party of Labor CARDS Community Assistance for Reconstruction, Development...IMF International Monetary Fund IPA Instrument for Pre-accession assistance MEI Ministry of European Integration MFA Ministry of Foreign Affairs

A Relational Database System for Student Use.

ERIC Educational Resources Information Center

Fertuck, Len

1982-01-01

Describes an APL implementation of a relational database system suitable for use in a teaching environment in which database development and database administration are studied, and discusses the functions of the user and the database administrator. An appendix illustrating system operation and an eight-item reference list are attached. (Author/JL)

Architectural Analysis of Complex Evolving Systems of Systems

NASA Technical Reports Server (NTRS)

Lindvall, Mikael; Stratton, William C.; Sibol, Deane E.; Ray, Arnab; Ackemann, Chris; Yonkwa, Lyly; Ganesan, Dharma

2009-01-01

The goal of this collaborative project between FC-MD, APL, and GSFC and supported by NASA IV&V Software Assurance Research Program (SARP), was to develop a tool, Dynamic SAVE, or Dyn-SAVE for short, for analyzing architectures of systems of systems. The project team was comprised of the principal investigator (PI) from FC-MD and four other FC-MD scientists (part time) and several FC-MD students (full time), as well as, two APL software architects (part time), and one NASA POC (part time). The PI and FC-MD scientists together with APL architects were responsible for requirements analysis, and for applying and evaluating the Dyn-SAVE tool and method. The PI and a group of FC-MD scientists were responsible for improving the method and conducting outreach activities, while another group of FC-MD scientists were responsible for development and improvement of the tool. Oversight and reporting was conducted by the PI and NASA POC. The project team produced many results including several prototypes of the Dyn-SAVE tool and method, several case studies documenting how the tool and method was applied to APL s software systems, and several published papers in highly respected conferences and journals. Dyn-SAVE as developed and enhanced throughout this research period, is a software tool intended for software developers and architects, software integration testers, and persons who need to analyze software systems from the point of view of how it communicates with other systems. Using the tool, the user specifies the planned communication behavior of the system modeled as a sequence diagram. The user then captures and imports the actual communication behavior of the system, which is then converted and visualized as a sequence diagram by Dyn-SAVE. After mapping the planned to the actual and specifying parameter and timing constraints, Dyn-SAVE detects and highlights deviations between the planned and the actual behavior. Requirements based on the need to analyze two inter-system communication protocols that are representative of protocols used in the Aerospace industry have been specified. The protocols are related: APL s Common Ground System (CGS) as used in the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) and the Radiation Belt Space Probes (RBSP) missions. The analyzed communications were implementations of the Telemetry protocol and the CCSDS File Delivery Protocol (CFDP) protocol. Based on these requirements, three prototypes of Dyn-SAVE were developed and applied to these protocols. The application of Dyn-SAVE to these protocols resulted in the detection of several issues. Dyn-SAVE was also applied to several Testbeds that have previously been used for experimentation earlier on this project, as well as, to other protocols and logs for testing its broader applicability. For example, Dyn-SAVE was used to analyze 1) the communication pattern between a web browser and a web server, 2) the system log of a computer in order to detect offnominal computer shut-down behavior, and 3) the actual test cases of NASA Goddard s Core Flight System (CFS) and automatically generated test cases in order to determine the overlap between the two sets of test cases. In all cases, Dyn-SAVE assisted in providing insightful conclusions about each of the cases identified above.

Use of annual phosphorus loss estimator (APLE) model to evaluate a phosphorus index

USDA-ARS?s Scientific Manuscript database

Maryland’s Phosphorus Site Index (MD-PSI) has been used to guide management decisions to minimize the potential for phosphorus (P) loss from agricultural fields in Maryland since 2002. The index was recently revised and renamed the University of Maryland Phosphorus Management Tool (UM-PMT), and the...

27 CFR 447.21 - The U.S. Munitions Import List.

Code of Federal Regulations, 2014 CFR

2014-04-01

...) Tankers (YO, YOG, YW) (3) Lighters (YC, YCF, YCV, YF, YFN, YFNB, YFNX, YFR, YFRN, YFU, YG, YGN, YOGN, YON, YOS, YSR, YWN) (4) Floating Dry Docks (AFDB, AFDL, AFDM, ARD, ARDM, YFD) (5) Miscellaneous (APL, DSRV..., WHEC, WMEC) (2) Patrol Craft (WPB) (3) Icebreakers (WAGB) (4) Oceanography Vessels (WAGO) (5) Special...

Underwater Munitions Expert System to Predict Mobility and Burial

DTIC Science & Technology

2017-11-14

exposure and aggregation for underwater munitions. 15. SUBJECT TERMS Underwater Munitions, Mobility, Burial, Application Programmer Interface...Munitions Expert System: Demonstration and Evaluation Report Acronyms API – Application Programmer Interface APL – Applied Physics...comparisons and traditional metrics such as the coefficient of correlation. The summary statistic for the comparisons of burial results

Program For Finite-Element Analyses Of Phase-Change Fluids

NASA Technical Reports Server (NTRS)

Viterna, L. A.

1995-01-01

PHASTRAN analyzes heat-transfer and flow behaviors of materials undergoing phase changes. Many phase changes operate over range of accelerations or effective gravitational fields. To analyze such thermal systems, it is necessary to obtain simultaneous solutions for equations of conservation of energy, momentum, and mass, and for equation of state. Written in APL2.

A Study about Placement Support Using Semantic Similarity

ERIC Educational Resources Information Center

Katz, Marco; van Bruggen, Jan; Giesbers, Bas; Waterink, Wim; Eshuis, Jannes; Koper, Rob

2014-01-01

This paper discusses Latent Semantic Analysis (LSA) as a method for the assessment of prior learning. The Accreditation of Prior Learning (APL) is a procedure to offer learners an individualized curriculum based on their prior experiences and knowledge. The placement decisions in this process are based on the analysis of student material by domain…

The Time-Sharing Computer In Introductory Earth Science.

ERIC Educational Resources Information Center

MacDonald, William D.; MacDonald, Geraldine E.

Time-sharing computer-assisted instructional (CAI) programs employing the APL language are being used in support of introductory earth science laboratory exercises at the State University of New York at Binghamton. Three examples are sufficient to illustrate the variety of applications to which these programs are put. The BRACH program is used in…

A Computerized Three-Dimensional Program Budget and Its Implementation at Cambridge School Department.

ERIC Educational Resources Information Center

Wong, S. Godwin

This report describes the APL (Accountable unit, Program, and line item) budget system, a computerized three-dimensional program budget system that has been implemented in the Cambridge (Massachusetts) School Department. Various chapters discuss the differences between traditional budgeting and program budgeting, present an overview of te APL…

Self-Assessment in University Assessment of Prior Learning Procedures

ERIC Educational Resources Information Center

Brinke, D. Joosten-Ten; Sluijsmans, D. M. A.; Jochems, W. M. G.

2009-01-01

Competency-based university education, in which lifelong learning and flexible learning are key elements, demands a renewed vision on assessment. Within this vision, Assessment of Prior Learning (APL), in which learners have to show their prior learning in order for their goals to be recognised, becomes an important element. This article focuses…

Arsenic compounds as anticancer agents.

PubMed

Wang, Z Y

2001-08-01

In this paper the use of arsenic compounds as anticancer agents in clinical trials and in in vitro investigations is reviewed, including the experience at our institute. Treatment of newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3) has been found to result in complete remission (CR) rates of 85-93% when given by intravenous infusion for 2-3 h at a dose of 10 mg/day diluted in 5% glucose saline solution. Patients exhibit a response in 28-42 days. CR rates after administration of Composite Indigo Naturalis tablets containing arsenic sulfide and of pure tetraarsenic tetrasulfide reached 98% and 84.9%, respectively. At higher concentrations (1-2 microM), arsenic induced apoptosis, while at lower concentrations (0.1-0.5 microM), it triggered cell differentiation in vitro. As2O3-induced apoptosis has been observed in many cancer cell lines, including esophageal carcinoma, gastric cancer, neuroblastoma, lymphoid malignancies, and multiple myeloma. Its effectiveness was confirmed in the treatment of multiple myeloma. Arsenic compounds are effective agents in the treatment of APL and their activity against other types of cancer requires further investigation.

Cooperative organic mine avoidance path planning

NASA Astrophysics Data System (ADS)

McCubbin, Christopher B.; Piatko, Christine D.; Peterson, Adam V.; Donnald, Creighton R.; Cohen, David

2005-06-01

The JHU/APL Path Planning team has developed path planning techniques to look for paths that balance the utility and risk associated with different routes through a minefield. Extending on previous years' efforts, we investigated real-world Naval mine avoidance requirements and developed a tactical decision aid (TDA) that satisfies those requirements. APL has developed new mine path planning techniques using graph based and genetic algorithms which quickly produce near-minimum risk paths for complicated fitness functions incorporating risk, path length, ship kinematics, and naval doctrine. The TDA user interface, a Java Swing application that obtains data via Corba interfaces to path planning databases, allows the operator to explore a fusion of historic and in situ mine field data, control the path planner, and display the planning results. To provide a context for the minefield data, the user interface also renders data from the Digital Nautical Chart database, a database created by the National Geospatial-Intelligence Agency containing charts of the world's ports and coastal regions. This TDA has been developed in conjunction with the COMID (Cooperative Organic Mine Defense) system. This paper presents a description of the algorithms, architecture, and application produced.

KSC-06pd2389

NASA Image and Video Library

2006-10-25

KENNEDY SPACE CENTER, FLA. - The mobile service tower (right) begins to roll away from the STEREO spacecraft aboard the Delta II launch vehicle in preparation for launch. Liftoff is scheduled in a window between 8:38 and 8:53 p.m. on Oct. 25. STEREO (Solar Terrestrial Relations Observatory) is a two-year mission using two nearly identical observatories, one ahead of Earth in its orbit and the other trailing behind. The duo will provide 3-D measurements of the sun and its flow of energy, enabling scientists to study the nature of coronal mass ejections and why they happen. The ejections are a major source of the magnetic disruptions on Earth and are a key component of space weather. The disruptions can greatly effect satellite operations, communications, power systems, humans in space and global climate. Designed and built by the Johns Hopkins University Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. Photo credit: NASA/Kim Shiflett

KSC-06pd2388

NASA Image and Video Library

2006-10-25

KENNEDY SPACE CENTER, FLA. - The mobile service tower begins to roll away from the STEREO spacecraft aboard the Delta II launch vehicle in preparation for launch. Liftoff is scheduled in a window between 8:38 and 8:53 p.m. on Oct. 25. STEREO (Solar Terrestrial Relations Observatory) is a two-year mission using two nearly identical observatories, one ahead of Earth in its orbit and the other trailing behind. The duo will provide 3-D measurements of the sun and its flow of energy, enabling scientists to study the nature of coronal mass ejections and why they happen. The ejections are a major source of the magnetic disruptions on Earth and are a key component of space weather. The disruptions can greatly effect satellite operations, communications, power systems, humans in space and global climate. Designed and built by the Johns Hopkins University Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. Photo credit: NASA/Kim Shiflett

KSC-06pd2390

NASA Image and Video Library

2006-10-25

KENNEDY SPACE CENTER, FLA. - The mobile service tower (left) rolls away from the STEREO spacecraft aboard the Delta II launch vehicle in preparation for launch. Liftoff is scheduled in a window between 8:38 and 8:53 p.m. on Oct. 25. STEREO (Solar Terrestrial Relations Observatory) is a two-year mission using two nearly identical observatories, one ahead of Earth in its orbit and the other trailing behind. The duo will provide 3-D measurements of the sun and its flow of energy, enabling scientists to study the nature of coronal mass ejections and why they happen. The ejections are a major source of the magnetic disruptions on Earth and are a key component of space weather. The disruptions can greatly effect satellite operations, communications, power systems, humans in space and global climate. Designed and built by the Johns Hopkins University Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. Photo credit: NASA/Kim Shiflett

Analysis of continuous GPS measurements from southern Victoria Land, Antarctica

USGS Publications Warehouse

Willis, Michael J.

2007-01-01

Several years of continuous data have been collected at remote bedrock Global Positioning System (GPS) sites in southern Victoria Land, Antarctica. Annual to sub-annual variations are observed in the position time-series. An atmospheric pressure loading (APL) effect is calculated from pressure field anomalies supplied by the European Centre for Medium-Range Weather Forecasts (ECMWF) model loading an elastic Earth model. The predicted APL signal has a moderate correlation with the vertical position time-series at McMurdo, Ross Island (International Global Navigation Satellite System Service (IGS) station MCM4), produced using a global solution. In contrast, a local solution in which MCM4 is the fiducial site generates a vertical time series for a remote site in Victoria Land (Cape Roberts, ROB4) which exhibits a low, inverse correlation with the predicted atmospheric pressure loading signal. If, in the future, known and well modeled geophysical loads can be separated from the time-series, then local hydrological loading, of interest for glaciological and climate applications, can potentially be extracted from the GPS time-series.

KSC-06pd2394

NASA Image and Video Library

2006-10-25

KENNEDY SPACE CENTER, FLA. - The Delta II launch vehicle carrying the STEREO spacecraft hurtles through the smoke and steam after liftoff from Launch Pad 17-B at Cape Canaveral Air Force Station. Liftoff was at 8:52 p.m. EDT. STEREO (Solar Terrestrial Relations Observatory) is a two-year mission using two nearly identical observatories, one ahead of Earth in its orbit and the other trailing behind. The duo will provide 3-D measurements of the sun and its flow of energy, enabling scientists to study the nature of coronal mass ejections and why they happen. The ejections are a major source of the magnetic disruptions on Earth and are a key component of space weather. The disruptions can greatly effect satellite operations, communications, power systems, humans in space and global climate. Designed and built by the Johns Hopkins University Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results.

KSC-06pd2401

NASA Image and Video Library

2006-10-25

KENNEDY SPACE CENTER, FLA. - The Delta II rocket carrying the STEREO spacecraft on top streaks through the smoke as it climbs to orbit. Liftoff from Launch Pad 17-B at Cape Canaveral Air Force Station was at 8:52 p.m. EDT. STEREO (Solar Terrestrial Relations Observatory) is a two-year mission using two nearly identical observatories, one ahead of Earth in its orbit and the other trailing behind. The duo will provide 3-D measurements of the sun and its flow of energy, enabling scientists to study the nature of coronal mass ejections and why they happen. The ejections are a major source of the magnetic disruptions on Earth and are a key component of space weather. The disruptions can greatly effect satellite operations, communications, power systems, humans in space and global climate. Designed and built by the Johns Hopkins University Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results.

High WT1 expression is an early predictor for relapse in patients with acute promyelocytic leukemia in first remission with negative PML-RARa after anthracycline-based chemotherapy: a single-center cohort study.

PubMed

Yoon, Jae-Ho; Kim, Hee-Je; Kwak, Dae-Hun; Park, Sung-Soo; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Eom, Ki-Seong; Kim, Yoo-Jin; Lee, Seok; Min, Chang-Ki; Cho, Seok-Goo; Kim, Dong-Wook; Lee, Jong Wook; Min, Woo-Sung

2017-01-23

Wilms' tumor gene 1 (WT1) expression is a well-known predictor for relapse in acute myeloid leukemia. We monitored WT1 decrement along the treatment course to identify its significant role as a marker for residual disease in acute promyelocytic leukemia (APL) and tried to suggest its significance for relapse prediction. In this single center retrospective study, we serially measured PML-RARa and WT1 expression from 117 APL patients at diagnosis, at post-induction and post-consolidation chemotherapies, and at every 3 months after starting maintenance therapy. All 117 patients were in molecular remission after treatment of at least 2 consolidation chemotherapies. We used WT1 ProfileQuant™ kit (Ipsogen) for WT1 monitoring. High WT1 expression (>120 copies/10 4 ABL1) after consolidation and at early period (3 months) after maintenance therapy significantly predicted subsequent relapse. All paired PML-RARa RQ-PCR were not detected except for one sample with early relapse. Patients with high WT1 expression at 3 months after maintenance therapy (n = 40) showed a significantly higher relapse rate (30.5 vs. 6.9%, P < 0.001) and inferior disease free survival (62.8 vs. 91.4%, P < 0.001). Multivariate analysis revealed that high peak leukocyte counts at diagnosis (HR = 6.4, P < 0.001) and high WT1 expression at 3 months after maintenance therapy (HR = 7.1, P < 0.001) were significant factors for prediction of relapse. Our data showed high post-remission WT1 expression was a reliable marker for prediction of subsequent molecular relapse in APL. In this high-risk group, early intervention with ATRA ± ATO, anti-CD33 antibody therapy, and WT1-specific therapy may be used for relapse prevention. Clinical Research Information Service (CRIS), KCT0002079.

Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial.

PubMed

Zhu, Hong-Hu; Wu, De-Pei; Jin, Jie; Li, Jian-Yong; Ma, Jun; Wang, Jian-Xiang; Jiang, Hao; Chen, Sai-Juan; Huang, Xiao-Jun

2013-11-20

This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of an oral tetra-arsenic tetra-sulfide (As4S4) -containing formula named the Realgar-Indigo naturalis formula (RIF) compared with intravenous arsenic trioxide (ATO) as both induction and maintenance therapies for newly diagnosed acute promyelocytic leukemia (APL). In all, 242 patients with APL were randomly assigned (1:1) to oral RIF (60 mg/kg) or ATO (0.16 mg/kg) combined with all-trans retinoic acid (ATRA; 25 mg/m(2)) during induction therapy. After achieving complete remission (CR), all patients received three courses of consolidation chemotherapy and maintenance treatment with sequential ATRA followed by either RIF or ATO for 2 years. The primary end point was the rate of disease-free survival (DFS) at 2 years, which was assessed for noninferiority with a 10% noninferiority margin. The median follow-up time was 39 months. DFS at 2 years was 98.1% (106 of 108) in the RIF group and 95.5% (107 of 112) in the ATO group. The DFS difference was 2.6% (95% CI, -3.0% to 8.0%). The lower limit of the 95% CI of DFS difference was greater than the -10% noninferiority margin, confirming noninferiority (P < .001). No significant differences were noted between the RIF and ATO groups with regard to the CR rate (99.1% v 97.2%; P = .62) or the overall survival at 3 years (99.1% v 96.6%; P = .18). The rates of adverse events were similar in the two groups. Oral RIF plus ATRA is not inferior to intravenous ATO plus ATRA as first-line treatment of APL and may be considered as a routine treatment option for appropriate patients.

Joint operations planning for space surveillance missions on the MSX satellite

NASA Technical Reports Server (NTRS)

Stokes, Grant; Good, Andrew

1994-01-01

The Midcourse Space Experiment (MSX) satellite, sponsored by BMDO, is intended to gather broad-band phenomenology data on missiles, plumes, naturally occurring earthlimb backgrounds and deep space backgrounds. In addition the MSX will be used to conduct functional demonstrations of space-based space surveillance. The JHU/Applied Physics Laboratory (APL), located in Laurel, MD, is the integrator and operator of the MSX satellite. APL will conduct all operations related to the MSX and is charged with the detailed operations planning required to implement all of the experiments run on the MSX except the space surveillance experiments. The non-surveillance operations are generally amenable to being defined months ahead of time and being scheduled on a monthly basis. Lincoln Laboratory, Massachusetts Institute of Technology (LL), located in Lexington, MA, is the provider of one of the principle MSX instruments, the Space-Based Visible (SBV) sensor, and the agency charged with implementing the space surveillance demonstrations on the MSX. The planning timelines for the space surveillance demonstrations are fundamentally different from those for the other experiments. They are generally amenable to being scheduled on a monthly basis, but the specific experiment sequence and pointing must be refined shortly before execution. This allocation of responsibilities to different organizations implies the need for a joint mission planning system for conducting space surveillance demonstrations. This paper details the iterative, joint planning system, based on passing responsibility for generating MSX commands for surveillance operations from APL to LL for specific scheduled operations. The joint planning system, including the generation of a budget for spacecraft resources to be used for surveillance events, has been successfully demonstrated during ground testing of the MSX and is being validated for MSX launch within the year. The planning system developed for the MSX forms a model possibly applicable to developing distributed mission planning systems for other multi-use satellites.

Teaching Mathematical Biology in High School Using Adapted Primary Literature

ERIC Educational Resources Information Center

Norris, Stephen P.; Stelnicki, Nathan; de Vries, Gerda

2012-01-01

The study compared the effect of two adaptations of a scientific article on students' comprehension and use of scientific inquiry skills. One adaptation preserved as much as possible the canonical form of the original article (APL, Adapted Primary Literature) and the other was written in a more narrative mode typical of secondary literature (SL).…

The Implementation of IAS 16 and IAS 41 at Andrew Peller Limited

ERIC Educational Resources Information Center

Lapointe-Antunes, Pascale; Moore, James

2013-01-01

This case asks students to play the role of Doug Grodeckie, Manager of Financial Reporting at Andrew Peller Limited (APL). Doug was asked to prepare a report analyzing Andrew Peller Limited's current tangible long-lived assets disclosures and making recommendations on how best to comply with International Accounting Standard (IAS) 16 Property,…

The Impact of Federal Preemption of State Antipredatory Lending Laws on the Foreclosure Crisis

ERIC Educational Resources Information Center

Ding, Lei; Quercia, Roberto G.; Reid, Carolina K.; White, Alan M.

2012-01-01

State antipredatory lending laws (APLs) are designed to protect borrowers against predatory lending that can increase the risk of default and deplete the home equity held by borrowers. Federal regulators instituted preemption that limited the scope and reach of state antipredatory lending regulations for certain lenders. Based on the variation in…

Geothermal Energy Resources of Navy/Marine Corps Installations on the Atlantic and Gulf Coastal Plain.

DTIC Science & Technology

1980-03-01

Geological Survey ( AAPG -USGS) thermal gradient map of North America, at a scale of 1:5,000,000, gives the hypothesized average depth (by contours) in...file reports; USGS topographic and geologic maps; AAPG -USGS special geologic maps; APL/JHU reports; VPI-SU progress re- ports to DOE/DGE; technical

An Investigation of Momentum Exchange Parameterizations and Atmospheric Forcing for the Coastal Mixing and Optics Program

DTIC Science & Technology

1998-09-01

Stenner , 1996.] Figure 2.2. Coastal Mixing and Optics central 3 m discus buoy. [From Baumgartner and Anderson, 1997 (Figure 4).] 12 2.2.2. SoNIC...Meteorology, 78, 247-290. Stenner , R., 1996: Coastal Mixing and Optics Experimental Site (http://wavelet.apl.washington.edu/CMO/CMO_bath.html). Thiermann

78 FR 36182 - APL SouthTex Transmission Company LP, Formerly TEAK Texana Transmission Company, LP; Notice of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-17

....214). Protests will be considered by the Commission in determining the appropriate action to be taken... must file a notice of intervention or motion to intervene, as appropriate. Such notices, motions, or... before the intervention or protest date need not serve motions to intervene or protests on persons other...

Theoretical Aspect of Low Pressure Discharges in Simple Gasses

DTIC Science & Technology

1994-03-28

electrons, ions and atoms satisfies the relation: NeNi /Na - [exp-Ei/T]GeGi/Ga (5.7) where Ei ionization energy and Ga - 7.*jgjaexp -{(Eja-Eoa)/T) (5.8) for...ionization with recombination gives neni /na = aiOWi (5.14) while balancing photoionization with radiative recombination gives neni /na = apl/jp (5.15

Using the annual phosphorus loss estimator (APLE) model to evaluate the University of Maryland phosphorus management tool

USDA-ARS?s Scientific Manuscript database

Maryland’s phosphorus site index (PSI) has been used to guide management decisions to minimize the potential for P loss from agricultural fields in Maryland since the adoption of the Water Quality Improvement Act of 1998. The index was recently revised and renamed the University of Maryland Phospho...

Low-Frequency Shallow Water Acoustics (20 to 500 Hz),

DTIC Science & Technology

1986-05-01

developed by Hastrup 49 and the results are shown in Figure V-1. See also Table 11-4. 20- 16.m ./ \\ 12. Fig. V-I. SILT Computed reflection loss...33-39. APL-UW 8606 91 UNIVERSITY OF WASHINGTON • APPLIED PHYSICS LABORATORY 49. O.F. Hastrup , "Some bottom-reflection loss anomalies near grazing and

APL: An Alternative to the Multi-Language Environment for Education. Systems Research Memo Number Four.

ERIC Educational Resources Information Center

Lippert, Henry T.; Harris, Edward V.

The diverse requirements for computing facilities in education place heavy demands upon available resources. Although multiple or very large computers can supply such diverse needs, their cost makes them impractical for many institutions. Small computers which serve a few specific needs may be an economical answer. However, to serve operationally…

OTEC modular experiment cold water pipe concept evaluation. Volume III. Appendices

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

Not Available

1979-04-01

The Cold Water Pipe System Design Study was undertaken to evaluate the diverse CWP concepts, recommend the most viable alternatives for a 1984 deployment of the 10 to 40 MWe MEP, and carry out preliminary designs of three concepts. The concept evaluation phase reported involved a systems analysis of design alternatives in the broad categories of rigid walled (with hinges), compliant walled, stockade and bottom mounted buoyant. Quantitative evaluations were made of concept performance, availability, deployment schedule, technical feasibility and cost. CWP concepts were analyzed to determine if they met or could be made to meet established system requirements andmore » could be deployed by 1984. Fabrication, construction and installation plans were developed for successful concepts, and costs were determined in a WBS format. Evaluations were performed on the basis of technical and cost risk. This volume includes the following appendices: (A) materials and associated design criteria; (B) summary of results of dynamic flow and transportation analysis; (C) CWP sizing analysis; (D) CWP thermal performance; and (E) investigation of the APL/ABAM CWP design. (WHK)« less

The BLAZE language: A parallel language for scientific programming

NASA Technical Reports Server (NTRS)

Mehrotra, P.; Vanrosendale, J.

1985-01-01

A Pascal-like scientific programming language, Blaze, is described. Blaze contains array arithmetic, forall loops, and APL-style accumulation operators, which allow natural expression of fine grained parallelism. It also employs an applicative or functional procedure invocation mechanism, which makes it easy for compilers to extract coarse grained parallelism using machine specific program restructuring. Thus Blaze should allow one to achieve highly parallel execution on multiprocessor architectures, while still providing the user with onceptually sequential control flow. A central goal in the design of Blaze is portability across a broad range of parallel architectures. The multiple levels of parallelism present in Blaze code, in principle, allow a compiler to extract the types of parallelism appropriate for the given architecture while neglecting the remainder. The features of Blaze are described and shows how this language would be used in typical scientific programming.

Protective Role of Spirulina platensis against Acute Deltamethrin-Induced Toxicity in Rats

PubMed Central

Abdel-Daim, Mohamed M.; Abuzead, Said M. M.; Halawa, Safaa M.

2013-01-01

Deltamethrin is a broad-spectrum synthetic pyrethroid insecticide and acaricide widely used for agricultural and veterinary purposes. However, its human and animal exposure leads to hepatonephrotoxicity. Therefore, the present study was undertaken to examine the hepatonephroprotective and antioxidant potential of Spirulina platensis against deltamethrin toxicity in male Wistar albino rats. Deltamethrin treated animals revealed a significant increase in serum biochemical parameters as well as hepatic and renal lipid peroxidation but caused an inhibition in antioxidant biomarkers. Spirulina normalized the elevated serum levels of AST, ALT, APL, uric acid, urea and creatinine. Furthermore, it reduced deltamethrin-induced lipid peroxidation and oxidative stress in a dose dependent manner. Therefore, it could be concluded that spirulina administration able to minimize the toxic effects of deltamethrin by its free radical-scavenging and potent antioxidant activity. PMID:24039839

the APL Balloonborne High Altitude Research Platform (HARP)

NASA Astrophysics Data System (ADS)

Adams, D.; Arnold, S.; Bernasconi, P.

2015-09-01

The Johns Hopkins University Applied Physics Laboratory (APL) has developed and demonstrated a multi-purpose stratospheric balloonborne gondola known as the High Altitude Research Platform (HARP). HARP provides the power, mechanical supports, thermal control, and data transmission for multiple forms of high-altitude scientific research equipment. The platform has been used for astronomy, cosmology and heliophysics experiments but can also be applied to atmospheric studies, space weather and other forms of high altitude research. HARP has executed five missions. The first was Flare Genesis from Antarctica in 1993 and the most recent was the Balloon Observation Platform for Planetary Science (BOPPS) from New Mexico in 2014. HARP will next be used to perform again the Stratospheric Terahertz Observatory mission, a mission that it first performed in 2009. The structure, composed of an aluminum framework is designed for easy transport and field assembly while providing ready access to the payload and supporting avionics. A light-weighted structure, capable of supporting Ultra-Long Duration Balloon (ULDB) flights that can last more than 100 days is available. Scientific research payloads as heavy as 600 kg (1322 pounds) and requiring up to 800 Watts electrical power can be supported. The platform comprises all subsystems required to support and operate the science payload, including both line-of-sight (LOS) and over-the-horizon (0TH) telecommunications, the latter provided by Iridium Pilot. Electrical power is produced by solar panels for multi-day missions and batteries for single-day missions. The avionics design is primarily single-string; however, use of ruggedized industrial components provides high reliability. The avionics features a Command and Control (C&C) computer and a Pointing Control System (PCS) computer housed within a common unpressurized unit. The avionics operates from ground pressure to 2 Torr and over a temperature range from —30 C to +85 C. Science data is stored on-board and also flows through the C&C computer where it is packetized for real-time downlink. The telecommunications system is capable of LOS downlink up to 3000 kbps and 0TH downlink up to 120 kbps. The pointing control system (PCS) provides three-axis attitude stability to 1 arcsec and can be used to aim at a fixed point for science observations, to perform science scans, and to track an object ephemeris. This paper provides a description of HARP, summarizes its performance on prior flights, describes its use on upcoming missions and outlines the characteristics that can be customized to meet the needs of the high altitude research community to support future missions.

Childhood Acute Myeloid Leukemia Treatment (PDQ®)—Health Professional Version

Cancer.gov

Acute myeloid leukemia (AML), juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (APL) and chronic myeloid leukemia (CML) account for about 20% of childhood myeloid leukemias. Other myeloid malignancies include transient abnormal myelopoiesis and myelodysplastic syndrome. Get detailed information about the classification, clinical presentation, diagnostic and molecular evaluation, prognosis, and treatment of newly diagnosed and recurrent disease in this summary for clinicians.

Three-Dimensional, Primitive-Variable Model for Solid-Fuel Ramjet Combustion.

DTIC Science & Technology

1984-02-01

INITIAL DISTRIBUTION LIST ,jo. of Copies 1. Library, Code 0212 2 Dean of Research, Code 012 2 Naval Postgraduate School Monterey, CA 93943 2...Dunlap I G. Jensen I P. Willoughby I P. LaForce 7. Chemical Propulsion Information Agency 2 APL-JHU Johns Hopkins Road Laurel, MD 20810 8. AFAPL 2 Wright-Patterson AFB, OH 45433 R. 0. Stull 19

TREX13 Data Analysis/Modeling

DTIC Science & Technology

2018-03-29

www.apl.washington.edu 29 Mar 2018 To: Dr. Robert H. Headrick Office of Naval Research (Code 322) 875 North Randolph Street Arlington, VA 22203-1995...Benjamin Blake Naval Research Laboratory Defense Technical Information Center DISTRIBUTION STATEMENT A. Approved for public release; distribution is... quantitatively impact sound behavior. To gain quantitative knowledge, TREX13 was designed to contemporaneously measure acoustics quantities and environmental

U.S. EPA, Pesticide Product Label, , 11/05/1985

EPA Pesticide Factsheets

2011-04-21

... Ap,l, ., p,.-~I... •• 1 ~I ••• "ra". Us. 0.75 I. I p •••• , r 100 ,.II •• s •• ,.ndiA, 00 dis •• s. ,.v.rily. ",y •• IS.. it lOountnh sp,.ys .t •• uiulnl nhs. fll' it,"1 .ppli,.tion II. ...

The Bulletin of Military Operations Research. PHALANX. Volume 31, Number 4. December 1998.

DTIC Science & Technology

1998-12-01

1999 side of our house in good order. Publica - guest speaker for the Junior and Senior The Johns Hopkins University/APL tions of the Society are being...receive "free" sug- gestions from your peers on how your analysis is going and how you can make it better. Like the 66th MORSS, the Composite Group

Acute myeloid leukemia in children: Current status and future directions.

PubMed

Taga, Takashi; Tomizawa, Daisuke; Takahashi, Hiroyuki; Adachi, Souichi

2016-02-01

Acute myeloid leukemia (AML) accounts for 25% of pediatric leukemia and affects approximately 180 patients annually in Japan. The treatment outcome for pediatric AML has improved through advances in chemotherapy, hematopoietic stem cell transplantation (HSCT), supportive care, and optimal risk stratification. Currently, clinical pediatric AML studies are conducted separately according to the AML subtypes: de novo AML, acute promyelocytic leukemia (APL), and myeloid leukemia with Down syndrome (ML-DS). Children with de novo AML are treated mainly with anthracyclines and cytarabine, in some cases with HSCT, and the overall survival (OS) rate now approaches 70%. Children with APL are treated with an all-trans retinoic acid (ATRA)-combined regimen with an 80-90% OS. Children with ML-DS are treated with a less intensive regimen compared with non-DS patients, and the OS is approximately 80%. HSCT in first remission is restricted to children with high-risk de novo AML only. To further improve outcomes, it will be necessary to combine more accurate risk stratification strategies using molecular genetic analysis with assessment of minimum residual disease, and the introduction of new drugs in international collaborative clinical trials. © 2015 Japan Pediatric Society.

KSC-04pd1366

NASA Image and Video Library

2004-06-28

KENNEDY SPACE CENTER, FLA. - At Astrotech in Titusville, Fla., technicians with The Johns Hopkins University Applied Physics Laboratory (APL) prepare one of two solar array panels on the MESSENGER spacecraft for deployment. The panels will provide MESSENGER’s power on its journey to Mercury. MESSENGER is scheduled to launch Aug. 2 aboard a Boeing Delta II rocket from Pad 17-B, Cape Canaveral Air Force Station, Fla. It will return to Earth for a gravity boost in July 2005, then fly past Venus twice, in October 2006 and June 2007. The spacecraft uses the tug of Venus’ gravity to resize and rotate its trajectory closer to Mercury’s orbit. Three Mercury flybys, each followed about two months later by a course-correction maneuver, put MESSENGER in position to enter Mercury orbit in March 2011. During the flybys, MESSENGER will map nearly the entire planet in color, image most of the areas unseen by Mariner 10, and measure the composition of the surface, atmosphere and magnetosphere. It will be the first new data from Mercury in more than 30 years - and invaluable for planning MESSENGER’s year-long orbital mission. MESSENGER was built for NASA by APL in Laurel, Md.

KSC-04pd1368

NASA Image and Video Library

2004-06-28

KENNEDY SPACE CENTER, FLA. - At Astrotech in Titusville, Fla., a technician with The Johns Hopkins University Applied Physics Laboratory (APL) watches as one of the solar array panels on the MESSENGER spacecraft is deployed. The two panels will provide MESSENGER’s power on its journey to Mercury. MESSENGER is scheduled to launch Aug. 2 aboard a Boeing Delta II rocket from Pad 17-B, Cape Canaveral Air Force Station, Fla. It will return to Earth for a gravity boost in July 2005, then fly past Venus twice, in October 2006 and June 2007. The spacecraft uses the tug of Venus’ gravity to resize and rotate its trajectory closer to Mercury’s orbit. Three Mercury flybys, each followed about two months later by a course-correction maneuver, put MESSENGER in position to enter Mercury orbit in March 2011. During the flybys, MESSENGER will map nearly the entire planet in color, image most of the areas unseen by Mariner 10, and measure the composition of the surface, atmosphere and magnetosphere. It will be the first new data from Mercury in more than 30 years - and invaluable for planning MESSENGER’s year-long orbital mission. MESSENGER was built for NASA by APL in Laurel, Md.

KSC-04pd1370

NASA Image and Video Library

2004-06-28

KENNEDY SPACE CENTER, FLA. - At Astrotech in Titusville, Fla., technicians with The Johns Hopkins University Applied Physics Laboratory (APL) check one of two solar panels on the MESSENGER spacecraft after a deployment test. The other panel is at right, undeployed. The solar arrays will provide MESSENGER’s power on its journey to Mercury. MESSENGER is scheduled to launch Aug. 2 aboard a Boeing Delta II rocket from Pad 17-B, Cape Canaveral Air Force Station, Fla. It will return to Earth for a gravity boost in July 2005, then fly past Venus twice, in October 2006 and June 2007. The spacecraft uses the tug of Venus’ gravity to resize and rotate its trajectory closer to Mercury’s orbit. Three Mercury flybys, each followed about two months later by a course-correction maneuver, put MESSENGER in position to enter Mercury orbit in March 2011. During the flybys, MESSENGER will map nearly the entire planet in color, image most of the areas unseen by Mariner 10, and measure the composition of the surface, atmosphere and magnetosphere. It will be the first new data from Mercury in more than 30 years - and invaluable for planning MESSENGER’s year-long orbital mission. MESSENGER was built for NASA by APL in Laurel, Md.

KSC-04pd1367

NASA Image and Video Library

2004-06-28

KENNEDY SPACE CENTER, FLA. - At Astrotech in Titusville, Fla., technicians with The Johns Hopkins University Applied Physics Laboratory (APL) prepare one of two solar array panels on the MESSENGER spacecraft for deployment. The panels will provide MESSENGER’s power on its journey to Mercury. MESSENGER is scheduled to launch Aug. 2 aboard a Boeing Delta II rocket from Pad 17-B, Cape Canaveral Air Force Station, Fla. It will return to Earth for a gravity boost in July 2005, then fly past Venus twice, in October 2006 and June 2007. The spacecraft uses the tug of Venus’ gravity to resize and rotate its trajectory closer to Mercury’s orbit. Three Mercury flybys, each followed about two months later by a course-correction maneuver, put MESSENGER in position to enter Mercury orbit in March 2011. During the flybys, MESSENGER will map nearly the entire planet in color, image most of the areas unseen by Mariner 10, and measure the composition of the surface, atmosphere and magnetosphere. It will be the first new data from Mercury in more than 30 years - and invaluable for planning MESSENGER’s year-long orbital mission. MESSENGER was built for NASA by APL in Laurel, Md.

GSK3 is a regulator of RAR-mediated differentiation

PubMed Central

Gupta, K; Gulen, F; Sun, L; Aguilera, R; Chakrabarti, A; Kiselar, J; Agarwal, MK; Wald, DN

2015-01-01

Acute myeloid leukemia (AML) is the most common form of leukemia in adults. Unfortunately, the standard therapeutic agents used for this disease have high toxicities and poor efficacy. The one exception to these poor outcomes is the use of the retinoid, all-trans retinoic acid (ATRA), for a rare subtype of AML (APL). The use of the differentiation agent, ATRA, in combination with low-dose chemotherapy leads to the long-term survival and presumed cure of 75–85% of patients. Unfortunately ATRA has not been clinically useful for other subtypes of AML. Though many non-APL leukemic cells respond to ATRA, they require significantly higher concentrations of ATRA for effective differentiation. Here we show that the combination of ATRA with glycogen synthase kinase 3 (GSK3) inhibition significantly enhances ATRA-mediated AML differentiation and growth inhibition. These studies have revealed that ATRA's receptor, the retinoic acid receptor (RAR), is a novel target of GSK3 phosphorylation and that GSK3 can impact the expression and transcriptional activity of the RAR. Overall, our studies suggest the clinical potential of ATRA and GSK3 inhibition for AML and provide a mechanistic framework to explain the promising activity of this combination regimen. PMID:22222598

KSC-04pd1373

NASA Image and Video Library

2004-06-28

KENNEDY SPACE CENTER, FLA. - At Astrotech in Titusville, Fla., technicians with The Johns Hopkins University Applied Physics Laboratory (APL) prepare to cover the MESSESNGER spacecraft for a move to a hazardous processing facility in preparation for loading the spacecraft’s complement of hypergolic propellants. MESSENGER is scheduled to launch Aug. 2 aboard a Boeing Delta II rocket from Pad 17-B, Cape Canaveral Air Force Station, Fla., on a journey to Mercury. It will return to Earth for a gravity boost in July 2005, then fly past Venus twice, in October 2006 and June 2007. The spacecraft uses the tug of Venus’ gravity to resize and rotate its trajectory closer to Mercury’s orbit. Three Mercury flybys, each followed about two months later by a course-correction maneuver, put MESSENGER in position to enter Mercury orbit in March 2011. During the flybys, MESSENGER will map nearly the entire planet in color, image most of the areas unseen by Mariner 10, and measure the composition of the surface, atmosphere and magnetosphere. It will be the first new data from Mercury in more than 30 years - and invaluable for planning MESSENGER’s year-long orbital mission. MESSENGER was built for NASA by APL in Laurel, Md.

KSC-04pd1372

NASA Image and Video Library

2004-06-28

KENNEDY SPACE CENTER, FLA. - At Astrotech in Titusville, Fla., technicians with The Johns Hopkins University Applied Physics Laboratory (APL) prepare the MESSESNGER spacecraft for a move to a hazardous processing facility in preparation for loading the spacecraft’s complement of hypergolic propellants. MESSENGER is scheduled to launch Aug. 2 aboard a Boeing Delta II rocket from Pad 17-B, Cape Canaveral Air Force Station, Fla., on a journey to Mercury. It will return to Earth for a gravity boost in July 2005, then fly past Venus twice, in October 2006 and June 2007. The spacecraft uses the tug of Venus’ gravity to resize and rotate its trajectory closer to Mercury’s orbit. Three Mercury flybys, each followed about two months later by a course-correction maneuver, put MESSENGER in position to enter Mercury orbit in March 2011. During the flybys, MESSENGER will map nearly the entire planet in color, image most of the areas unseen by Mariner 10, and measure the composition of the surface, atmosphere and magnetosphere. It will be the first new data from Mercury in more than 30 years - and invaluable for planning MESSENGER’s year-long orbital mission. MESSENGER was built for NASA by APL in Laurel, Md.

KSC-04pd1369

NASA Image and Video Library

2004-06-28

KENNEDY SPACE CENTER, FLA. - At Astrotech in Titusville, Fla., technicians with The Johns Hopkins University Applied Physics Laboratory (APL) monitor the progress of the solar array deployment on the MESSENGER spacecraft. The two panels will provide MESSENGER’s power on its journey to Mercury. MESSENGER is scheduled to launch Aug. 2 aboard a Boeing Delta II rocket from Pad 17-B, Cape Canaveral Air Force Station, Fla. It will return to Earth for a gravity boost in July 2005, then fly past Venus twice, in October 2006 and June 2007. The spacecraft uses the tug of Venus’ gravity to resize and rotate its trajectory closer to Mercury’s orbit. Three Mercury flybys, each followed about two months later by a course-correction maneuver, put MESSENGER in position to enter Mercury orbit in March 2011. During the flybys, MESSENGER will map nearly the entire planet in color, image most of the areas unseen by Mariner 10, and measure the composition of the surface, atmosphere and magnetosphere. It will be the first new data from Mercury in more than 30 years - and invaluable for planning MESSENGER’s year-long orbital mission. MESSENGER was built for NASA by APL in Laurel, Md.

KSC-06pd2391

NASA Image and Video Library

2006-10-25

KENNEDY SPACE CENTER, FLA. - After the mobile service tower has rolled away, the Delta II rocket with the STEREO spacecraft at top stands alone next to the launch gantry. Liftoff is scheduled in a window between 8:38 and 8:53 p.m. on Oct. 25. STEREO (Solar Terrestrial Relations Observatory) is a two-year mission using two nearly identical observatories, one ahead of Earth in its orbit and the other trailing behind. The duo will provide 3-D measurements of the sun and its flow of energy, enabling scientists to study the nature of coronal mass ejections and why they happen. The ejections are a major source of the magnetic disruptions on Earth and are a key component of space weather. The disruptions can greatly effect satellite operations, communications, power systems, humans in space and global climate. Designed and built by the Johns Hopkins University Applied Physics Laboratory (APL) , the STEREO mission is being managed by NASA Goddard Space Flight Center. APL will maintain command and control of the observatories throughout the mission, while NASA tracks and receives the data, determines the orbit of the satellites, and coordinates the science results. Photo credit: NASA/Kim Shiflett

Petroleum developments in North Africa in 1979

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

Nicod, M.A.

In the 6 countries covered by this report, the extent of valid petroleum rights, seismic work, and drilling was nearly the same as in 1978. The success rate of wildcat drilling decreased slightly, to 28% (33% in 1978), with 26 oil or gas discoveries. In southwestern Tunisia, the Amoco Sabrina Nord 1 tested 930 bbl of 39/sup 0/ APl oil from Cambrian-Ordovician sandstones - the first oil to come from lower Paleozoic rocks in Tunisia. First commercial oil from Cambrian-Ordovician rocks in western Libya was discovered by Agip A1-NC40 which flowed 1,400 b/d. Highlight of the year in North Africamore » was in the interior basin of Sudan where the Chevron Abu Gabra 1 tested 900 BOPD of 40/sup 0/ APl oil from Cretaceous rocks; 2 other wells, spudded in late 1979 in the same area, have tested 3,200 and 7,300 b/d, respectively, in early 1980. Discovery well of the interior basin was Chevron Unity 1 which tested small amounts of oil in 1978. Oil production in North Africa in 1979 averaged 3,939,500 b/d compared with 3,802,800 b/d in 1978, an increase of 3.6%.« less

Enhancement of caffeic acid phenethyl ester on all-trans retinoic acid-induced differentiation in human leukemia HL-60 cells

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

Kuo, H.-C.; Kuo, W.-H.; Lee, Y.-J.

2006-10-01

All-trans retinoic acid (ATRA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL); however, the response is sometimes very slow. Furthermore, relapse and resistance to treatment often occur despite continued treatment with ATRA. Thereafter, combination treatment strategies have been suggested to circumvent these problems. The present study demonstrates that caffeic acid phenethyl ester (CAPE), a major component of honeybee propolis, enhanced ATRA-induced granulocytic differentiation in HL-60, a human promyelocytic cell line. The differentiation was assessed by Wright-Giemsa stain, nitroblue tetrazolium reduction, and membrane differentiation marker CD11b. In addition, CAPE enhanced ATRA-induced cell cycle arrest atmore » the G1 phase by decreasing the association of cdk2-cyclin E complex. Finally, it was demonstrated that CAPE promoted the ATRA-mediated nuclear transcription activation of RAR{alpha} assessed by EMSA assay and enhanced the expression of target genes including RAR{alpha}, C/EBP{epsilon}, and p21 protein resulting in the differentiation development of leukemia. It is suggested that CAPE possesses the potential to enhance the efficiency of ATRA in the differentiation therapy of APL.« less

Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway.

PubMed

Lallemand-Breitenbach, Valérie; Jeanne, Marion; Benhenda, Shirine; Nasr, Rihab; Lei, Ming; Peres, Laurent; Zhou, Jun; Zhu, Jun; Raught, Brian; de Thé, Hugues

2008-05-01

In acute promyelocytic leukaemia (APL), arsenic trioxide induces degradation of the fusion protein encoded by the PML-RARA oncogene, differentiation of leukaemic cells and produces clinical remissions. SUMOylation of its PML moiety was previously implicated, but the nature of the degradation pathway involved and the role of PML-RARalpha catabolism in the response to therapy have both remained elusive. Here, we demonstrate that arsenic-induced PML SUMOylation triggers its Lys 48-linked polyubiquitination and proteasome-dependent degradation. When exposed to arsenic, SUMOylated PML recruits RNF4, the human orthologue of the yeast SUMO-dependent E3 ubiquitin-ligase, as well as ubiquitin and proteasomes onto PML nuclear bodies. Arsenic-induced differentiation is impaired in cells transformed by a non-degradable PML-RARalpha SUMOylation mutant or in APL cells transduced with a dominant-negative RNF4, directly implicating PML-RARalpha catabolism in the therapeutic response. We thus identify PML as the first protein degraded by SUMO-dependent polyubiquitination. As PML SUMOylation recruits not only RNF4, ubiquitin and proteasomes, but also many SUMOylated proteins onto PML nuclear bodies, these domains could physically integrate the SUMOylation, ubiquitination and degradation pathways.

Annexin A2-S100A10 heterotetramer is upregulated by PML/RARα fusion protein and promotes plasminogen-dependent fibrinolysis and matrix invasion in acute promyelocytic leukemia.

PubMed

Huang, Dan; Yang, Yan; Sun, Jian; Dong, Xiaorong; Wang, Jiao; Liu, Hongchen; Lu, Chengquan; Chen, Xueyu; Shao, Jing; Yan, Jinsong

2017-09-01

Aberrant expression of annexin A2-S100A10 heterotetramer (AIIt) associated with PML/RARα fusion protein causes lethal hyperfibrinolysis in acute promyelocytic leukemia (APL), but the mechanism is unclear. To facilitate the investigation of regulatory association between ANXA2 and promyelocytic leukemia/retinoic acid receptor a (PML/RARα) fusion protein, this work was performed to determine the transcription start site of ANXA2 promoter with rapid amplification of 5'-cDNA ends analysis. Zinc-induced U937/PR9 cells expressed PML/RARα fusion protein, and resultant increases in ANXA2 transcripts and translational expressions of both ANXA2 and S100A10, while S100A10 transcripts remained constitutive. The transactivation of ANXA2 promoter by PML/RARα fusion protein was 3.29 ± 0.13 fold higher than that by control pSG5 vector or wild-type RARα. The overexpression of ANXA2 in U937 transfected with full-length ANXA2 cDNA was associated with increased S100A10 subunit, although S100A10 transcripts remained constitutive. The tPA-dependent initial rate of plasmin generation (IRPG) in zinc-treated U937/PR9 increased by 2.13-fold, and cell invasiveness increased by 27.6%. Antibodies against ANXA2, S100A10, or combination of both all remarkably inhibited the IRPG and invasiveness in U937/PR9 and NB4. Treatment of zinc-induced U937/PR9 or circulating APL blasts with all-trans retinoic acid (ATRA) significantly reduced cell surface ANXA2 and S100A10 and associated reductions in IRPG and invasiveness. Thus, PML/RARα fusion protein transactivated the ANXA2 promoter to upregulate ANXA2 and accumulate S100A10. Increased AIIt promoted IRPG and invasiveness, both of which were partly abolished by antibodies against ANXA2 and S100A10 or by ATRA.

Proceedings of the 1993 Scientific Conference on Obscuration and Aerosol Research Held in Aberdeen Proving Ground on 22-24 Jun 1993

DTIC Science & Technology

1994-03-01

equation (4.1.27) is not a finite rank integral equation, it suggests that an approxi- mate finite rank integral equation Pf" = Pg + APL(K~p) Pfa 4 \\PNPfa...Harry Salem Richard Farrell Mark Seaver Dennis F Flanigan George Sehmel David Freund Jungshik Shin Robert H Frickel Orazio I Sindoni Edward Fry Michael

Tunable and Memory Metamaterials

DTIC Science & Technology

2015-12-02

THz beams [APL   102,   224103   (2013)]. In 2014 our group reported for the first time an observation of propagating phonon polaritons in a...Finally, we have fabricated hybrid graphene/hBN structures and proposed a new concept of a van der Walls polaritonic metamaterial. In these...structures plasmon polaritons of graphene hybridize with phonon polaritons of hBN. The hybrid polaritons DISTRIBUTION A: Distribution approved for public

High Resolution Measurements of Nonlinear Internal Waves and Mixing on the Washington Continental Shelf

DTIC Science & Technology

2015-09-30

hour tidally -resolving transects showing the generation conditions leading to wave formation 6. Nine synthetic aperture images collected during...High resolution measurements of nonlinear internal waves and mixing on the Washington continental...email: jmickett@apl.washington.edu Grant Number: N00014-13-1-0390 LONG-TERM GOALS We are interested in the general problems of internal waves and

Comparative Proteomics of Tandem Mass Spectrometry Analyses for Bacterial Strains Identification and Differentiation

DTIC Science & Technology

2012-02-01

risk, bio -terrorism utility, Homeland Security, agricultural monitoring, quality of foodstuffs, environmental monitoring, and biological warfare agents...CAL19717 Putative surface antigen CAL21872 Putative sigma 54 modulation protein NP_395233 Plasminogen activator protease precursor CAL19882 OMP...S. (2005). Chemical and biological weapons : current concepts for future defenses. Johns Hopkins APL Tech. Digest, 26, 321-333. Dworzanski, J.P

TNT Testbed for Self-Organizing Tactical Networking and Collaboration

DTIC Science & Technology

2009-06-01

Univ. of Bundeswehr - Munich Carnegie Mellon Univ. of Florida Case Virginia Tech JHU/APL WPI MIT WVHTF NDU UM, Columbia, UCSD, UCCS UC...interdicting small craft possessing nuclear radiation threat. One goal is to test the applicability of using a wireless network for data sharing ...interdiction and data sharing between boarding parties conducted in three geographically distributed locations. Each MIO experiment appears to

Accreditation of Prior Learning as a Lever for Lifelong Learning: Lessons Learnt from the New Opportunities Initiative, Portugal

ERIC Educational Resources Information Center

Carneiro, Roberto, Ed.

2011-01-01

The New Opportunities Initiative (NOI) is a Portuguese flagship programme to recognise and accredit prior learning (RPL, APL) and to endow low-skilled adults with upper secondary qualifications, which is defined as the minimum entry threshold to the exercise of a full citizenship in a knowledge-rich society. NOI's major achievement has been its…

Achieving a satisfactory clinical and biochemical response in antiphospholipid syndrome and severe thrombocytopenia with rituximab: two case reports.

PubMed

Gamoudi, Donia; Cutajar, Melanie; Gamoudi, Nadia; Camilleri, David James; Gatt, Alex

2017-06-01

In AP syndrome (APS) with severe thrombocytopenia, rituximab represents a unique drug which can balance the effect of bleeding and thrombosis. By reducing the production of autoantibodies, rituximab can simultaneously raise the platelets and reduce the chance of thrombosis by suppressing APL antibodies. Rituximab can supersede splenectomy as second-line therapy in similar patients.

APL-UW Deep Water Propagation: Philippine Sea Signal Physics and North Pacific Ambient Noise and NPANL Support

DTIC Science & Technology

2014-09-30

involve us in workshops focusing on the impact of ambient noise on the acoustic marine soundscape , and and invite DOS Kauai Linux CPU 294± ≈ 15 286... SoundScapes ” and a planning letter titled “GLOSS: GLobal Ocean SoundScapes : Phase I Connecting the worlds oceans through sound” have been produced in order

BCL-x{sub L}/MCL-1 inhibition and RARγ antagonism work cooperatively in human HL60 leukemia cells

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

Perri, Mariarita; Yap, Jeremy L.; Yu, Jianshi

2014-10-01

The acute promyelocytic leukemia (APL) subtype of acute myeloid leukemia (AML) is characterized by chromosomal translocations that result in fusion proteins, including the promyelocytic leukemia–retinoic acid receptor, alpha fusion protein (PML–RARα). All-trans retinoic acid (atRA) treatment is the standard drug treatment for APL yielding cure rates >80% by activating transcription and proteasomal degradation of retinoic acid receptor, alpha (RARα). Whereas combination therapy with As{sub 2}O{sub 3} has increased survival further, patients that experience relapse and are refractory to atRA and/or As{sub 2}O{sub 3} is a clinically significant problem. BCL-2 family proteins regulate apoptosis and over-expression of anti-apoptotic B-cell leukemia/lymphoma 2more » (BCL-2) family proteins has been associated with chemotherapeutic resistance in APL including impairment of the ability of atRA to induce growth arrest and differentiation. Here we investigated the novel BH3 domain mimetic, JY-1-106, which antagonizes the anti-apoptotic BCL-2 family members B-cell lymphoma-extra large (BCL-x{sub L}) and myeloid cell leukemia-1 (MCL-1) alone and in combination with retinoids including atRA, AM580 (RARα agonist), and SR11253 (RARγ antagonist). JY-1-106 reduced cell viability in HL-60 cells alone and in combination with retinoids. The combination of JY-1-106 and SR11253 had the greatest impact on cell viability by stimulating apoptosis. These studies indicate that dual BCL-x{sub L}/MCL-1 inhibitors and retinoids could work cooperatively in leukemia treatment. - Highlights: • Novel Bcl-x{sub L}/Mcl-1 inhibitor JY-1-106 reduces HL60 cell viability. • JY-1-106 is investigated in combination with retinoic acid, AM580, and SR11253. • AM580 is an RARα agonist; SR11253 is an RARγ antagonist. • Combined use of JY-1-106/SR11253 exhibited the greatest cell viability reduction. • JY-1-106 alone or in combination with retinoids induces apoptosis.« less

beta 2-glycoprotein I (apolipoprotein H) modulates uptake and endocytosis associated chemiluminescence in rat Kupffer cells.

PubMed

Gomes, L F; Gonçalves, L M; Fonseca, F L A; Celli, C M; Videla, L A; Chaimovich, H; Junqueira, V B C

2002-07-01

beta 2-Glycoprotein I (beta 2 GPI) is known to influence macrophage uptake of particles with phosphatidylserine containing surfaces, as apoptotic thymocytes and unilamellar vesicles in vitro. Nevertheless, effects upon macrophage activation induced by this interaction are still unknown. beta 2 GPI influence upon the reactive species production by Kupffer cells was evaluated in order to investigate whether beta 2 GPI modulates the macrophage response to negatively charged surfaces. Chemiluminescence of isolated non-parenchymal rat liver cells was measured after phagocytosis of opsonized zymosan or phorbolymristate acetate (PMA) stimulation, in the presence and absence of large unilamellar vesicles (LUVs) containing 25 mol% phosphatidylserine (PS) or 50 mol% cardiolipin (CL) and complementary molar ratio of phosphatidylcholine (PC). beta 2 GPI decreased by 50% the chemiluminescence response induced by opsonized zymosan, with a 66% reduction of the initial light emission rate. PMA stimulated Kupffer cell chemiluminescence was insensitive to human or rat beta 2 GPI. Albumin (500 micrograms/ml) showed no effect upon chemiluminescence. beta 2 GPI increased PS/PC LUV uptake and degradation by Kupffer cells in a concentration-dependent manner, without leakage of the internal contents of the LUVs, as shown by fluorescence intensity enhancement. LUVs opsonized with antiphospholipid antibodies (aPL) from syphilitic patients increased light emission by Kupffer cells. Addition of beta 2 GPI to the assay reduced chemiluminescence due to opsonization with purified IgG antibodies from systemic lupus erythematosus (SLE or syphilis (Sy) patient sera. A marked net increase in chemiluminescence is observed in the presence of Sy aPL antibodies, whereas a decrease was found when SLE aPL were added to the assay, in the presence or absence of beta 2 GPI. At a concentration of 125 micrograms/ml, beta 2 GPI significantly reduced Kupffer cell Candida albicans phagocytosis index and killing score by 50 and 10%, respectively. The present data strongly suggest that particle uptake in the presence of beta 2 GPI is coupled to an inhibition of reactive species production by liver macrophages during the respiratory burst, supporting the role of beta 2 GPI as a mediator of senescent cell removal.

Childhood acute promyelocytic leukemia: no benefit of all-trans-retinoic acid administered in a short-course schedule.

PubMed

Zubizarreta, P A; Rose, A B; Felice, M S; Alfaro, E; Delfino, S; Cygler, A M; Sackmann-Muriel, F

2000-03-01

From January 1990 to August 1997, 29 consecutive patients were treated with newly diagnosed primary acute promyelocytic leukemia (APL) at the authors' Institution. Of these, 27 (16 boys and 11 girls) were evaluable. Median age at diagnosis was 6.3 (range: 1.9-15.7) years. This population was treated with two consecutive protocols: 13 patients were included in the AML-HPG-90 protocol and 14 in the AML-HPG-95. The initial treatment was the same for both protocols: an induction 8-day phase with cytarabine, idarubicin, and etoposide was followed by a consolidation with cyclophosphamide, cytarabine, 6-mercaptopurine, vincristine, doxorubicin, and prednisone. Two courses of intensification with high-dose (HD) cytarabine and etoposide were given in the first study. Only one intensification course was administered in the second study, with HD cytarabine plus idarubicin or etoposide decided by randomization. Complete remission was achieved in 67% (18/27) of cases. Mortality on induction was quite high, 30% (8/27) mainly due to hemorrhages from disseminated intravascular coagulation (DIC). The event-free survival estimate for all patients was 0.47 (SE: 0.1). From April 1994, all-trans-retinoic acid (ATRA) was administered just during the first days of the induction phase (median: 9, range: 2-27) to stop or prevent DIC. Eighteen patients received ATRA and 9 did not. Three patients developed signs of ATRA syndrome during the first days of administration but no one died due to this toxicity. The impact of a short course of ATRA on early control of DIC was studied by analyzing the number of platelet, cryoprecipitate, and fresh frozen plasma transfusions during the induction phase in both groups. No statistical differences in complete remission rate, early mortality, need of transfusion of blood components for DIC, and survival estimates could be established between patients who received ATRA and those who did not. ATRA used in a short-course schedule during induction of APL did not stop early mortality due to DIC. Moreover, survival results did not improve with this method of ATRA usage. Longer periods of ATRA administration during APL therapy are strongly recommended.

Impact Flash Physics: Modeling and Comparisons With Experimental Results

NASA Astrophysics Data System (ADS)

Rainey, E.; Stickle, A. M.; Ernst, C. M.; Schultz, P. H.; Mehta, N. L.; Brown, R. C.; Swaminathan, P. K.; Michaelis, C. H.; Erlandson, R. E.

2015-12-01

Hypervelocity impacts frequently generate an observable "flash" of light with two components: a short-duration spike due to emissions from vaporized material, and a long-duration peak due to thermal emissions from expanding hot debris. The intensity and duration of these peaks depend on the impact velocity, angle, and the target and projectile mass and composition. Thus remote sensing measurements of planetary impact flashes have the potential to constrain the properties of impacting meteors and improve our understanding of impact flux and cratering processes. Interpreting impact flash measurements requires a thorough understanding of how flash characteristics correlate with impact conditions. Because planetary-scale impacts cannot be replicated in the laboratory, numerical simulations are needed to provide this insight for the solar system. Computational hydrocodes can produce detailed simulations of the impact process, but they lack the radiation physics required to model the optical flash. The Johns Hopkins University Applied Physics Laboratory (APL) developed a model to calculate the optical signature from the hot debris cloud produced by an impact. While the phenomenology of the optical signature is understood, the details required to accurately model it are complicated by uncertainties in material and optical properties and the simplifications required to numerically model radiation from large-scale impacts. Comparisons with laboratory impact experiments allow us to validate our approach and to draw insight regarding processes that occur at all scales in impact events, such as melt generation. We used Sandia National Lab's CTH shock physics hydrocode along with the optical signature model developed at APL to compare with a series of laboratory experiments conducted at the NASA Ames Vertical Gun Range. The experiments used Pyrex projectiles to impact pumice powder targets with velocities ranging from 1 to 6 km/s at angles of 30 and 90 degrees with respect to horizontal. High-speed radiometer measurements were made of the time-dependent impact flash at wavelengths of 350-1100 nm. We will present comparisons between these measurements and the output of APL's model. The results of this validation allow us to determine basic relationships between observed optical signatures and impact conditions.

The BLAZE language - A parallel language for scientific programming

NASA Technical Reports Server (NTRS)

Mehrotra, Piyush; Van Rosendale, John

1987-01-01

A Pascal-like scientific programming language, BLAZE, is described. BLAZE contains array arithmetic, forall loops, and APL-style accumulation operators, which allow natural expression of fine grained parallelism. It also employs an applicative or functional procedure invocation mechanism, which makes it easy for compilers to extract coarse grained parallelism using machine specific program restructuring. Thus BLAZE should allow one to achieve highly parallel execution on multiprocessor architectures, while still providing the user with conceptually sequential control flow. A central goal in the design of BLAZE is portability across a broad range of parallel architectures. The multiple levels of parallelism present in BLAZE code, in principle, allow a compiler to extract the types of parallelism appropriate for the given architecture while neglecting the remainder. The features of BLAZE are described and it is shown how this language would be used in typical scientific programming.

Association between magnetic field fluctuations and energetic particle bursts in the earth's magnetotail

NASA Technical Reports Server (NTRS)

Lui, A. T. Y.; Krimigis, S. M.; Armstrong, T. P.

1982-01-01

The association between energetic protons (0.29-0.50 MeV) and simultaneous local fluctuations of magnetic field at 35 to 45 earth radii in the magnetotail is examined statistically with data from APL/JHU particle telescopes aboard IMP 7 and IMP 8. About four satellite years of 5.5 min averaged measurements are used in this study. In addition to confirming that the level of magnetic field fluctuations generally increases with the presence of energetic protons and their streaming anisotropy, it is found that increases in occurrence frequency of streaming of energetic protons are ordered far better by magnetic field fluctuations than by proximity to the neutral sheet. However, the presence of large magnetic field fluctuations (delta B greater than 5 nT or delta B/B greater than 50%) is neither a necessary nor a sufficient condition for the detection of large streaming in energetic protons.

Excess atherosclerosis in systemic lupus erythematosus,—A matter of renal involvement: Case control study of 281 SLE patients and 281 individually matched population controls

PubMed Central

Gustafsson, Johanna T.; Herlitz Lindberg, Marie; Gunnarsson, Iva; Pettersson, Susanne; Elvin, Kerstin; Öhrvik, John; Larsson, Anders; Jensen-Urstad, Kerstin

2017-01-01

Background Systemic lupus erythematosus (SLE), is a heterogeneous disease which predominantly affects young females (90%). SLE is associated with a shorter life expectancy than in the general population. Standardized mortality ratios (SMR) of 2.4 have been reported, which is comparable to diabetes. In modern societies cardiovascular disease (CVD) is the major cause of premature mortality. Accelerated atherosclerosis is generally assumed to be the underlying cause for SLE related CVD. However, previous studies diverge regarding whether atherosclerosis is more common in SLE than in controls. With this in mind and based on own clinical experience we hypothesized that accelerated atherosclerosis is not a general feature of SLE, but prevails in SLE subgroups. Methods 281 SLE patients and 281 individually age and sex matched population controls, were investigated clinically. Fasting blood samples and risk factor data were collected. All participants were subject to B-mode ultrasonography of the carotid arteries. Carotid plaque occurrence and mean intima media thickness (mIMT) were recorded. Two SLE subgroups previously described to be at high CVD risk; 1) patients with nephritis and 2) patients with anti-phospholipid antibodies (aPL), and one subgroup reported to be at comparatively lower CVD risk; patients positive for Sjögren´s syndrome antigens A/B (SSA/SSB) antibodies were analyzed separately in comparison with their respective matched controls. Results Median age was 49 (IQR 36–59) years, 93% were females. Manifest CVD; ischemic heart, cerebro- and peripheral vascular disease, prevailed in patients (12% vs. 1%, p<0.0001). Overall plaque prevalence did not differ (20% vs. 16%), but patients had slightly higher mIMT than controls (0.56 vs. 0.53 mm, p<0.0033). After age adjustment plaques, but not mIMT, remained associated with previous CVD events. Therefore we focused further analyses on plaques, a more robust measure of atherosclerosis. Patients with nephritis (40%), but neither aPL (25%) nor SSA/SSB (40%) positive patients, had more plaques than their respective controls (23% vs. 11%, p = 0.008). Notably, patients with nephritis were younger than other SLE patients (45 vs.49 years, p = 0.02). To overcome the confounding effect of age we performed an age-matched nested case-control analysis, which demonstrated that patients with nephritis had twice as often plaques (23%) as both non-nephritis patients (11%, p = 0.038) and controls (12%, p = 0.035). Conclusions In SLE excess carotid plaques are essentially confined to the SLE subgroup with nephritis. This subgroup had plaques twice as often as age-matched non-nephritis SLE patients and population controls. Non-nephritis SLE patients, including the aPL positive subgroup, which has a high CVD risk, had similar prevalence of plaques as controls. To prevent later CVD events, this novel observation calls for risk factor screening and initiation of anti-atherosclerotic treatment selectively in SLE nephritis patients. Preferably at nephritis onset, which is often at a young age. In a general perspective this study demonstrates the importance to perform careful clinical subgroup analyses when investigating heterogeneous, hitherto not clearly defined, conditions like SLE. PMID:28414714

Comparison of two underwater acoustic communications techniques for multi-user access

NASA Astrophysics Data System (ADS)

Hursky, Paul; Siderius, T. Martin; Kauaiex Group

2004-05-01

Frequency hopped frequency shift keying (FHFSK) and code division multiple access (CDMA) are two different modulation techniques for multiple users to communicate with a single receiver simultaneously. In July 2003, these two techniques were tested alongside each other in a shallow water coastal environment off the coast of Kauai. A variety of instruments were used to measure the prevailing oceanography, enabling detailed modeling of the channel. The channel was acoustically probed using LFM waveforms and m-sequences as well. We will present the results of demodulating the FHFSK and CDMA waveforms and discuss modeling the channel for the purpose of predicting multi-user communications performance. a)Michael B. Porter, Paul Hursky, Martin Siderius (SAIC), Mohsen Badiey (UD), Jerald Caruthers (USM), William S. Hodgkiss, Kaustubha Raghukumar (SIO), Dan Rouseff, Warren Fox (APL-UW), Christian de Moustier, Brian Calder, Barbara J. Kraft (UNH), Keyko McDonald (SPAWARSSC), Peter Stein, James K. Lewis, and Subramaniam Rajan (SSI).

Orbit Determination and Navigation of the Solar Terrestrial Relations Observatory (STEREO)

NASA Technical Reports Server (NTRS)

Mesarch, Michael A.; Robertson, Mika; Ottenstein, Neil; Nicholson, Ann; Nicholson, Mark; Ward, Douglas T.; Cosgrove, Jennifer; German, Darla; Hendry, Stephen; Shaw, James

2007-01-01

This paper provides an overview of the required upgrades necessary for navigation of NASA's twin heliocentric science missions, Solar TErestrial RElations Observatory (STEREO) Ahead and Behind. The orbit determination of the STEREO spacecraft was provided by the NASA Goddard Space Flight Center's (GSFC) Flight Dynamics Facility (FDF) in support of the mission operations activities performed by the Johns Hopkins University Applied Physics Laboratory (APL). The changes to FDF's orbit determination software included modeling upgrades as well as modifications required to process the Deep Space Network X-band tracking data used for STEREO. Orbit results as well as comparisons to independently computed solutions are also included. The successful orbit determination support aided in maneuvering the STEREO spacecraft, launched on October 26, 2006 (00:52 Z), to target the lunar gravity assists required to place the spacecraft into their final heliocentric drift-away orbits where they are providing stereo imaging of the Sun.

Orbit Determination and Navigation of the Solar Terrestrial Relations Observatory (STEREO)

NASA Technical Reports Server (NTRS)

Mesarch, Michael; Robertson, Mika; Ottenstein, Neil; Nicholson, Ann; Nicholson, Mark; Ward, Douglas T.; Cosgrove, Jennifer; German, Darla; Hendry, Stephen; Shaw, James

2007-01-01

This paper provides an overview of the required upgrades necessary for navigation of NASA's twin heliocentric science missions, Solar TErestrial RElations Observatory (STEREO) Ahead and Behind. The orbit determination of the STEREO spacecraft was provided by the NASA Goddard Space Flight Center's (GSFC) Flight Dynamics Facility (FDF) in support of the mission operations activities performed by the Johns Hopkins University Applied Physics Laboratory (APL). The changes to FDF s orbit determination software included modeling upgrades as well as modifications required to process the Deep Space Network X-band tracking data used for STEREO. Orbit results as well as comparisons to independently computed solutions are also included. The successful orbit determination support aided in maneuvering the STEREO spacecraft, launched on October 26, 2006 (00:52 Z), to target the lunar gravity assists required to place the spacecraft into their final heliocentric drift-away orbits where they are providing stereo imaging of the Sun.

Electro-optic Modulation in Single-crystal Film of DAST Measured at 1.55 microns

NASA Astrophysics Data System (ADS)

Titus, Jitto; Swamy, Rajendra; Govindan Kutty, Srivatsa; Khatavkar, Sanchit; Thakur, Mrinal

2003-03-01

Exceptionally large electro-optic coefficient and high-speed modulation at 750 nm in DAST single-crystal film has been recently reported.[1] In this presentation, our measurement of electro-optic modulation in DAST single-crystal film at 1.55 microns will be discussed. The single-crystal film was prepared by the modified shear method. The modulation measurement was performed in the transverse configuration using the field-induced birefringence method. A semiconductor laser was used for this experiment. The light beam was propagated perpendicular to the film and the modulation was recorded for an ac field applied along the dipole axis on the film. About 6.5at a low field leading to a magnitude of the electro-optic coefficient (r11) of about 200 pm/V at 1.55 microns. 1. M. Thakur, A. Mishra, J. Titus and A.C. Ahyi, APL, 81 3738 (2002).

Shuttle user analysis (study 2.2): Volume 3. Business Risk And Value of Operations in space (BRAVO). Part 4: Computer programs and data look-up

NASA Technical Reports Server (NTRS)

1974-01-01

Computer program listings as well as graphical and tabulated data needed by the analyst to perform a BRAVO analysis were examined. Graphical aid which can be used to determine the earth coverage of satellites in synchronous equatorial orbits was described. A listing for satellite synthesis computer program as well as a sample printout for the DSCS-11 satellite program and a listing of the symbols used in the program were included. The APL language listing for the payload program cost estimating computer program was given. This language is compatible with many of the time sharing remote terminals computers used in the United States. Data on the intelsat communications network was studied. Costs for telecommunications systems leasing, line of sight microwave relay communications systems, submarine telephone cables, and terrestrial power generation systems were also described.

Simulation of the dusty plasma environment of 65803 Didymos for the Asteroid Impact Mission (AIM)

NASA Astrophysics Data System (ADS)

Cipriani, Fabrice; Rodgers, David; Hilgers, Alain; Hess, Sebastien; Carnelli, Ian

2016-10-01

The Asteroid Impact and Deflection Assessment mission (AIDA) is a joint European-US technology demonstrator mission including the DART asteroid impactor (NASA/JHU/APL) and the AIM asteroid rendezvous platform (ESA/DLR/OCA) set to reach Near Earth binary Object 65803 Didymos in October 2022. Besides technology demonstration in the deep space communications domain and the realization of a kinetic impact on the moonlet to study deflection parameters, this asteroid rendezvous mission is an opportunity to carry out in-situ observations of the close environment of a binary system, addressing some fundamental science questions. The MASCOT-2 lander will be released from the AIM platform and operate at the surface of the moonlet of 65803 Didymos, complemented by the ability of the Cubesat Opportunity Payloads (COPINS) to sample the close environment of the binary.In this context, we have developed an model describing the plasma and charged dust components of the near surface environment of the moonlet (170m in diameter), targeted by the MASCOT-2 lander and of the DART impactor. We performed numerical simulations in order to estimate the electrostatic surface potentials at various locations of the surface, resulting from its interaction with the solar wind plasma and solar photons. In addition, we describe charging levels, density profiles, and velocity distribution of regolith grains lifted out from the surface up to about 70m above the surface.

The effect of meteorological data on atmospheric pressure loading corrections in VLBI data analysis

NASA Astrophysics Data System (ADS)

Balidakis, Kyriakos; Glaser, Susanne; Karbon, Maria; Soja, Benedikt; Nilsson, Tobias; Lu, Cuixian; Anderson, James; Liu, Li; Andres Mora-Diaz, Julian; Raposo-Pulido, Virginia; Xu, Minghui; Heinkelmann, Robert; Schuh, Harald

2015-04-01

Earth's crustal deformation is a manifestation of numerous geophysical processes, which entail the atmosphere and ocean general circulation and tidal attraction, climate change, and the hydrological circle. The present study deals with the elastic deformations induced by atmospheric pressure variations. At geodetic sites, APL (Atmospheric Pressure Loading) results in displacements covering a wide range of temporal scales which is undesirable when rigorous geodetic/geophysical analysis is intended. Hence, it is of paramount importance that the APL signal are removed at the observation level in the space geodetic data analysis. In this study, elastic non-tidal components of loading displacements were calculated in the local topocentric frame for all VLBI (Very Long Baseline Interferometry) stations with respect to the center-of-figure of the solid Earth surface and the center-of-mass of the total Earth system. The response of the Earth to the load variation at the surface was computed by convolving Farrell Green's function with the homogenized in situ surface pressure observations (in the time span 1979-2014) after the subtraction of the reference pressure and the S1, S2 and S3 thermal tidal signals. The reference pressure was calculated through a hypsometric adjustment of the absolute pressure level determined from World Meteorological Organization stations in the vicinity of each VLBI observatory. The tidal contribution was calculated following the 2010 International Earth Rotation and Reference Systems Service conventions. Afterwards, this approach was implemented into the VLBI software VieVS@GFZ and the entirety of available VLBI sessions was analyzed. We rationalize our new approach on the basis that the potential error budget is substantially reduced, since several common errors are not applicable in our approach, e.g. those due to the finite resolution of NWM (Numerical Weather Models), the accuracy of the orography model necessary for adjusting the former as well as the inconsistencies between them, and the interpolation scheme which yields the elastic deformations. Differences of the resulting TRF (Terrestrial Reference Frame) determinations and other products derived from VLBI analysis between the approach followed here and the one employing NWM's data for obtaining the input pressure fields, are illustrated. The providers of the atmospheric pressure loading models employed for our comparisons are GSFC/NASA, the University of Luxembourg, the University of Strasbourg, the Technical University of Vienna and GeoForschungsZentrum of Potsdam.

Does sterilization with fractionated electron beam irradiation prevent ACL tendon allograft from tissue damage?

PubMed

Schmidt, T; Grabau, D; Grotewohl, J H; Gohs, U; Pruß, A; Smith, M; Scheffler, S; Hoburg, A

2017-02-01

Allografts are frequently used for anterior cruciate ligament (ACL) reconstruction. However, due to the inherent risk of infection, a method that achieves complete sterilization of grafts is warranted without impairing their biomechanical properties. Fractionation of electron beam (FEbeam) irradiation has been shown to maintain similar biomechanical properties compared to fresh-frozen allografts (FFA) in vitro. Therefore, aim of this study was to evaluate the biomechanical properties and early remodelling of grafts that were sterilized with fractionated high-dose electron beam irradiation in an in vivo sheep model. ACL reconstruction was performed in 18 mature merino mix sheep. Sixteen were reconstructed with allografts sterilized with FEbeam irradiation (8 × 3.4 kGy) and two with FFA. Eight FFA from prior studies with identical surgical reconstruction and biomechanical and histological analyzes served as controls. Half of the animals were sacrificed at 6 and 12 weeks, and biomechanical testing was performed. Anterior-posterior laxity (APL) was assessed with an AP drawer test at 60° flexion, and load to failure testing was carried out. Histological evaluation of mid-substance samples was performed for descriptive analysis, cell count, crimp and vessel density. For statistical analysis a Kruskal-Wallis test was used for overall group comparison followed by a Mann-Whitney U test for pairwise comparison of the histological and biomechanical parameters. Biomechanical testing showed significantly decreased stiffness in FEbeam compared to FFA at both time points (p ≤ 0.004). APL was increased in FEbeam compared to FFA, which was significant at 6 weeks (p = 0.004). Median of failure loads was decreased in FEbeam grafts, with 12 reconstructions already failing during cyclic loading. Vessel density was decreased in FEbeam compared to FFA at both time points, with significant differences at 12 weeks (p = 0.015). Crimp length was significantly shorter in FEbeam compared to FFA at both time points (p ≤ 0.004) and decreased significantly in both groups from 6 to 12 weeks (p ≤ 0.025). ACL reconstruction with fractionated Ebeam sterilization significantly alters the biomechanical properties and the early remodelling process of treated grafts in vivo. Therefore, this sterilization method cannot be recommended for clinical application. As substantial changes in the remodelling are inherent in this study, care in the rehabilitation of even low-dose sterilized allografts, used for ACL reconstruction, is recommended.

A matrix solution for the simulation of magnetic fields with ideal current loops

NASA Technical Reports Server (NTRS)

Stankiewicz, N.

1979-01-01

A matrix formulation is presented for describing axisymmetric magnetic field data with ideal current loops. A computer program written in APL is used to invert the matrix and hence to solve for the coil strengths which are used to represent the field data. Examples are given of the coil representation for (1) measured magnetic data, (2) refocusing fields, and (3) PPM focusing fields.

Androgen Deprivation Enhances PLZF-Repressed Cistrome that Promotes the Castration-Resistant Phenotype

DTIC Science & Technology

2015-12-01

leukemia zinc finger protein (PLZF) which plays different roles in growth control, senescence, self-renewal, and tumor suppression in various cancer types...Cancer/Prostate Cancer Foundation (SU2C/PCF) study recently revealed that ~10% of tumors harbor promyelocytic leukemia zinc finger (PLZF) genomic...promyelocytic leukemia (APL) patients [7] and was reported as an androgen-responsive tumor suppressor gene[8]. However, the role of PLZF in

United States Air Force Summer Faculty Research Program (1987). Program Technical Report. Volume 1.

DTIC Science & Technology

1987-12-01

Mechanical Engineering Specialty: Engineering Science Rose-Hulman Institute Assigned: APL 5500 Wabash Avenue - Terre Haute, IN 47803 (812) 877-1511 Dr...Professor/Di rector 1973 Dept. of Humanities Specialty: Literature/Language Rose-Hulman Inst. of Technology Assigned: HRL/LR 5500 Wabash Avenue - Terre...1976 Assistant Professor Specialty: Computer Science Dept. of Computer Science Assigned: AL Rose-Hulman Inst. of Technology 5500 Wabash Ave. Terre Haute

"Boldness be my friend" (Shakespeare; Cymbeline).

PubMed

Altman, Jessica K; Tallman, Martin S

2011-12-15

Au et al report in this issue of Blood that oral arsenic trioxide (ATO) may be safely used in maintenance therapy in acute promyelocytic leukemia (APL). This is a major improvement in convenience given that intravenous (IV)ATO requires daily administration for weeks at a time. In addition, the oral formulation may be less toxic. The time seems right to carefully explore the introduction of oral ATO earlier in treatment of the disease.

The Effects of Sand Sediment Volume Heterogeneities on Sound Propagation and Scattering

DTIC Science & Technology

2011-09-01

previously developed at APL- UW for the study of high-frequency acoustics . These models include perturbation models applied to scattering from the...shell shapes (Figure 1). The acoustic modeling to this point has utilized Ivakin’s unified approach to volume and roughness scattering [3...sediments: A modeling approach and application to a shelly sand-mud environment,” in the Proceeding of the European Conference on Underwater Acoustics

Acoustic paramagnetic logging tool

DOEpatents

Vail, III, William B.

1988-01-01

New methods and apparatus are disclosed which allow measurement of the presence of oil and water in geological formations using a new physical effect called the Acoustic Paramagnetic Logging Effect (APLE). The presence of petroleum in formation causes a slight increase in the earth's magnetic field in the vicinity of the reservoir. This is the phenomena of paramagnetism. Application of an acoustic source to a geological formation at the Larmor frequency of the nucleons present causes the paramagnetism of the formation to disappear. This results in a decrease in the earth3 s magnetic field in the vicinity of the oil bearing formation. Repetitively frequency sweeping the acoustic source through the Larmor frequency of the nucleons present (approx. 2 kHz) causes an amplitude modulation of the earth's magnetic field which is a consequence of the APLE. The amplitude modulation of the earth's magnetic field is measured with an induction coil gradiometer and provides a direct measure of the amount of oil and water in the excitation zone of the formation . The phase of the signal is used to infer the longitudinal relaxation times of the fluids present, which results in the ability in general to separate oil and water and to measure the viscosity of the oil present. Such measurements may be preformed in open boreholes and in cased well bores.

Pharmacodynamics of S-dimethylarsino-glutathione, a putative metabolic intermediate of inorganic arsenic, in mice.

PubMed

Kato, Ayaka; Kobayashi, Yayoi; Udagawa, Osamu; Hirano, Seishiro

2017-02-15

Inorganic arsenicals are well-known carcinogens, whereas arsenite (iAs III ) compounds are now recognized as potent therapeutic agents for several leukemias, and arsenic trioxide has been used for the treatment of recurrent acute promyelocytic leukemia (APL). However, recent clinical trials revealed that arsenite is not always effective for non-APL malignancies. Another arsenical, S-dimethylarsino-glutathione ([DMA III (GS)]), which is a putative metabolic intermediate in the hepatic metabolism of iAs III , shows promise for treating several types of lymphoma. However, the metabolism of [DMA III (GS)] has not been well investigated, probably because [DMA III (GS)] is not stable in biological fluids where the concentration of glutathione is low. In the present study, we injected [DMA III (GS)] intravenously into mice and compared the tissue distribution and metabolic dynamics of [DMA III (GS)] with those of sodium arsenite (NaAsO 2 ). We found a unique organ preference for the distribution of [DMA III (GS)] to the lung and brain in comparison to NaAsO 2 . Furthermore, [DMA III (GS)] appeared to bind to serum albumin by exchanging its glutathione moiety quickly after administration, providing novel insights into the longer retention of [DMA III (GS)] in plasma. Copyright © 2016 Elsevier Inc. All rights reserved.