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Zeitschriftenartikel zum Thema "UL 2 regulation"
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McCormick, Stanley R., Craig W. S. Howe, Pierre Brousset, Anil K. Tadavarthy, Cathy Quelen, Nicole Dastugue, Lisa M. Bartholomaus et al. „Myeloproliferative Neoplasm Resembling Polycythemia Vera In a Patient with t(2;11)(p21;q23) Translocation and Persistently Elevated MiR-125b-1“. Blood 116, Nr. 21 (19.11.2010): 5067. http://dx.doi.org/10.1182/blood.v116.21.5067.5067.
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Abstract Abstract 5067 Background: Hematologic neoplasms associated with the chromosomal translocation t(2;11)(p21;q23) form a distinct genetic entity with diverse manifestations, and have been strongly linked with up-regulation of the microRNA miR-125b-1 (Bousquet et al, J Exp Med, 2008). Of 41 patients with myeloid malignancies and t(2;11)(p21;23) reported in the world's literature, all but 2 were cases of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), the latter cases frequently high-grade MDS transforming to AML. In 20 of 41 cases deletion of 5q was detected as a secondary cytogenetic abnormality. Only two cases of chronic myeloproliferative disorders associated with t(2;11)(p21;23) have been reported: one of chronic myeloid leukemia with a secondary t(9;22) (Ph) translocation (Royer-Pokora et al, Leukemia, 2003) and one of polycythemia vera (Acar et al, Amer J Hematol, 2006). We encountered a patient with a mixed myelodysplastic/myeloproliferative neoplasm clinically resembling polycythemia vera that was associated with t(2;11)(p21;q23) who was found to have persistent elevation in the blood of the microRNA miR-125b-1. Case Report: A 52 year-old male presented with upper extremity pain and headache. A CBC revealed the white blood cell count was 12.5 ×103/uL (55% neutrophils, 12% lymphocytes, 8% monocytes, 5% eosinophils, 21% basophils), red blood cell count 6.62 × 106/uL, hemoglobin 22.4 g/dL, hematocrit 68.1%, MCV 103 fL, and platelets 112 × 103/uL. Bone marrow aspiration and biopsy revealed a markedly hypercellular marrow (100%) with 1+ reticulin fibrosis, mild trilineal dysplastic morphology, and a blast count of 0.8%. Cytogenetic studies disclosed 46, XY, t(2;11)(p21;q23) [4]/46, idem, del (5)(q15q31) [4]/46, XY, del (5) (q13q31) [2]/46, XY[10]. FISH studies were negative for BCR/ABL1 fusion and MLL rearrangement. Molecular analysis for the JAK2V617F allele was negative. A diagnosis of mixed myelodysplastic/myeloproliferative neoplasm, unclassified was made (WHO 2008). The patient was begun on hydroxyurea, 500 mg daily. Four months after diagnosis the blood counts were within normal range, at which time quantitative real-time PCR (qRT-PCR; Bousquet et al, J Exp Med, 2008) performed on a sample of whole blood revealed a twenty-fold elevation of the microRNA species miR-125b-1, compared to healthy donors (n=3), and JAK2V617F-negative (n=3) and JAK2V617F-positive (n=2) polycythemia vera controls. Repeat qRT-PCR performed on whole blood 15 months after diagnosis confirmed persistently elevated miR-125b-1, nearly 200-fold above healthy donor controls (n=3). 18 months after diagnosis the patient remains healthy, with normal blood counts on 500 mg of hydroxyurea daily (white blood cell count 5.54 ×103/uL, red cell count 5.35 × 106/uL, hemoglobin 13.7 g/dL, hematocrit 47.2%, MCV 88.2, platelets 132.0 × 103/uL). Conclusion: This case expands the clinical-pathologic spectrum of hematologic malignancies associated with t(2;11)(p21;23), and confirms the link between t(2;11)(p21;23) and up-regulation of miR-125b-1. Translocation t(2;11)(p21;23) with miR-125b-1 up-regulation should be considered as a rare possibility in the differential diagnosis of JAK2V617F-negative polycythemia vera. Disclosures: No relevant conflicts of interest to declare.
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Gidron, Adi, John Eklund, Brenda Martone, Alfred W. Rademaker, Charles Goolsby, Laura Marszalek und Timothy M. Kuzel. „Concurrent Treatment with Denileukin Diftitox (DD) To Deplete T-Regulatory Cells Enhances Rebound Lymphocytosis and Eosinophilia in Patients Treated with High-Dose IL-2 (HDIL-2) for Metastatic Renal Cell Cancer (MRCC).“ Blood 108, Nr. 11 (16.11.2006): 1729. http://dx.doi.org/10.1182/blood.v108.11.1729.1729.
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Abstract Background: CD4+CD25+hi T cells (Treg) play a suppressive role in immune regulation. DD is an IL-2 receptor specific cytotoxin. We postulated depletion of Treg with DD may enhance immune effector cell populations after HDIL-2 treatment, including rebound lymphocytosis and also eosinophilia which has been reported to be involved in immune response to neoplasm (Mattes J Exp Med 197: 387, 2003). Methods: In this pilot study, 12 pts (8 male, median age 58 yrs) with MRCC were tx with HDIL-2 and DD in different schedules to determine safety and effect on immune response as manifested by changes in Treg, peak lymphocyte, and eosinophil counts. Pts were treated with IL-2 600,000 IU/kg Q8H on days (d) 1–5 and 15–19. Three (group A) and 4 (group B) pts were given 6 and 9ug/kg daily on d8–10 respectively, while 5 (group C) pts received 9ug/kg of DD on d −4 to −2. Nine (group D) pts with metastatic melanoma who received HDIL-2 as above but without DD were included as controls. Flow cytometry was done on days −4, 1,8,10,15,22 for group C and on days 1,8,10,15,22 for groups B, and D. CBC was obtained concurrent or within 24 hours of flow cytometry. Group A pts were evaluated for safety only and were excluded from analysis. Results: Prior to enrollment, all pts had undergone nephrectomy and four patients received interferon-alpha. One pt from group B withdrew from study and was not included in analysis. Administration of DD resulted in a median decline of 25% in Treg number (not significant). DD given before HDIL-2 was associated with a greater increase in Treg post HDIL-2. In Group C there was an increase of rebound median Treg count of 0.88k/ul compared with 0.060k/ul in group B (p=0.025). Absolute lymphocytosis was higher in the combined group getting DD compared to control (median maximal increase of 7.6 vs 4.7 k/ul, respectively) although the difference did not reach statistical significance. However, group C pts had a greater increase in absolute lymphocytosis than did group B pts in which absolute lymphocytosis actually decreased (median increase 10.6 vs. median decrease 0.4 k/ul, p=0.025). A higher peak level of eosinophilia was noted in groups B and C compared with group D (mean increase of 10.5 vs. 4.0 k/ul p=0.2). Group C had a greater peak eosinophilia than group B (11.2 vs 2.2 k/ul p=0.053) Toxicity was manageable and consistent with those seen with HDIL-2. Median HDIL-2 dose given was 21 (range, 14–28). No clinical responses were observed. Of 11 pts included in the analysis 1 pt from group A expired 68 weeks after enrollment. All remaining patients are alive. Survival from enrollment ranges from 11 to 93 weeks. Conclusion: Overall, the combination of DD and HDIL-2 results in a stimulatory effect as manifested by increased rebound lymphocytosis and eosinophilia compared to HDIL-2 alone. Administration of DD in conjunction with HDIL-2 was associated with a rebound in Treg that may be schedule and dose dependent. The results suggest an enhanced immune stimulatory effect as manifested by lymphocytosis and peak eosinophilia in group C. However, this stimulatory effect also extends to Treg that may prove detrimental clinically. Further exploration of these effects in immunotherapy naïve patients would be beneficial.
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Koltsova, Alla S., Olga A. Efimova, Anna A. Pendina, Olga G. Chiryaeva, Natalia S. Osinovskaya, Natalia Y. Shved, Maria I. Yarmolinskaya et al. „Uterine Leiomyomas with an Apparently Normal Karyotype Comprise Minor Heteroploid Subpopulations Differently Represented in vivo and in vitro“. Cytogenetic and Genome Research 161, Nr. 1-2 (2021): 43–51. http://dx.doi.org/10.1159/000513173.
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In the present study, we aimed to check whether uterine leiomyomas (ULs) with an apparently normal karyotype in vitro comprise “hidden” cell subpopulations with numerical chromosome abnormalities (heteroploid cells). A total of 32 ULs obtained from 32 patients were analyzed in the study. Each UL was sampled for in vivo and in vitro cytogenetic studies. Karyotyping was performed on metaphase preparations from the cultured UL samples. A normal karyotype was revealed in 20 out of the 32 ULs, of which 9 were selected for further study based on the good quality of the interphase preparations. Then, using interphase FISH with centromeric DNA probes, we analyzed the copy number of chromosomes 7 and 16 in 1,000 uncultured and 1,000 cultured cells of each selected UL. All of the ULs included both disomic cells representing a predominant subpopulation and heteroploid cells reaching a maximum frequency of 21.6% (mean 9.8%) in vivo and 11.5% (mean 6.1%) in vitro. The spectrum of heteroploid cells was similar in vivo and in vitro and mostly consisted of monosomic and tetrasomic cells. However, their frequencies in the cultured samples differed from those in the uncultured ones: while the monosomic cells decreased in number, the tetrasomic cells became more numerous. The frequency of either monosomic or tetrasomic cells both in vivo and in vitro was not associated with the presence of <i>MED12</i> exon 2 mutations in the tumors. Our results suggest that ULs with an apparently normal karyotype consist of both karyotypically normal and heteroploid cells, implying that the occurrence of minor cell subpopulations with numerical chromosome abnormalities may be considered a characteristic of UL tumorigenesis. Different frequencies of heteroploid cells in vivo and in vitro suggest their dependence on microenvironmental conditions, thus providing a pathway for regulation of their propagation, which may be important for the UL pathogenesis.
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Gidron, A., J. Eklund, B. Mortone, A. W. Rademaker, C. Goolsby und T. Kuzel. „Treg depletion with denileukin difititox (DD) enhances lymphocytosis and eosinphilia in patients treated with high-dose IL-2 (HDIL-2) for metastatic renal cell cancer (MRCC)“. Journal of Clinical Oncology 24, Nr. 18_suppl (20.06.2006): 14627. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.14627.
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14627 Background: CD4+CD25+ T cells (Treg) play a suppressive role in immune regulation. DD is an IL-2 receptor specific cytotoxin. We postulated depletion of Treg with DD may enhance immune effector cell populations during HDIL-2 tx, including eosinophilia which was reported to be involved in immune response to neoplasm (Mattes et al. J Exp Med 197: 387, 2003). Methods: Seven pts (5 male, median age 58 yrs) with MRCC were tx’d with HDIL-2 and DD in different schedules to determine safety and effect on immune response as manifested by changes in Treg, lymphocyte, and peak eosinophil counts. Pts were tx’d with IL-2 600,000 IU/kg Q8H on days (d) 1–5 and 15–19. Three (group A) and 2 (group B) pts were given 6 and 9 ug/kg daily on d 8–10 respectively, while 2 (group C) pts received 9 ug/kg of DD on d -4- -2. Four (group D) pts with metastatic melanoma who received HDIL-2 as above but without DD were included as controls. Flow cytometry was done on days -4, 1,8,10,15 for group C and on days 1, 8, 10, 15, 22 for groups A, B, and D. CBC was obtained within 24 hours of flow cytometry. Results: After DD Treg increased in group A (mean change in absolute T-reg count of 16%) and decreased in groups B and C (34.5 and 20% respectively) compared to baseline. Group C trended toward a greater lymphocytosis at day 8 compared to all other groups (mean increase of 8.6 vs. 3.3 K/ul p = 0.059). A higher peak level of eosinophilia was noted in group C compared with groups A, B and D combined (mean increase of 9.9 vs. 3.0 k/ul p = 0.03). Group C demonstrated a higher mean % change in absolute number of CD8+ T-cells between onset of therapy and Day 8 compared to groups A, B, D combined (increase of 1095% vs. 496% respectively, p = 0.35). Toxicity was similar to that expected with HDIL-2. Conclusions: Administration of DD in conjunction with HDIL-2 was associated with a decrease in Treg that may be schedule and dose dependent. The results suggest an enhanced immune stimulatory effect as manifested by lymphocytosis and peak eosinophilia and CD8+ T-cells in group C. Despite small pt numbers, results suggest that pre-treatment with DD may confer an advantage. It is too early to know if laboratory results correlate to clinical benefit. [Table: see text]
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Rajasekar, Reena M., Vikram Mathews, Kavitha M. Lakshmi, Auro Viswabandya, Biju George, Mammen Chandy und Alok Srivastava. „Dendritic Cell Type 2 Counts on Day 28 in HLA-Matched Related Allogeneic PBSCT Predicts the Incidence of Acute and Chronic GVHD.“ Blood 108, Nr. 11 (16.11.2006): 2893. http://dx.doi.org/10.1182/blood.v108.11.2893.2893.
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Abstract Dendritic cells (DC) are antigen-presenting cells involved in induction and regulation of immune responses. We investigated the impact of the number of infused and engrafted (day 28) dendritic cells, DC1 (lin−HLA-DR+CD11c+) and DC2 (lin−HLA-DR+CD123+) on the development of acute and chronic graft-versus-host disease (GVHD). Thirty three consecutive patients with hematological malignancies who underwent HLA-matched related G-CSF mobilized allogeneic PBSCT were included in the analysis. The mean follow up was 293 days (range: 36–417). There were 20 males and 13 females (median age: 29 years, range: 15–55). Conditioning regimen was myeloablative in 25 (Bu/Cy=13; Cy/TBI = 12) and non myeloablative in 8 patients (Flu/Mel = 7; Flu/Cy = 1). All patients received cyclosporine and short course methotrexate as GVHD prophylaxis. Three of them received steroids before day 28 for treatment of GVHD. Ten patients developed acute GVHD (grade II–IV) and 11 patients had chronic GVHD. The median DC2 count in the peripheral blood on day 28 was significantly lower among patients who developed acute GVHD as compared to those who did not and there was a trend to a lower count among patients with chronic GVHD [Table 1]. Based on the day 28 DC2 count patients were divided into a low DC2 quartile (<2.3cell/ul, n=8) and the rest were grouped as high DC2 (>2.3cell/ul, n=25). The two groups were comparable with regard to patient and graft characteristics (CD34, CD133, CD3, CD4, CD4CD45RO, CD4CD45RA, CD8, CD8CD45RO, CD8CD45RA, CD19, NK, DC1and DC2 cell dose). Patients in the low DC2 quartile group had higher probability of developing acute (P=0.000) and chronic GVHD (P= 0.022). Cox regression analysis revealed that low day 28 DC2 counts is associated with higher incidence of acute GVHD (HR=11.4; 95%CI=2.9–44.9; P=0.001) and chronic GVHD (HR=7.07; 95%CI=1.9–26.6; P=0.004). In a multivariate analysis which included other standard risk factors such as female to male transplants, conditioning regimen, CD34 and CD3 cell dose, low day 28 DC2 was found to be a risk factor for acute GVHD (HR=21.1; 95%CI=3–149.9; P=0.002) together with patient age (HR=1.1; 95%CI=1–1.3; P=0.039). DC1, DC2 counts in the graft and day 28 DC1 count did not correlate with the development of acute or chronic GVHD. Excluding patients who had developed acute GVHD before day 28 (n=3), a low day 28 DC2 count (<2.3/ul) had a positive predictive value of 80% for acute GVHD and 75% for chronic GVHD. These results suggest that the DC2 count in the peripheral blood on day 28 is a strong predictor for development of GVHD in recipients of PBSC in matched related allogeneic HSCT. Table 1: Median day 28 DC2 count and GVHD n, median DC2 x 103/ml (range) Yes No P-value Acute GVHD (II=IV) 10, 2.06(0.6–24.8) 23, 11.5(1.1–46.6) 0.004 Chronic GVHD 11, 2.4(1.1–46.6) 17, 8.19(1.6–44.9) 0.070
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Ohno, Tsunehisa, Mi Jin Yoo, Erik R. Swanson, Shigeru Hirano, Robert H. Ossoff und Bernard Rousseau. „Regenerative Effects of Basic Fibroblast Growth Factor on Extracellular Matrix Production in Aged Rat Vocal Folds“. Annals of Otology, Rhinology & Laryngology 118, Nr. 8 (August 2009): 559–64. http://dx.doi.org/10.1177/000348940911800805.
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Objectives We investigated acute changes in extracellular matrix (ECM) gene expression and histologic changes in the deposition of collagen and hyaluronan (hyaluronic acid; HA) after basic fibroblast growth factor (bFGF) treatment of the aged rat vocal fold. Methods For the polymerase chain reaction (PCR) experiments, we divided ten 18-month-old Sprague-Dawley rats into two groups that received serial injections of sham (saline solution) or bFGF (2 ng/uL) and euthanized them 2 weeks after the initial injection to investigate acute changes in ECM gene expression. We treated a separate group of 5 animals unilaterally and sacrificed them 4 weeks after the initial injection to investigate histologic changes in the deposition of collagen and HA. Results Real-time PCR revealed significantly up-regulated HA synthase (HAS)-2, HAS-3, matrix metalloproteinase (MMP)-2, and procollagen type I gene expression in the bFGF treatment group as compared to the sham treatment group. Histologic staining revealed significantly increased deposition of HA in the bFGF-treated vocal fold as compared to the sham-treated vocal fold. No differences in ECM collagen levels were observed between treatment sides. Conclusions Basic fibroblast growth factor induced the up-regulation of HAS-2, HAS-3, MMP-2, and procollagen type I. Histologically, aged vocal folds treated with bFGF revealed increased deposition of HA as compared to sham-treated vocal folds.
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Matsuoka, Ken-ichi, John Koreth, Haesook T. Kim, O. Gregory Bascug, Sean McDonough, Joseph H. Antin, Robert Soiffer und Jerome Ritz. „Effects of Daily Low Dose IL-2 Therapy on Homeostatic Regulation of CD4+Foxp3+ Regulatory T Cells In Patients with Chronic Graft-Versus-Host Disease“. Blood 116, Nr. 21 (19.11.2010): 895. http://dx.doi.org/10.1182/blood.v116.21.895.895.
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Abstract Abstract 895 CD4+FoxP3+ regulatory T cells (Treg) play a central role in the maintenance of tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) and recent studies have demonstrated that Treg deficiency leads to the development of chronic GHVD (cGVHD). Interleukin-2 (IL-2) is known to promote thymic generation and maintenance of peripheral Treg and IL-2 deficiency results in a profound deficiency of Treg in vivo. Based on these findings we initiated a clinical trial to evaluate the safety, clinical efficacy and immunologic effects of low dose recombinant IL-2 in patients with steroid-refractory cGVHD. We recently reported the clinical outcomes of this trial demonstrating that IL-2 administration preferentially increased Treg in patients with active cGVHD and resulted in clinical improvement with only minor toxicities (Koreth et al, ASBMT 2010). However, the mechanisms responsible for Treg expansion in patients during IL-2 administration have not been characterized. To elucidate these mechanisms, we examined phenotypic and functional characteristics of Treg in 14 patients who received daily subcutaneous IL-2 (3×105-3×106IU/m2/day) for 8 weeks. Peripheral blood samples were obtained before and at 1, 2, 4, 6, 8, 10 and 12 weeks after starting IL-2. Treg were compared to conventional CD4+FoxP3- T cells (Tcon) within individual patient samples and examined for expression of Ki-67, PD-1 and BCL-2. In some experiments, Treg and Tcon were further divided into subpopulations by the expression of CD45RA and CD31. Absolute numbers of functionally suppressive Treg increased 5-fold in the first 4 weeks of therapy. Treg numbers then slowly decreased despite continued IL-2 therapy, but remained 2-fold higher than baseline at 8 weeks. Absolute numbers of Tcon increased 2-fold in the first 4 weeks and then returned to baseline levels at 8 weeks. This resulted in a sustained increase of Treg/Tcon ratio for the entire duration of therapy, which persisted for at least 4 weeks after treatment was completed. Plasma IL-2 levels peaked at 1 week and gradually declined despite continued treatment at the same dose. Nevertheless, IL-2 levels remained significantly higher than baseline throughout treatment (median 1.4pg/ml at baseline and 18.1pg/ml at 8 weeks, p<0.05). The proliferative response to IL-2 was examined by measuring expression of Ki-67 in each subset. Initially, Ki-67 expression in Treg rapidly increased in an IL-2 dose-dependent manner. Ki-67 also increased in Tcon but at a significantly lower level (median 20.0% Treg vs 6.7% Tcon, p=0.0001). Increased Ki-67 was seen in both CD45RA+CD31+ recent thymic emigrant Treg (RTE-Treg) and CD45RA- activated/memory Treg (MEM-Treg) at similar levels (median 20.1% and 18.5%, respectively, p=0.54). Treg proliferation peaked in the first week of IL-2, and rapidly returned to baseline levels in weeks 2–3. Despite changes in proliferation, the absolute number of RTE-Treg remained significantly elevated (median 1.05/ul at baseline, 9.43/ul at 4 weeks, p=0.001). In contrast, the absolute number of RTE-Tcon did not change. Phenotypic analysis of Treg showed that expression of both PD-1 and BCL-2 increased during IL-2 therapy (%PD-1+ Treg; median 15.7% at baseline and 38.3% at 8 weeks, p=0.02: relative BCL-2 MFI; median 1.00 at baseline and 1.59 at 8 weeks, p=0.04). To determine the functional effects of these changes on susceptibility to apoptosis, Treg and Tcon were purified and cultured with or without agonistic FAS antibody, and apoptosis was measured using Annexin-V staining. Remarkably, Treg obtained during IL-2 therapy were relatively resistant to apoptosis compared to baseline. In summary, these results indicate that the selective expansion of Treg during prolonged IL-2 administration is characterized by a series of homeostatic changes. Initial high levels of IL-2 lead to selective and rapid Treg proliferation. Treg proliferation is not maintained as numbers of Treg increase and IL-2 levels decrease. Subsequent maintenance of increased Treg appears to be mediated primarily by increased resistance to apoptosis and prolonged survival. Increased thymic output of Treg also appears to support this peripheral homeostatic process. These findings demonstrate the complex effects of IL-2 on Treg homeostasis and provide important information for developing strategies to promote immune tolerance. Disclosures: No relevant conflicts of interest to declare.
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Abrahamsson, Annelie, Ifat Geron, Jason Gotlib, Jeffrey Durocher, Remi Creusot, Edward Kavalerchik, Daniel Goff et al. „Aberrant Regulation of Wnt/Beta-Catenin Pathway Mediators in Chronic Myelogenous Leukemia Stem Cells.“ Blood 108, Nr. 11 (01.11.2006): 2135. http://dx.doi.org/10.1182/blood.v108.11.2135.2135.
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Abstract Background Recent research suggests that self-renewing leukemia stem cells (LSC) with increased beta-catenin expression are involved in chronic myelogenous leukemia (CML) progression. We investigated whether aberrant regulation of beta-catenin destruction complex genes contributed to the enhanced self-renewal potential of CML LSC. Methods FACS Aria purified normal and CML hematopoietic stem cells (HSC), granulocyte-macrophage progenitors (GMP) and lineage positive cells were transduced for 48 hours with lentiviral luciferase GFP and transplanted intrahepatically into newborn RAG2−/−gama−/− mice. At 8 to 12 weeks human CD45+ cells were FACS-purified and transplanted into secondary recipients to establish a bioluminescent CML LSC model. RT-PCR for BCR-ABL was used to confirm CML engraftment. Wnt mediator mutation analysis was performed on cDNA via fluorescent denaturing high performance liquid chromatography (DHPLC) technology and SURVEYOR mismatch cleavage analysis both with the WAVE-HS System (Transgenomic, Gaithersberg, MD). Aliquots of PCR product (3-15 ul) from all samples were scanned for mutations by DHPLC and confirmed by Surveyor mismatch cleavage, and identified with bidirectional sequence analysis on an ABI 3100 sequencer using BigDye V3.1 terminator chemistry. Quantitative RT-PCR was also performed on CML progenitors using destruction complex gene specific primers. FACS analysis was performed with the aid of a FACS Aria to analyze changes in Wnt signaling pathway mediators. Results Advanced phase CML was typified by expansion of a GMP population with aberrantly activated beta-catenin expression, enhanced in vitro replating capacity as well as serial transplantation potential in a CML LSC bioluminescent imaging model suggesting that the GMP population was enriched for LSC (Figure 1). A targeted Wnt mutation analysis revealed a mutation in a key component of the beta-catenin destruction complex - glycogen synthase kinase 3beta (GSK) in progenitors from three of six blast crisis CML samples analyzed. Decreased GSK expression was confirmed via FACS analysis using a GSK specific antibody in three separate experiments with CML blast crisis progenitors (Figure 2). Some CML blast crisis progenitors also demonstrated a decrease in axin 2 by quantitative RT-PCR. Conclusions Altered expression of Wnt signaling pathway regulators, such as GSK3, may result in increased LSC self-renewal capacity and may represent novel therapeutic targets for advanced phase CML. Figure 1. Bioluminescent Chronic Myeloneous Leukemis stem cell Model Figure 1. Bioluminescent Chronic Myeloneous Leukemis stem cell Model Figure 2. GSK FACS Analysis. Figure 2. GSK FACS Analysis.
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Selasih, Ni Nengah. „PERANAN SENTRAL GURU AGAMA HINDU DALAM PENCAPAIAN TUJUAN PENDIDIKAN NASIONAL DI INDONESIA DAN PEMBANGUNAN KARAKTER BANGSA YANG BERAKHLAK MULIA, JUJUR, TERAMPIL, BERHATI SUCI DAN BERSIH LAHIR BATIN“. Jurnal Penjaminan Mutu 1, Nr. 1 (09.02.2016): 54. http://dx.doi.org/10.25078/jpm.v1i1.39.
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<p><em>The teachers of Hindu religion classes play central role in the effort to reach the goal of the national education as well as to build the characters that include honesty, skillfullness, clean and good-heartedness, as described in the national standard of education regulation No 20/2003 in which it states that the curriculum has to provide religious education (Pasal 37 UU Sisdiknas). The government attention to the education is implemented too by the issue of the Regulation on Teachers and Lecturers which states that teachers are professional educators with main duty to educate, teach, guide, train, and evaluate the students in the formal elementary, secondary, and high schools (UU RI No. 14/2005) Purwanto (2004:10).Education is the intentional enlightening from the adult to the younger ones in relation to their development in order to make them useful for themselves and in the society“</em><em></em></p><p><em>The Indonesian national education systemas stated in UU No.2/1989 Bab, II, pasal 4, states that the goal of the education is to develop a complete Indonesia people who are religious, good in their characters, have good knowledge and skills, healthy physically and mentally, independent, responsible for the society and nation. In line with that, the Hindu teachers should refer to the Vedic teachings and consider the physical, psychological, and social environments of study, the life as students (</em>Sisya/Brahmacari<em>), their roles (</em>Acarya<em>), the curriculum, the mteaching methods, as well as the goal of the education. These all should be centered on </em><em></em></p><ul><li><em>teaching with the emphasis on directing and motivating to reach the character building</em></li><li><em>facilitating that through learning experience </em></li><li><em>helping to develop attitudes, values, and self adaptation </em></li></ul><p class="ParaAttribute1"><em>At schools teachers should commit themselves to be 1) role models, 2) inspirators, 3) motivators, 4) regulator, 5) evaluator besides having good vision. Without these all, the goal of education will fail. </em><em></em></p>
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Geer, Eliza B., Lilian Varricchio, Fabrizio Martelli, Wu He, Lizette Couto, Yelena Lazar, Vanessa Cohen und Anna Rita Migliaccio. „Glucocorticoid Regulation of Erythropoiesis in Humans: A Study of Patients with Cushing's Disease“. Blood 126, Nr. 23 (03.12.2015): 2135. http://dx.doi.org/10.1182/blood.v126.23.2135.2135.
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Abstract Cushing's disease (CD) is a rare endocrine disorder (1.2-2.4/million/year) characterized by chronic excess endogenous glucocorticoids (GC) due to an adrenocorticotropic hormone-secreting pituitary adenoma. Untreated CD results in increased mortality and multiple morbidities (obesity, diabetes, hypertension, cardiovascular disease) and, in one case report, erythrocytosis (Gursoy et al, J End Invest. 2006;29:742). The effects of chronic GC exposure on erythropoiesis in a CD cohort have not yet been studied. We prospectively quantified hematocrit (Hct), hemoglobin (Hb) and platelets (ptl) values in CD patients before (v1) and after surgical remission (v2, mean time since surgery=14.5 months) and in matched healthy controls (HC). Frequency, antigenic profiling and erythroid (Ery) expansion potential of circulating hematopoietic progenitor cells (HPC) in the three cohorts were also evaluated. The subjects analyzed included 28 v1 [6 males, 22 females, mean age=41 years; body mass index (BMI)=33.3 kg/m2 ] and 13 HC [2 males, 11 females, mean age=41 years; BMI=30.7 kg/m2 (range 26.7-34.7, p=0.073). Eleven patients were analyzed over time in both v1 and v2. Mean cortisol in v1 (22.2±6.3 ug/dL) was higher than in HC (8.5±3.8 ug/dL, p=3.4E-07) and decreased in v2 (17.6±5.1% vs. 8.7±3.9%, N= 11, p=0.0006). Hct was higher in v1 than in HC (39.8±4.7%, vs. 38.8±2.7%, p = 0.045). In the 11 patients analyzed over time, hct decreased in v2 vs. v1 (39.2±4.7% vs. 42.3±4.4%, p=0.011). Hb in v1 was not different than in HC (13.10±1.6 vs. 13.12±3.8 g/dL, p =0.225) but decreased in patients studied both in v1 and V2 (14.1±1.5 g/dL vs. 13.2±1.8 g/dL, p=0.009). Similarly, plts were not different in v1 and HC (272.3±81.4 vs. 240.8±76.0 K/uL, p=0.274) but decreased in v2 (307.7±112.1 vs. 270.6±74.5 K/uL, p=0.021). In v1, Hct did not correlate with serum (R = 0.34, p = 0.33) or 24h urine (R = 0.072, p = 0.73) cortisol concentrations. There was no difference in frequency of HPC among v1, v2 and HC [2.6±3.0, 0.34±0.28 and 1.26±0.67% of CD34+ cells and 30.2±27.2, 23.7±13.2 and 16.5±11.5 CFC/105 mononuclear cells (MNC) in v1, v2 and HC]. CD34pos cells from all groups expressed similar levels of cKIT, IL-3Rβ and prominin1, but a greater proportion of those from v1 and v2 expressed thrombospondin and thrombopoietin (Mpl) receptors than those from HC (2 vs 0.4%), suggesting that CD HPC are biased toward erythro-megakaryocytopoiesis. Consistently, in cultures without the synthetic GC dexamethasone (Dex), MNC from v1 (12±6 %) and v2 (19%) generated in 10 days a greater proportion of Erys than MNC from HC (2±1% ). However, in cultures with Dex, MNC from v1 (48±25), but not those from v2 (70±23), generated less Erys than MNC from HC (83±26 , p=0.03), suggesting that Erys from v1 HPC respond poorly to Dex. This was tested by comparing the ability of Dex to induce biochemical (GRα phosphorylation at S211 and cell-surface expression of CXCR4/calreticulin) and biological (proliferation in synergy with growth factors, GFs) responses in Erys from CD and HC. Erys from v1, v2 and HC expressed equivalent levels of GRα but those from v1 Erys contained lower levels of pGRαS211/S203 than those from v2 or HC (Fig 1A). In contrast with HC Erys, Dex decreased GRα and did not induce pGRαS211 in v1 Erys (Fig 1B). Moreover, Dex increased cell-surface expression of CXCR4 (MFI from 580 to 700) and calreticulin (MFI from 300 to 700) and proliferation (by 30%) in HC Erys but not in those from v1 s (CXCR4 MFI from 278 to 154, calreticulin MFI from 136 to 152; proliferation increases by 6%). These results indicate that chronic GC excess increases Hct values but may also activate a post-transcriptional mechanism that reduces GRα expression inducing desensitization of erythroid cells to GC. Figure 1. A) Levels of total, pS211 and pS203 GRα in Erys from HC, v1 and v2. B) levels of GRα and GRα phosphorylated at pS203 in Erys from HC and v1 exposed from 15' to Dex alone or in combination with the GR inhibitor RU486. Figure 1. A) Levels of total, pS211 and pS203 GRα in Erys from HC, v1 and v2. B) levels of GRα and GRα phosphorylated at pS203 in Erys from HC and v1 exposed from 15' to Dex alone or in combination with the GR inhibitor RU486. Disclosures No relevant conflicts of interest to declare.
Dissertationen zum Thema "UL 2 regulation"
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Serediuk, Vadym. „Návrh průkazných statických pevnostních zkoušek letounu v kategorii UL“. Master's thesis, Vysoké učení technické v Brně. Fakulta strojního inženýrství, 2021. http://www.nusl.cz/ntk/nusl-443247.
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The diploma thesis involves the design of certification static strength tests for the newly developed aircraft of the TL-Ultralight company. At the beginning of the work, the theory of aircraft testing is generally discussed with emphasis on static strength tests. Furthermore, an analysis of the requirements of the Czech regulation UL 2 and the German LTF-UL, which represent the certification basis for this aircraft, is performed. The requirements of regulations on the construction of the aircraft (or its individual parts) and the requirements for strength tests are discussed in detail. Based on the regulation and the provided calculation protocols, individual test cases and test plans of the wing, tail surfaces, engine bed, and chassis are calculated and prepared. In the end, the calculation of the rocker system and the basic design of jigs are performed.
Buchteile zum Thema "UL 2 regulation"
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„and T B ab F le 5 shows 6%. Th R e -1 mobsyt several FR-HIPS f ec atliovgeen le v (5 el .8 o5f % ano ti fmeoarcmh) ulw at h io e n re stuhse ing a1:1 mixture of Dechlorane Plus at 3.2 mm. The lowest afterglow is al osnoyaotx th id ee4s % ee m s material decreases the afterglow in the UL-94 test an level. e T he wh d gives aUaL dd -9 it“. In Tomorrows Trends in Fire Retardant Regulations, Testing, and Applications, 43. CRC Press, 1996. http://dx.doi.org/10.1201/9781498705837-2.
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„bro Tmaibnlaet ed 2 gives several FR-ABS formulation using a mixture of chlorinated and ( TFhoermhu ig la hte io stf la o m xy egreen ta ridnadnetxs . is Thoebtoax in ygen index n #3). This is also the only efdorwmhue la ntetshefrreom is th ais1t : a1b le miisxtpulroet te odf in C ion that is UL-94 V-0 at both 3.2lFiagnudreB4r . 1.6 mm. mm and mix Ttaub re le oxygen iC3lasn ho dws the ndex is B re raicnhth re e sults of using d ed aftoarbmouultat6i % on . anI ti tiafp fe preeanrtsafm ro omunatsp of mony oxide (Figu lroetaonf tim 3). this ondyattar , i o th x a id teawmia th x im au1m :1“. In Tomorrows Trends in Fire Retardant Regulations, Testing, and Applications, 37–41. CRC Press, 1996. http://dx.doi.org/10.1201/9781498705837-0.
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Bussel, J. „FOR MODULATION AS A MEANS OF ELEVATING THE PLATELET COUNT IN ITP“. In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644761.
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ITP is an autoantibody-mediated disease which would logically be treated by decreasing the level of autoantibody. However, the most exciting developments in understanding the pathophysiology of the thrombocytopenia and its treatment involve a better understanding of the MPS FcR system and ways in which it can be modulated. This work has focussed on phagocytic paralysis or FcR blockade (FcRBl): the slowing of destruction of antibody-coated platelets despite the persistent presence of antibody on the surface of the platelet.Several areas have been explored in learning about the MPS system. Investigation by Kurlander among others have revealed that at least 2 FcR's exist on mononuclear phagocytes: one with high and one with low affinity for monomeric IgG. Study of the high affinity FcR expressed by circulating monocytes, by Schreiber among others, has explored the effect of Danazol to decrease the expression of this FcR. The clinical relevance of this receptor is uncertain however because it is saturated in vitro by physiologic concentrations of IgG. Unkeless defined the properties of the low affinity "immune complex" FcR, expressed on macrophages and neutrophils, via monoclonal antibody 3G8 (see below) which blocks ligand binding to this FcR. The exact roles of these two, and possibly more, FcR's are being explored. Another still unsolved controversy involves whether the interaction Fc portions of antibodies coating particles with FcR's is mediated by a conformational change of the Fc portion or by a multipoint attachment of several Fc parts.Studies by Mollison in the 60's demonstrated that the MPS had a limited capacity for removal of antibody-coated (red) cells. Shulman pursued MPS modulation by exploring the inhibition of thrombocytopenia caused by infusion of ITP plasma into normals. Kelton demonstrated that "compensated" ITP may be caused by a decreased clearance of antibody-coated cells and that the rate of clearance of antibody-coated cells may be correlated with rate of clearance of antibody-coated cells may be correlated with the intrinsic levels of IgG. Stossel investigated FcRBl as a mechanism of effect of corticosteroids and related it clinically. Subsequently intravenous gammaglobulin (IVGG) was introducedas a treatment of ITP and Fehr et al first demonstrated FcRBl as the mechanism of effect of IVGG. Exploration of the mechanism of the FcRBl caused by IVGGled Salama and Mueller-Eckhardt to demonstrate the therapeutic effect of I anti-D, which apparentlycoats RBC with antibody and causes their destruction atthe coats RBC with antibody and causes their destruction at the expense of antibody-coated platelets. A similar degree of FcRBl has been shown for aldometrelated to the development of antibody on RBC.Our studies, including Drs. Clarkson, Kimberly, Nachman, and Unkeless, have focussed on the role of the low affinity or "Immune complex" FcR by using monoclonal antibody 3G8 in vivo. An infusion of 1 mg/kg of 3G8 in chimpanzees caused a reproducible FcRBl demonstrable by a slowing of the destruction of antibody-coated RBC for > 10 days (JEM, 1986). Less effect of 3G8 to inhibit CIC removal was seen using DNA-anti-DNA as the immune complex. In view of the wel1-documented effects of IVGG infusion to create FcRBl, we infused 3G8 into 6 adults with refractory ITP (NEJM, 1986). Specifically these patients were refractory to all forms of conventional therapy including splenectomy, steroids, vinca alkaloid infusion, immunosuppressives and danazol . 3 of the 6 patients had peak platelet responses to >80,000/ul. The other 3 had short-lived platelet increases from 10 to 30,000/ul. These responses confirmed the effect of FcRBl, specifically of the low affinity FcR, to underlie a dramatic platelet increase in therapy of ITP. Surprisingly 3 of the patients had apparent longterm effects of this therapy demonstrable in 2 cases as a maintenance of the platelet count >20,0C0/ul without any further therapy and in 1 case as a clearly enhanced responsiveness to other therapies following 3G8 infusion. Since Natural Killer activity was (transiently) ablated by 3G8 infusion, we speculate that an alternation of regulation of (auto) antibody production by NK cells may be responsible for this effect and that FcR interactions include regulatory roles in addition to their primary function of removal of CIC.