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Articles de revues sur le sujet "B-060"
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Sawyer, Eileen K., Sander Gielen, Jaap Twisk, Alison Long et Robert Gut. « Clearance of Vector DNA Following Systemic Administration of AAV5-hFIX or AAV5-hFIX Padua in Patients with Severe or Moderate-Severe Hemophilia B ». Blood 134, Supplement_1 (13 novembre 2019) : 2062. http://dx.doi.org/10.1182/blood-2019-129786.
Texte intégralRésumé :
Introduction Current adeno-associated viral (AAV) vector-based gene therapy strategies for hemophilia rely on systemic administration of the vector. Durable expression of the transgene over the span of years has been reported from several trials, yet information on the clearance of vector material from bodily fluids is still limited and monitoring of "shedding" is required during trials despite lack of evidence of environmental or transmission risk. Here, we examined the magnitude and duration of the presence of vector DNA in participants from a Phase I/II study of an AAV5-hFIX wildtype construct (AMT-060; NCT02396342) and from a Phase IIb study utilizing the enhanced version, AAV5-hFIX Padua (AMT-061; NCT03489291). Methods Adult male participants with severe or moderately severe hemophilia B received a single intravenous infusion of either AMT-060 at 5x1012 genome copies(gc)/kg (low dose) or 2×1013 gc/kg (high dose), or AMT-061 at 2x1013gc/kg in one of two ongoing trials. Assessments in both trials included efficacy and safety outcomes as well as vector shedding in whole blood and semen. Vector shedding was also measured in nasal secretions, feces, urine, and saliva in participants receiving AMT-060. Vector shedding was analyzed using a validated quantitative real time polymerase chain reaction (qPCR) based assay measuring presence of vector DNA in the bodily fluids. Vector clearance was reached when vector DNA was either zero or below the limit of detection (LOD) for three consecutive measurements. The range in time to the first and the third consecutive negative measurement for each dose group are provided. Results Treatment with AMT-060 resulted in sustained improvement in FIX activity for up to 3.5 years [Mean FIX activity was 5.1% (low dose group at 3.5 years) and 7.5% (high dose group at 3 years)] and treatment with AMT-061 resulted in mean FIX activity of 45% over 36 weeks. AMT-060 and AMT-061 reduced the mean number of annualized bleeds by between 82% and 100% respectively. AMT-060 reduced the requirement for exogenous FIX administration by 86% and was abrogated with AMT-061. Both AAV5-hFIX and AAV5-hFIX Padua were safe and well tolerated and no unexpected TRAEs have been observed with longer-term follow up. Table 1 describes the time in weeks to the first and last of three consecutive measures of vector DNA of either zero or <LOD for all bodily fluids for AMT-060 and AMT-061. AMT-060 at the higher dose was cleared from semen, feces, urine, nasal secretions and saliva in all participants by week 64 (range 7-64 weeks). In blood, the lower dose of AMT-060 was cleared in all participants by 3 years (range 1.0-3.0 years). The higher AMT-060 dose was cleared in 4 of 5 participants by 2.5 years (range 1.8-2.5 years), and while below the LOD in the 5th participant by year 3, had not achieved the definition of vector clearance. With AMT-061, vector DNA were <LOD or below the lower limit of quantification in blood in all 3 participants by weeks 36-40 and in semen by week 26 in 2 of 3 participants but had not achieved the definition of vector clearance. Conclusions Post-AMT-060 treatment, vector DNA was undetectable in all participants in the high dose group by 10 months and considered cleared by 16 months in all bodily fluids except blood. AMT-060 was cleared from the blood in 100% of participants in the low dose group at 3 years and 80% of participants in the high dose group by 2.5 years. As expected, AMT-061 vector DNA was detectable at 36 weeks in blood and in the semen of 1 of 3 participants, although clearance had not yet been established in the remaining participants. The presence of vector DNA in bodily fluids assessed was not associated with any adverse safety or efficacy findings. Disclosures Sawyer: Uniqure BV: Employment. Gielen:uniQure Biopharma: Employment. Twisk:uniQure Biopharma: Employment. Long:Uniqure BV: Employment. Gut:Uniqure BV: Employment.
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Heuser, M., P. Andrieux, S. Petit et H. Stanjek. « Iron-bearing smectites : a revised relationship between structural Fe, b cell edge lengths and refractive indices ». Clay Minerals 48, no 1 (mars 2013) : 97–103. http://dx.doi.org/10.1180/claymin.2013.048.4.06.
Texte intégralRésumé :
AbstractStructural iron in smectites correlates with the cell edge length b and increases the refractive index. The cell edge length b is usually obtained from the position of the (060) reflection, but in this work we show that such b values differ from the values obtained from Rietveld fits because contributions from (hkl) reflections shift the position of the (060) reflection. The correlation between Fe and cell edge length b was significant (r2 > 0.99); the relationship is b [Å] = 8.9977(0.0035) + 0.1117(0.0032) × Fetot. Furthermore, we present for the first time measurements of the refractive index n of Fe-bearing smectites, applying a recently published turbidity method (Weidler & Friedrich, 2007). The refractive index correlates both with structural iron (r2 = 0.64) and with b (r2 = 0.94).
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Leebeek, Frank, K. Meijer, Michiel Coppens, Peter Kampmann, Robert Klamroth, Roger Schutgens, Giancarlo Castaman et al. « Reduction in Annualized Bleeding and Factor IX Consumption up to 2.5 Years in Adults with Severe or Moderate-Severe Hemophilia B Treated with AMT-060 (AAV5-hFIX) Gene Therapy ». Blood 132, Supplement 1 (29 novembre 2018) : 3476. http://dx.doi.org/10.1182/blood-2018-99-109995.
Texte intégralRésumé :
Abstract Introduction: AMT-060 consists of an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized wildtype human factor IX (FIX) gene under control of a liver-specific promoter. We have previously reported on the safety and efficacy of AMT-060 gene therapy at 2 dose levels in adults with moderate-severe or severe hemophilia B with up to 1-year follow-up. Here we present longer-term follow-up data on reductions in annualized bleed rates and FIX consumption up to 2.5 years post-treatment. Methods: Multi-national, open-label, dose-escalating study in participants (pts) with FIX activity ≤2 % of normal, and a severe bleeding phenotype (NCT02396342). Pts received either 5x1012 gc/kg (Cohort 1, n=5) or 2×1013 gc/kg (Cohort 2, n=5) of AMT-060 iv. Duration of follow-up was 2.5 and 2 years in Cohort 1 and Cohort 2, respectively. Efficacy assessments include FIX activity (measured ≥10 days after use of exogenous FIX), reduction of FIX use, and annualized total bleeding rates. Bleeds were counted for each individual patient starting after discontinuation of prophylaxis post-AMT-060. For Cohort 1, exogenous FIX use and bleeds for "year 3" are presented as a calculated annualized mean using data captured between 2 and 2.5 years. Safety assessments include treatment-related adverse events, immunological and inflammatory biomarkers. Results: Nine pts with severe (FIX <1 %) and 1 with moderate-severe (FIX 1.5 %) hemophilia B were enrolled and received AMT-060. Nine were receiving exogenous FIX prophylaxis and one was receiving on-demand exogenous FIX. Mean FIX activity over the course of follow up was 4.9 % in Cohort 1 and 7.4% in Cohort 2. Disease severity improved in all pts: from severe to mild (n=6), severe to moderate (n=3), and moderate to mild (n=1). Eight of nine pts on FIX prophylaxis at study entry discontinued use after AMT-060 infusion. In Cohort 1, annualized exogenous FIX use (excluding use for surgeries) decreased from a pre-treatment cumulative total of 1,562,000 IU by 85%, 96% and 93% for years 1, 2 and 3 of follow-up (n=4, excluding patient who remained on prophylaxis post-treatment). In Cohort 2, exogenous FIX use was reduced from a pre-treatment cumulative total of 866,000 IU by 78% and 93% for years 1 and 2 of follow-up (n=5). Mean annualized total bleeds decreased from 14.4 in the year prior to AMT-060 to 7.6, 2.8 and 7.8, in years 1, 2, and 3 of follow-up in Cohort 1. Among the three patients with FIX activity >5% in Cohort 1, a single bleed was reported in year 2 and no bleeds were reported to data cut-off in year 3. For the two patients with FIX activity <5%, one patient with mean FIX activity of 4-4.3% reported 4 bleeds for year 2 and 4 bleeds to data cutoff in year 3, while the patient remaining on prophylaxis reported 8 and 9 bleeds during the same period. In Cohort 2, mean annualized total bleeds were reduced from a pre-therapy mean of 4.0 to 1.5 and 0.5 in years 1 and 2, respectively. One pt in Cohort 2 was not included in the calculation as historical bleed data was not available; he experienced one traumatic bleed approximately 7.5 months after the discontinuation of prophylaxis. No pts developed inhibitors to FIX and there were no detectable signs of sustained AAV5 capsid-specific T-cell activation. Fourteen treatment-emergent adverse events were reported in the first 3.5 months after treatment, including three patients who experienced transient mild elevations in alanine aminotransferase as previously disclosed. There were no additional treatment-related adverse events reported during this additional follow-up period up to 2.5 years post-treatment. Conclusions: Stable endogenous FIX concentrations >4% have now been observed out to 2.5 years post-treatment with AMT-060. In addition, we have observed continued reductions in annualized bleeds to near zero with the higher dose of AMT-060, and a 78-93% reduction in exogenous FIX use. The lack of additional safety concerns or treatment-related adverse events over the longer study period, including no recurring changes in ALT, support the continued development and transition of AMT-060 to AMT-061, which will use the same AAV5 vector to deliver the 2×1013 gc/kg dose with the enhanced Padua transgene, which is anticipated to increase FIX activity 6-8 fold. Disclosures Leebeek: CSL Behring: Research Funding; Uniqure: Research Funding; Baxalta/Shire: Research Funding. Meijer:BMS: Honoraria; Aspen: Honoraria; Boehringer Ingelheim: Honoraria; Pfizer: Research Funding; Sanquin: Honoraria, Research Funding; Bayer: Honoraria, Other: Travel support, Research Funding; UniQure: Research Funding. Coppens:Bayer: Honoraria, Other: Non-financial support, Research Funding; CSL Behring: Honoraria, Other: non-financial support, Research Funding; Uniqure BV: Research Funding. Kampmann:Uniqure BV: Research Funding. Klamroth:Baxalta (Shire), Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Shire, and SOBI: Consultancy; Baxalta (Shire), Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Shire, and SOBI: Research Funding. Schutgens:Baxalta/Shire: Research Funding; Novo Nordisk: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; Uniqure BV: Research Funding. Seifried:Medac: Other: BSD owns IP and is contract manufacturer; Uniqure BV: Research Funding. Schwaeble:UniQure BV: Research Funding. Bonig:Kiadis Pharma: Consultancy. Sawyer:Uniqure BV: Employment. Miesbach:Bayer, Shire, Biotest, pfizer, Octapharma, LFB, CSL Behring, SOBI, Biogen, BPL: Consultancy; UniQure BV: Research Funding; Novo Nordisk: Consultancy, Research Funding.
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Munoz, Ernesto, et Allison Carilli. « CLO23-060 : Extranodal Presentation of Double Hit High Grade B Cell Lymphoma ». Journal of the National Comprehensive Cancer Network 21, no 3.5 (31 mars 2023) : CLO23–060. http://dx.doi.org/10.6004/jnccn.2022.7219.
Texte intégral
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Leebeek, Frank W. G., Marco Tangelder, Karina Meijer, Giancarlo Castaman, Federica Cattaneo, Michiel Coppens, Peter Kampmann et al. « Interim Results from a Dose Escalating Study of AMT-060 (AAV5-hFIX) Gene Transfer in Adult Patients with Severe Hemophilia B ». Blood 128, no 22 (2 décembre 2016) : 2314. http://dx.doi.org/10.1182/blood.v128.22.2314.2314.
Texte intégralRésumé :
Abstract Introduction: The development of gene transfer for hemophilia is advancing rapidly and offers the potential to shift the disease severity from severe to mild with a single treatment. AMT-060 consists of an AAV5 vector with a gene cassette containing an LP1 liver specific promoter and codon-optimized wild type hFIX gene that has previously been shown to result in durable increases in FIX activity of at least 4 years1. This phase 1/2 study aims to investigate the safety and efficacy of AMT-060 in adult patients with severe hemophilia B. Methods: This is a multi-national, multi-center, open-label, dose-escalating study in patients with FIX activity ≤ 2% of normal, and a severe bleeding phenotype. To be eligible, patients had to require either prophylactic exogenous FIX, or on-demand exogenous FIX with more than 4 bleeds per year or suffer from hemophilic arthropathy. Ten patients were treated in two subsequent, escalating dose cohorts, with AMT-060 5x 1012 gc/kg (n=5) or 2x 1013 gc/kg (n=5). Patients received AMT-060 via a single intravenous infusion over 30 minutes. Efficacy assessments include endogenous FIX activity, measured at least 10 days after the most recent administration of exogenous FIX; reduction of exogenous FIX use; and annualized spontaneous bleeding rates. Safety assessments include treatment related adverse events and immunological assessments, including T-cell response to capsid antigens. Results : There were no screen failures for pre-existing antibodies against AAV5. The age of enrolled patients ranged from 33 to 72 years. At enrollment, nine patients were on FIX prophylaxis, and one patient in the high dose cohort used on-demand FIX therapy. At the time of submission, all ten patients have received AMT-060. The mean of all endogenous FIX activity values after cessation of prophylaxis in the low-dose cohort was 5.4% (95% CI 5.0-5.8%, range 3.1-6.7%; n=4), and stable during the 39 weeks of follow-up. Four out of five patients in the low-dose cohort were able to stop FIX prophylaxis. These patients demonstrated a mean reduction in annualized total FIX usage of 82% after treatment with AMT-060. For all five patients in the low-dose cohort, the mean annualized total FIX usage declined 75% after treatment with AMT-060. Following AMT-060 administration, one patient in the lower dose cohort had a mild, asymptomatic, elevation of ALT at week 10 that resolved with a seven weeks course of tapering prednisolone. No change in FIX activity, and no T-cell response or other possibly associated immunogenicity or inflammatory abnormalities were seen during the ALT elevation. Efficacy and safety results will be updated up to 52 weeks of follow up for the low-dose cohort. Initial efficacy and safety results from the higher-dose cohort up to 26 weeks of follow up will also be presented. Conclusions: Follow up of patients with severe hemophilia B who received either the low or higher dose of AMT-060 is ongoing. A single infusion of AMT-060 was generally well-tolerated. FIX activity increased to levels sufficient to provide endogenous prophylaxis in four of five patients in the low-dose cohort, relieving them from the need for exogenous FIX prophylaxis and resulting in marked decrease of FIX usage. 1Nathwani et al. NEJM 2014; 371:1994-2004 Disclosures Leebeek: UniQure: Consultancy; Netherlands Hemophilia Foundation: Research Funding; CSL Behring: Research Funding; Baxter: Research Funding. Tangelder:uniQure: Employment. Meijer:Baxter: Research Funding; Bayer: Honoraria, Research Funding; Pfizer: Research Funding; Sanquin: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Bristol-Myers Squibb: Honoraria. Castaman:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxalta-Shire: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Cattaneo:Chiesi: Employment. Coppens:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; BMS/Pfizer: Consultancy, Honoraria, Research Funding; Sanquin: Consultancy, Honoraria, Research Funding. Klamroth:SOBI: Other: honoraria for advisory boards and speaker fees; uniqure: Other: honoraria for advisory boards and speaker fees; pfizer: Other: honoraria for advisory boards and speaker fees; NovoNordisk: Other: honoraria for advisory boards and speaker fees; Octapharma: Other: honoraria for advisory boards and speaker fees; Baxalta: Other: honoraria for advisory boards and speaker fees ; Bayer: Other: honoraria for advisory boards and speaker fees; Biogen Idec: Other: honoraria for advisory boards and speaker fees; CSL Behring: Other: honoraria for advisory boards and speaker fees. Schutgens:CSL Behring: Research Funding; Sanquin: Research Funding. Hendriks:uniQure: Employment. Corzo:uniQure: Employment. Miesbach:Grifols: Honoraria; CSL Behring: Research Funding; Pfizer: Honoraria; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Semenova, Lioubov I., Alexander N. Sobolev, Brian W. Skelton et Allan H. White. « Structural Systematics of Rare Earth Complexes. XV Tris(2,2′:6′,2″-terpyridine)lanthanoid(III) Tris(perchlorate) Complexes ». Australian Journal of Chemistry 52, no 6 (1999) : 519. http://dx.doi.org/10.1071/ch98046.
Texte intégralRésumé :
Room-temperature single-crystal X-ray structure determinations of the 1 : 3 adducts of the trivalent lanthanoid perchlorates with 2,2′:6′,2″-terpyridine (‘tpy’) as crystallized from acetonitrile are recorded. The Ln = La complex is the only one of its structural type, being modelled as La(ClO4)3/tpy/MeCN/H2O (1 : 3 : 2 :2/3), trigonal P 3c1, Z = 6, a 13·063(7), c 53·04(4) Å, recorded on an interim basis, with conventional R on |F| 0·081 for No 2889 ‘observed’ (I >3σ(I)) reflections. For Ln = Ce, (Pr, Sm,) Eu and, by presumption, other intermediate members, a monosolvate is found, monoclinic P 21/n, a ≈ 9·3, b ≈ 21·1, c ≈ 24·7 Å, β ≈ 91°, Z = 4, R being 0·045, (0·060, 0·049,) 0·047 for No 4420, (4199, 3931,) 3713. The Ln = Eu adduct has also been obtained unsolvated in a form representative of Ln = Eu, Lu and, by presumption, intermediate members, as well as Y, which is monoclinic C 2/c, Z = 4, R being 0·051, 0·044, 0·061 for No 4386, 4407, 3713. All monoclinic systems are of the form [Ln(tpy)3] (ClO4)3(.S), Ln being nine-coordinate, and in the case of the C 2/c phase lying on a crystallographic 2 axis. The Ln = La adduct was modelled with three independent cations, all with crystallographic 3 symmetry, two with their coordination number augmented by the approach of solvent along the 3 axis.
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Smirnova, D., E. Sloeva, N. Kuvshinova, A. Krasnov, M. Ustinov, D. Romanov et G. Nosachev. « P.2.b.060 Language phenomenon in the diagnostic criteria of mild depression ». European Neuropsychopharmacology 23 (octobre 2013) : S354—S355. http://dx.doi.org/10.1016/s0924-977x(13)70559-5.
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Lee, Shinduk, Marcia Ory, Deborah Vollmer Dahlke, Tiffany Shubert, Steve Popovich et Matthew Smith. « Conservation of Resources Theory : Technology and Caregiver Strain ». Innovation in Aging 4, Supplement_1 (1 décembre 2020) : 468. http://dx.doi.org/10.1093/geroni/igaa057.1515.
Texte intégralRésumé :
Abstract Using the Conservation of Resources Theory, this study examined how caregiver strain was influenced by care recipients’ use of falls alert wearables. Online survey data from 486 unpaid caregivers for adults aged 50 and older were analyzed. Structural equation modeling was used to test the following hypotheses: (1) caregivers with fewer financial resources would engage in fewer resource conservation strategies (e.g., care recipients’ use of falls alert wearables); (2) resource conservation strategy engagement would be associated less resource loss; and (3) the effect of resource conservation strategies on caregiver strain would be less salient than the effect of resources used on caregiving (e.g., time and social support). The hypothesized model had a good model fit (CFI=.910), with SRMR (.060) and RMSEA (.062) being close to .05. All hypothesized paths were statistically-significant, except for the direct effect of using falls alert wearables on social support (p=.076) and caregiver strain (p=.135). As hypothesized, higher income was associated with greater likelihood of using falls alert wearables (b=.10, p>.022). Technology use was associated with less time spent on caregiving (b=-.16, p<.001) and had statistically-significant indirect effects on caregiver strain (b=-.03, p=.008). The total effect of using falls alert wearables (b=.04, p=.394) on caregiver strain was less powerful than the effect of time (b=.20, p<.001) or social support (b=-.28, p<.001). Study findings suggest the benefits of using falls alert wearables to alleviate time-related burdens and downstream caregiver strain among unpaid caregivers. Future efforts should investigate the relative advantage of wearables for other caregiving purposes.
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Leebeek, Frank W. G., Karina Meijer, Michiel Coppens, Peter Kampmann, Robert Klamroth, Roger Schutgens, Giancarlo Castaman et al. « AMT-060 Gene Therapy in Adults with Severe or Moderate-Severe Hemophilia B Confirm Stable FIX Expression and Durable Reductions in Bleeding and Factor IX Consumption for up to 5 Years ». Blood 136, Supplement 1 (5 novembre 2020) : 26. http://dx.doi.org/10.1182/blood-2020-139225.
Texte intégralRésumé :
Background: Gene therapy aims to provide long-term therapeutic benefit from a single administration. AMT-060 is an adeno-associated virus serotype 5 (AAV5) vector with a codon-optimized wildtype human factor IX (FIX) gene and liver-specific promoter. AMT-060 is being evaluated in an ongoing study of 10 participants with severe/moderate-severe hemophilia B (Phase 1/2 study, NCT02396342) over 5 years. Aim: To describe efficacy and safety outcomes from an analysis at up to 5-years post-AMT-060. Methods: Adult males with FIX activity ≤2% and a severe bleeding phenotype received a single intravenous infusion of AMT-060 (5x1012 gc/kg, Cohort 1, n=5) or (2×1013 gc/kg, Cohort 2, n=5). Assessments included FIX activity, FIX replacement use, annualized bleeding rate (ABR), treatment-related adverse events (TRAE), immunological and inflammatory biomarkers up to 5 years (Cohort 1) and 4.5 years (Cohort 2). Results: As of November 2019, for Cohort 1 the mean FIX activity (at 4.0 years) was 5.1% as compared to 4.4% in the first year, 6.8% in the second year, 7.3% in the third year and 7.0% in the fourth year. Mean FIX activity for Cohort 2 was 7.5% as compared to 7.1% in the first year, 8.4% in the second year 7.9% in the third year, and 7.4% in the fourth year. Eight of 9 participants using prophylaxis at baseline were able to discontinue use. During the last 12, and 6 months of observation respectively, the mean annualized bleed rate (ABR) was 3.3. for Cohort 1 and 0.0 for Cohort 2. These represent, respectively, a reduction in mean ABR to the year prior to treatment of 77% and 100% for Cohort 1 and Cohort 2. During this same period the consumption of FIX replacement therapy declined 90% and 100% relative to pre-treatment, respectively for Cohort 1 and Cohort 2. No participants developed FIX inhibitors or signs of sustained AAV5 capsid-specific T-cell activation. As previously reported, TRAE were mainly reported in the first 3.5 months after treatment, including three participants who experienced transient mild elevations in alanine aminotransferase. One additional TRAE (joint swelling post-exercise) was observed during the last 12 months of observation post-treatment. Updated data, up to 5-years of observation, will be presented for the first time. Conclusions: Long-term stable endogenous FIX activity and reductions in ABR and FIX replacement use were sustained over multiple years following a single treatment with AMT-060. There were no additional safety concerns with longer term follow-up. This data supports the ongoing Phase 3 study of the enhanced construct etranacogene dezaparvovec (AMT-061), which encodes the highly active Padua FIX variant. Disclosures Meijer: Bayer: Research Funding; Sanquin: Research Funding; Pfizer: Research Funding; Bayer: Speakers Bureau; Sanquin: Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; BMS: Speakers Bureau; Aspen: Speakers Bureau; Uniqure: Consultancy. Kampmann:Uniqure: Speakers Bureau; Shire Pharmaceuticals: Speakers Bureau. Klamroth:CSL Behring: Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Takeda/Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Biotest: Speakers Bureau; Grifols: Speakers Bureau; Biomarin: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau. Castaman:Novo Nordisk: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding; Ablynx: Honoraria; Alexion: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria, Research Funding; Kedrion: Speakers Bureau; Sobi: Honoraria, Research Funding, Speakers Bureau; Uniqure: Honoraria, Membership on an entity's Board of Directors or advisory committees; Werfen: Speakers Bureau; Baxalta/Shire: Honoraria. Bönig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Healthineers: Current equity holder in publicly-traded company; Sandor-Hexal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Polyphor: Research Funding; Miltenyi: Honoraria, Research Funding; Erydel: Research Funding; Chugai: Honoraria, Research Funding; Bayer: Research Funding; Terumo BCT: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kiadis: Honoraria; Uniqure: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Stage: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fresenius: Honoraria; medac: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Sawyer:uniQure: Current Employment. Miesbach:UniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioMarin Pharmaceutical Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: AMT-060 = AAV5 vector gene therapy in subjects with moderate to severe hemophilia B
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Lensink, Cornelis, et Graeme J. Gainsford. « Synthesis and Structure of Two Isomers of Di(indenyl)phenylphosphine Sulfide ». Australian Journal of Chemistry 51, no 8 (1998) : 667. http://dx.doi.org/10.1071/c97210.
Texte intégralRésumé :
Dichlorophenylphosphine reacts with indenyllithium in tetrahydrofuran followed by sulfur to yield di(1H-inden-3-yl)phenylphosphine sulfide (2). The same reaction sequence in toluene yields di(1H-inden-1-yl)phenylphosphine sulfide (3) as a mixture of (±) and two meso isomers. The structures of (2) and (±)-(3) were determined [(2): C24H19PS, Mr 370·42, monoclinic, P21/n, a 14·329(4), b 7·0936(10), c 19·405(5) Å, β 99·18(2)°, Z 4, R 0·060 for 2422 observed reflections; (3): C24H19PS, Mr 370·42, monoclinic, P21/n, a 9·521(5), b 16·223(8), c 12·930(6) Å, β 107·41(3)°, Z 4, R 0·105 for 923 reflections].
Thèses sur le sujet "B-060"
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SIMONETTI, GIORGIA. « B lymphoid malignancies : insights from mouse models ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/30033.
Texte intégralRésumé :
Despite several recent advancements in the treatment of B lymphoproliferative disorders, still a considerable number of lymphoma cases either cannot be cured or become incurable when relapsing. This issue reflects the need for better and more effective therapies that can be designed once novel pathogenic mechanisms have been designed and suitable preclinical models have been established. Therefore, aim of this thesis was to understand the molecular mechanisms leading to mature B lymphoid malignancies by using different mouse models, in order to identify novel potential therapeutic targets and obtain useful models for preclinical studies. In chapter 2 we show the establishment of a new xenograft
model obtained by injecting the CLL cell line MEC1 into immunodeficient Rag2‒/‒gammac‒/‒ mice. This model resembles the aggressive form of human CLL and is conceivably useful to test the efficacy of new therapeutic agents. In chapter 3 we show that HS1 is involved in the trafficking and homing of leukemic B cells and that its deficiency is responsible for an earlier onset of the disease and a reduced survival in the Emu-TCL1 mouse model of CLL. The same animal model was used to investigate the role of TLR pathway in CLL. In chapter 4 we report that the absence of TIR8 accelerates the appearance of the disease and favors the progression into an aggressive form characterized by the accumulation of “prolymphocytoid” cells. Finally in chapter 5 we demonstrate that mice lacking the negative regulator SIGLEC-G are susceptible to B cell lymphoma development with age indicating that the downregulation of SIGLEC10 may be involved in the malignant transformation of human B lymphocytes.
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Trimarco, Valentina. « Role of Nocodazole on the survival of chronic lymphocytic leukemia B cells ». Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3422967.
Texte intégralRésumé :
B-cell Chronic Lymphocytic Leukemia (B-CLL) is the most common leukemia in adults and is characterized by the accumulation of clonal CD19+/CD5+/CD23+ B lymphocytes, due to uncontrolled growth and resistance to apoptosis. Leukemic cells from B-CLL show reduced crosslink with specific molecules and high susceptibility to microtubule disrupting drugs, which suggest cytoskeletal alterations.
Microtubules play a crucial role in the vital functions of neoplastic cells, including mitosis, motility and cell-cell contact, and for this reason they became an important target in cancer therapies. In particular, tubulin, a cytoskeletal member, is the target of specific drugs, named microtubule inhibitors. Among these inhibitors, nocodazole induces tubulin depolimerization, mitotic process blocking and shows an apoptotic effect in B leukemic cells.
The aim of this study was to define the effects of nocodazole on B-CLL cells.
First of all, we verified nocodazole capability to favour the depolymerization of tubulin cytoskeleton in different cell types. In addition, we tested nocodazole-induced apoptosis in normal and leukemic B cells, in cell lines (Jurkat, Raji, and K562), in mesenchymal stromal cells (MSCs), and in T lymphocytes of B-CLL patients. Our data pointed out the high specificity of nocodazole for B-CLL cell apoptosis (leukemic cells: 57±25% vs normal B cells: 98±6%, p<0.0001; data are expressed as mean±standard deviation (SD) of percentage of viable cells after treatment with nocodazole) and the absence of toxicity to others cell types.
Growing evidence suggests that the marrow microenvironment, where MSCs are present, protects B-CLL cells from conventional anti-neoplastic drugs. The cultures of neoplastic B cells with MSCs and nocodazole demonstrated that nocodazole is able to overcome MSC protective effect, even after survival signal supplemental, such as CD40L or plasma from the same patients.
The action mechanism of nocodazole in B-CLL cells is still under investigation. However, we observed that nocodazole is able to turn off the increased basal tyrosine phosphorylation of leukemic cells mediated by Src-kinase Lyn through the down-modulation of Lyn active site. Since the specific inhibition of Lyn induces B-CLL cells apoptosis, this linking will be further investigated.
The results obtained in this study suggest a future role of nocodazole as a possible agent for treatment of B-CLL, for its extreme selectivity, the absence of toxicity and its ability to counteract the protective effect provided by marrow microenvironment.La Leucemia Linfatica Cronica di tipo B (LLC-B) è la forma più comune di leucemia nell’adulto ed è caratterizzata dall’accumulo clonale di piccoli linfociti B CD19+/CD5+/CD23+, dovuto sia ad una crescita incontrollata che ad una resistenza all’apoptosi. Le cellule leucemiche di LLC-B presentano inoltre alcune anomalie, come ridotta capacità di legare specifiche molecole e suscettibilità a farmaci che distruggono i microtubuli, che indicano la presenza di alterazioni a livello citoscheletrico. Il ruolo cruciale che i microtubuli rivestono nelle funzioni vitali delle cellule neoplastiche, quali mitosi, motilità e contatti cellula-cellula, li ha resi un importante target nelle terapie anti-tumorali. In particolar modo la tubulina, componente dei microtubuli, è il bersaglio di una categoria specifica di farmaci anti-tumorali, gli inibitori dei microtubuli; di questa famiglia fa parte anche il nocodazolo, un agente sintetico che induce la depolimerizzazione della tubulina, arresta il processo mitotico ed ha una peculiare specificità nell’indurre l’apoptosi nelle cellule B di LLC-B. Sulla base di queste considerazioni, abbiamo voluto approfondire gli effetti ed il meccanismo d’azione del nocodazolo sulle cellule di LLC-B. Dopo aver verificato che il nocodazolo sia effettivamente responsabile della depolimerizzazione dei filamenti di tubulina citoscheletrica in numerosi tipi cellulari, abbiamo valutato l’effetto apoptotico indotto dal nocodazolo in cellule B normali e di LLC-B, in linee cellulari (Jurkat, Raji e K562), in cellule stromali mesenchimali (MSC) e nei linfociti T residui di pazienti affetti da LLC-B. I risultati ottenuti evidenziano l’estrema selettività del nocodazolo nell’indurre l’apoptosi nelle sole cellule B di LLC-B (linfociti B di LLC-B: 57±25% vs B normali: 98±6%, p<0,0001; dati espressi come media±deviazione standard (DS) della percentuale di cellule vive dopo trattamento con nocodazolo) e l’assenza di tossicità nei confronti delle altre popolazioni cellulari prese in esame. Studi recenti suggeriscono che il microambiente midollare, in cui si trovano anche le MSC, sia in grado di proteggere le cellule leucemiche dall’azione dei farmaci chemioterapici convenzionali. La co-coltura di MSC e cellule B di LLC-B in presenza di nocodazolo ha dimostrato che tale inibitore è in grado di annullare l'effetto protettivo esercitato dalle MSC, nonostante la presenza di segnali di sopravvivenza quali CD40L o plasma ricavato dagli stessi pazienti. I meccanismi d’azione del nocodazolo rimangono ancora da chiarire, tuttavia abbiamo osservato come nelle cellule leucemiche di LLC-B il nocodazolo sia in grado di ridurre l’aumentata fosforilazione tirosinica basale mediata dalla Src-chinasi Lyn, mediante down-regolazione del sito attivatorio di Lyn. Dal momento che abbiamo dimostrato che l’inibizione specifica di Lyn induce apoptosi nelle cellule di LLC-B, questi primi risultati diventano rilevanti e dovranno essere ulteriormente indagati. In conclusione, i risultati ottenuti in questo studio hanno evidenziato l’estrema selettività del nocodazolo nell’indurre apoptosi nei linfociti B leucemici, l’assenza di tossicità in vitro e la capacità di contrastare l’effetto protettivo fornito dal microambiente midollare, suggerendo un futuro ruolo di questa sostanza quale possibile agente terapeutico per la cura della LLC-B.
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Mandato, Elisa. « Protein kinase CK2 in diffuse large b-cell lymphoma : defining its role to shape new therapies ». Doctoral thesis, Università degli studi di Padova, 2016. http://hdl.handle.net/11577/3424401.
Texte intégralRésumé :
CK2 is a highly conserved Ser/Thr protein kinase, consisting of two catalytic (a) and two regulatory (b) subunits assembled to form a tetramer. It is involved in a broad variety of cellular processes, among which survival, proliferation, differentiation, DNA damage and other stress responses, leading to the activation of context-specific transcription factors such as c-Myc and NF-kB. This kinase has been found overexpressed in several solid tumors and hematologic malignancies, and its overexpression seems to be an unfavorable prognostic marker. It has been fully demonstrated that CK2 acts as a potent antiapoptotic factor that promotes a “non-oncogene addiction” phenotype in cancer cells. In other words, high CK2 levels and activity contribute to create a cellular environment favorable to the establishment and maintenance of a neoplastic phenotype. In particular, it was recently shown that many B-cell derived tumors, like multiple myeloma, mantle cell lymphoma and chronic lymphocytic leukemia, rely on high CK2 activity and that its downmodulation induces malignant cell death without significantly affecting normal B lymphocytes.
Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive B-cell derived neoplasia that originates from follicles and is the most common type of non-Hodgkin lymphoma, accounting for about 40% of all cases. It is divided into two subtypes: Germinal Center B-cell like (GCB) and Activated B-Cell like (ABC) DLBCL, characterized by different genetic lesions and, therefore, variable response to therapy. Up to one-third of patients does not achieve cure with initial therapy and has refractory disease or relapse. The standard salvage treatment for these patients is autologous stem cell transplantation, but success rates are poor and most of them succumb to the disease. These facts clearly demonstrate the need for new rational combination therapeutics.
It is well known that the B-Cell Receptor (BCR) signalling strongly influences B-cell development and is fundamental for peripheral B-cell survival. After BCR ligation by the antigen, the signal is transduced across the plasma membrane and propagated inside the cell through a group of intracellular proteins, which interact to form a complex, called signalosome. Among these proteins there are the tyrosine kinases SYK and BTK, the phospholipase PLCg2 and the adaptor BLNK. Once activated by SYK, BTK phosphorylates PLCg2, which in turn generates IP3 thus causing Ca++ release from the endoplasmic reticulum stores. Ca++ acts in the cytoplasm as a second messenger that binds several Ca++-dependent proteins that are then able to activate transcription factors, like NFAT and NF-kB, modifying gene expression. The result of this process consists in activation, expansion, antigen presentation and B-cell differentiation. For these reasons, it comes as no surprise that inhibitors targeting the BCR signalling have shown promising therapeutic outcomes for patients with B-cell lymphomas.
Here we show that a and b subunits of protein kinase CK2 are overexpressed in ABC- and GCB-DLBCL primary patient samples and immortalized cell lines when compared with normal counterparts. Moreover, we demonstrate that CK2 inhibition with CX-4945, an ATP-competitive CK2 inhibitor currently under clinical trials, causes apoptosis of DLBCL cell lines in a dose and time dependent fashion, and that malignant cell death is significative even at low drug doses not toxic to normal counterparts. We also reveal that the downmodulation of CK2 catalytic activity leads to a reduction in Ca++ release from the endoplasmic reticulum stores, and impairs AKT and NF-kB RELA phosphorylation after BCR stimulation. These findings propose a role for CK2 downstream of the BCR engagement, in controlling survival pathways crucial for B-cell endurance. Furthermore, we found out that CX-4945 synergises with inhibitors of kinases, like SYK and BTK, essential in spreading the BCR signal, thus proving that this drug combination enhances DLBCL cell death and could be considered an effective therapeutic strategy.CK2 è una Ser/Thr chinasi altamente conservata dal punto di vista evolutivo, costituita da due subunità catalitiche (a) e due subunità regolatorie (b) unite a formare un tetramero. Essa è coinvolta in numerosi processi cellulari, tra cui sopravvivenza, proliferazione, differenziamento, risposta al danno al DNA e ad altri stress, portando in definitiva all’attivazione di specifici fattori di trascrizione, come c-Myc ed NF-kB. Questa chinasi è stata trovata sovrespressa in svariati tumori solidi e neoplasie ematologiche, portando ad una correlazione tra alti livelli di CK2 e prognosi sfavorevole. È stato ampiamente dimostrato che CK2 agisce come un potente fattore antiapoptotico nelle cellule tumorali, promuovendo un meccanismo definito “non-oncogene addiction”. In altre parole, l’overespressione e l’aumento dell’attività catalitica dell’enzima contribuiscono notevolmente a creare un ambiente intracellulare favorevole allo sviluppo e al consolidamento di un fenotipo neoplastico. In particolare, è stato recentemente dimostrato che molte neoplasie, derivate dalla trasformazione maligna dei linfociti B, come il mieloma multiplo, il linfoma mantellare e la leucemia linfatica cronica, dipendono da un’aumentata attività di CK2 per il loro mantenimento; infatti, una sua inibizione è in grado di indurre apoptosi cellulare. Il linfoma diffuso a grandi cellule (DLBCL) è una neoplasia di tipo aggressivo derivata dalla trasformazione dei linfociti B nel follicolo ed è il tipo più comune di linfoma non-Hodgkin, rappresentando circa il 40% di tutti i casi. È suddiviso in due sottotipi: uno di derivazione da cellule B del centro germinativo (GCB), l’altro di derivazione da cellule B post centro germinativo (ABC), che sono caratterizzati da differenti alterazioni genetiche e, di conseguenza, da una differente risposta alla terapia. Fino a un terzo dei pazienti non raggiunge la cura con la terapia iniziale e sviluppa una malattia refrattaria o ricade. Il trattamento di salvataggio standard per questi pazienti è il trapianto autologo di cellule staminali, ma il tasso di successo è scarso e la maggior parte di essi non sopravvive alla malattia, dimostrando chiaramente la necessità di nuove terapie di combinazione. È risaputo che il segnale generato dal recettore dell’antigene B (BCR) è in grado di influenzare il differenziamento del linfocita B nella milza e la sua sopravvivenza a livello periferico. In seguito al legame del recettore da parte dell’antigene, il segnale viene trasmesso attraverso la membrana plasmatica e propagato all’interno tramite un gruppo di proteine intracellulari, che si combinano a formare un complesso denominato signalosoma. Tra queste proteine figurano le tirosin chinasi SYK e BTK, la fosfolipasi PLCg2 e l’adattatore BLNK. Una volta attivata da SYK, BTK è in grado di fosforilare PLCg2, che, a sua volta, genera IP3, il quale induce il rilascio di Ca++ dal reticolo endoplasmatico. Il Ca++ agisce nel citoplasma come secondo messaggero, interagendo con varie proteine Ca++-dipendenti, che attivano fattori di trascrizione, come NFAT e NF-kB, modificando, in tal modo, l'espressione genica. Il risultato di questo processo consiste in attivazione, espansione, presentazione dell’antigene e differenziamento del linfocita B. Non sorprende, perciò, che gli inibitori della cascata del segnale del BCR abbiano dimostrato risultati terapeutici promettenti in pazienti con linfomi di tipo B. In questo lavoro di tesi si evidenzia che le subunità a e b di CK2 sono sovrespresse sia in campioni primari, che in linee cellulari immortalizzate di ABC- e GCB-DLBCL, rispetto alle controparti non neoplastiche. Inoltre, si dimostra che l'inibizione di CK2 con CX-4945, un inibitore di CK2 attualmente in trial clinici, provoca l'apoptosi di linee cellulari di DLBCL in maniera dose e tempo dipendente e che l'aumento della morte delle cellule neoplastiche è significativa anche alle dosi di farmaco che non uccidono le cellule normali. Inoltre, l’abbassamento dell’attività catalitica di CK2 porta ad una riduzione del Ca++ rilasciato dal reticolo endoplasmatico, e compromette la fosforilazione di AKT e NF-kB RELA, in seguito a stimolazione del BCR. Questi risultati propongono un ruolo per CK2 a valle del BCR, nel controllo di vie del segnale pro sopravvivenza centrali per il linfocita B. Infine, si evidenzia che il CX-4945 sinergizza con inibitori di chinasi essenziali per la propagazione del segnale del BCR, quali SYK e BTK, provando che questa combinazione di farmaci aumenta la morte delle cellule linfomatose e può considerarsi un’efficace strategia terapeutica.
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Martini, Veronica. « ESPRESSIONE DELLA CORTACTINA E SUO COINVOLGIMENTO NELL'AGGRESSIVITA' DELLA LEUCEMIA LINFATICA CRONICA B ». Doctoral thesis, Università degli studi di Padova, 2011. http://hdl.handle.net/11577/3421601.
Texte intégralRésumé :
B-cell chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia in adults. It is characterized by the accumulation of clonal CD5+ B lymphocytes due to uncontrolled growth and resistance to apoptosis. The Src tirosin kinase Lyn plays an important role in the survival of B lymphocytes. We previously observed that this kinase is overexpressed, constitutively active and anomalously distributed in malignant B cells as compared to normal B lymphocytes. Moreover we also found that one of its substrates, HS1, is overexpressed and involved in survival of B neoplastic cell; now we focused our attention on protein named cortactin, since this protein is homolog of HS1, a putative substrate of Lyn and it is overexpressed in many tumors.
In this study, by western blotting analysis and real-time RT-PCR, we demonstrated that in B neoplastic cells the protein cortactin is overexpressed with respect to normal B lymphocytes. When the expression level was correlated with somatic hypermutations of immunoglobulin heavy-chain variable region, one of the most important prognostic factors for B-CLL, we observed that the level of cortactin is higher in patients with poor prognosis with respect to those with favorable one. Moreover, we demonstrated that in neoplastic B lymphocytes cortactin overexpression correlated with both migration index and MMP9 production, suggesting that in these patients cortactin could be involved in the disease diffusion.
As reported in literature, cortactin can regulate cellular migration not only by its overexpression, but also by the expression of mRNA splicing variants. We found that normal B cells expressed only the SV1 splice variant, while in the neoplastic B lymphocytes about half of our patients expressed the WT variant. Since it has been reported that WT variant increases cell migration, we hypothesized that the expression of WT isoform could be another mechanism by which cortactin can modulate F-actin dynamics and cell migration.
All these findings converge to support a negative role of cortactin in clinical course of B-cell chronic lymphocytic leukemia, suggesting that cortactin could be involved in patogensis and progression of B-LLC.La leucemia linfatica cronica di tipo B (LLC-B) è la forma più comune di leucemia dell’adulto ed è caratterizzata dall’accumulo clonale di piccoli linfociti B CD5+ dovuto sia ad una crescita incontrollata che ad una resistenza all’apoptosi. Un ruolo importante nella sopravvivenza dei linfociti B leucemici è giocato dalla chinasi Lyn. Qualche anno fa abbiamo dimostrato che la Src chinasi Lyn è sovraespressa, costitutivamente attiva e distribuita in maniera anomala nelle cellule B neoplastiche rispetto ai linfociti B normali. Considerato che uno dei suoi substrati, la proteina HS1, si trova sovraespressa e coinvolta nella sopravvivenza del clone neoplastico, abbiamo focalizzato l’attenzione su un altro putativo substrato di Lyn: la proteina cortactina poiché omologa di HS1 e sovraespressa in diversi tumori. Mediante western blotting e real-time RT-PCR in questo studio abbiamo dimostrato che i linfociti B leucemici esprimono una maggiore quantità di cortactina rispetto ai linfociti B di soggetti sani. Correlando i dati di espressione con uno dei fattori prognostici più importanti della LLC-B, la presenza o assenza di ipermutazioni somatiche (SHM), abbiamo evidenziato che i livelli di espressione della cortactina sono più elevati in pazienti a prognosi sfavorevole (SHM-) rispetto a quelli a prognosi favorevole (SHM+). Inoltre, abbiamo dimostrato che nei linfociti B neoplastici la sovraespressione della cortactina correla sia con l’indice di migrazione cellulare (IdM) che con la produzione della metalloproteasi di matrice 9 (MMP-9), suggerendo come nei pazienti con LLC-B la cortactina possa essere in qualche modo coinvolta nel processo di invasione dei linfonodi e della milza. Come riportato in letteratura, la cortactina può influenzare la migrazione cellulare non solo attraverso la sua sovraespressione, ma anche mediante l’espressione di diverse varianti di splicing. Il nostro studio ha evidenziato che nei linfociti B normali è presente solo la variante di splicing SV1, mentre nei linfociti B di circa il 50% dei nostri pazienti è maggiormente espressa quella WT. Poiché è noto in letteratura che la variante WT rende alcuni tipi di cellule tumorali più aggressivi e mobili, si potrebbe pensare che l’espressione di tale isoforma abbia un ruolo rilevante nella diffusione della LLC-B. In conclusione, i dati finora ottenuti convergono tutti nell’affermare un ruolo negativo della cortactina nel decorso clinico della leucemia linfatica cronica di tipo B, suggerendo, quindi, che la cortactina possa essere coinvolta nella patogenesi della LLC-B.
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Macaccaro, Paolo. « Immunophenotypic characterization of B-lymphopoiesis in KO mice for oncogenic Ser / Thr kinases by multiparameter flow cytometry ». Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3422901.
Texte intégralRésumé :
Protein kinase CK2 and CK1 are a pleiotropic and evolutionary conserved serin-threonin kinase that is involved in several cellular processes. A number of studies revealed many mechanisms through which this kinase regulates cell cycle, apoptosis, cell survival and tumorigenesis.
CK2 participates in many developmental pathways, of which particularly relevant for hemo-lymphopoiesis are those dependent on Hedgehog, NF-κB and STAT3, which regulate cell differentiation, proliferation, self-renewal as well as lineage choice commitment.. CK1 regulates also molecular pathways which are important for multiple myeloma plasma cells survival, like WNT/β-catenin pathway and PI3K/AKT pathway.
However, despite all this data, little is known about the role of CK2 and CK1 in B-lymphopoiesis and lymphomagenesis.
To elucidate the physiological and pathogenetic role of CK2 and CK1 in B-lymphocytes, we generated B cell specific conditional KO mice, were we studied the effects of deletion during normal B cell development with multiparameter flow cytometry analysis.
In the bone marrow (BM), CK2β KO mice displayed a reduction of B cells, especially of the recirculating population of transitional and follicular (FO) B-cells. In peripheral blood and spleen the number of B-cells was markedly reduced. In the spleen of CK2β KO we observed an imbalance between the amount of FO and marginal zone (MZ) B-cells was found with an absolute reduction of FO B cells by approximately 2-folds and an increase of MZ B-cells and MZB cell precursors by up to three folds.. In vitro class-switch recombination assays demonstrated impairment in IgG1 and IgG3 class-switch and a marked reduction of the generation of antibody-producing cells. In CK1 KO mice we observed the totally absence of mature B cells and the presence of early precursors B cells. CK1 HET mice showed a reduction of B cells in bone marrow and an light imbalance of FO B cells an MZB cells in spleen. In vitro class-switch recombination assays doesn’t showed significant difference between HET and CTRL mice in IgG1 and IgG3 class-switch.
Here, we found that the β subunit of protein kinase CK2 is a novel regulator of peripheral B cell differentiation. CK2β has a role in regulation of the GC reaction and in homeostasis of FOB and MZB cells. Furthermore we found that CK1 has a pivotal role in early B cells development. On one side our data enrich the knowledge on the mechanisms regulating B-cell development, on the other side they inform about the potential mechanisms altered by CK2 and CK1 during B-cell tumorigenesis.Protein kinase CK2 and CK1 are a pleiotropic and evolutionary conserved serin-threonin kinase that is involved in several cellular processes. A number of studies revealed many mechanisms through which this kinase regulates cell cycle, apoptosis, cell survival and tumorigenesis. CK2 participates in many developmental pathways, of which particularly relevant for hemo-lymphopoiesis are those dependent on Hedgehog, NF-κB and STAT3, which regulate cell differentiation, proliferation, self-renewal as well as lineage choice commitment.. CK1 regulates also molecular pathways which are important for multiple myeloma plasma cells survival, like WNT/β-catenin pathway and PI3K/AKT pathway. However, despite all this data, little is known about the role of CK2 and CK1 in B-lymphopoiesis and lymphomagenesis. To elucidate the physiological and pathogenetic role of CK2 and CK1 in B-lymphocytes, we generated B cell specific conditional KO mice, were we studied the effects of deletion during normal B cell development with multiparameter flow cytometry analysis. In the bone marrow (BM), CK2β KO mice displayed a reduction of B cells, especially of the recirculating population of transitional and follicular (FO) B-cells. In peripheral blood and spleen the number of B-cells was markedly reduced. In the spleen of CK2β KO we observed an imbalance between the amount of FO and marginal zone (MZ) B-cells was found with an absolute reduction of FO B cells by approximately 2-folds and an increase of MZ B-cells and MZB cell precursors by up to three folds.. In vitro class-switch recombination assays demonstrated impairment in IgG1 and IgG3 class-switch and a marked reduction of the generation of antibody-producing cells. In CK1 KO mice we observed the totally absence of mature B cells and the presence of early precursors B cells. CK1 HET mice showed a reduction of B cells in bone marrow and an light imbalance of FO B cells an MZB cells in spleen. In vitro class-switch recombination assays doesn’t showed significant difference between HET and CTRL mice in IgG1 and IgG3 class-switch. Here, we found that the β subunit of protein kinase CK2 is a novel regulator of peripheral B cell differentiation. CK2β has a role in regulation of the GC reaction and in homeostasis of FOB and MZB cells. Furthermore we found that CK1 has a pivotal role in early B cells development. On one side our data enrich the knowledge on the mechanisms regulating B-cell development, on the other side they inform about the potential mechanisms altered by CK2 and CK1 during B-cell tumorigenesis.
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LORENZO, GARCIA MARIA MERCEDES. « SUBSTITUENT-DEPENDENT STEREOSELECTIVE SYNTHESIS OF HEXA-FUNCTIONALISED BORAZINES ». Doctoral thesis, Università degli Studi di Trieste, 2017. http://hdl.handle.net/11368/2908171.
Texte intégralRésumé :
In the growing field of polycyclic aromatic hydrocarbons, the doping by heteroatoms has emerged as one of the most versatile approaches to tune the optoelectronic properties of the materials. In particular, borazine derivatives attracted a lot of attention in the last years. While their synthesis, functionalisation and possible use in a broad spectrum of applications have previously been investigated, the effect of different substituents on the formation of the borazine ring and its functionalisation at the boron site has yet to be addressed. This doctoral thesis aims at filling this gap through an in-depth study of the synthesis of novel borazines derivatives.
Before addressing the detailed investigations of this thesis work, Chapter I of this manuscript introduces a brief insight into the history and generalities of borazines in the literature since its discovery in 1926 by Stock and Poland. This Chapter also includes the description of the synthetic approaches used for their production, as well as the chemical properties, stability and material applications.
The second Chapter of this manuscript describes the investigations developed toward the elucidation of the substituent’s effect during the functionalisation at the boron site of the borazine core. Following a [1+1’+1+1’+1+1’] hexamerisation route toward the formation of the borazine core (using an amino precursor and boron trichloride), the latter can be further functionalised by the addition of a nucleophile, which leads to the formation of stable borazine derivatives. Accordingly, the synthesis of multiple borazine moieties has been performed, using only one type of amino-precursor (aniline) and different organometallic derivatives during the functionalisation step. These organometallic moieties consist of aryl groups that contain one or two ortho-substituents, which allows for a partial- or full-protection of the borazine core, respectively. In the first case, the control of the stereoselectivity of the process in a reaction in which two different isomers (cc and ct) can be formed, is the main focus of this study. Finally, the chemical compatibility and the stability of this novel class of partially-protected borazine moieties developed along this doctoral thesis is also discussed.
Encouraged by the results obtained in Chapter II, the study developed in Chapter III aims at bringing light to the effect of the substituents on the formation of the borazine core together with the subsequent functionalisation toward the preparation of stable borazine moieties. For this purpose, the formation of the borazine core has been followed by reaction of different amino-precursors with boron trichloride. The later functionalisation at the boron site can lead to the formation of stable borazine derivatives, depending on the nature of the amino precursor.
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Ave, Elisa. « Le cellule mesenchimali staminali nella patogenesi della leucemia linfatica cronica di tipo B ». Doctoral thesis, Università degli studi di Padova, 2010. http://hdl.handle.net/11577/3427362.
Texte intégralRésumé :
B-cell Chronic Lymphocytic Leukemia (B-CLL) is the most common leukemia in adults and is characterized by the accumulation of mature clonal CD5+ B lymphocytes in peripheral blood, bone marrow and lymphoid tissues. The defect in programmed cell death favours the disease progression through a prolonged survival of malignant cells and the induction of the drug-resistance. The defective apoptosis of B-CLL cells is not only due to intrisic defects of the leukemic clone, but also to extrinsic factors that influence its behavior in the tissue microenvironment. Since the accumulation of monoclonal B cells is also supported by their interaction with surrounding cells, we focused our attention on mesenchymal stem cells (MSCs) in order to evaluate their role in survival and localization of neoplastic clone. MSCs can be isolated, expanded with high efficiency and induced to differentiate into multiple mesenchymal lineages under appropriated colture conditions. In addition, they show crucial immunoregulatory properties suppressing several T-, B- and NK-cell functions and affecting dendritic cell activities.
In the present study MSCs isolated from the bone marrow of 47 B-CLL patients were expanded ex vivo and characterized through fluocytometric analysis and differentiation coltures (adipocytes and osteocytes). While MSCs from B-CLL patients exhibited normal phenotype and differentiation capacities, when co-coltured with neoplastic B cells they exherted an anti-apoptotic effect reducing lymphocyte apoptosis. After 7 days of colture in presence of CLL-MSC, we observed a relevant extended survival of leukemic cells, but not of normal B lymphocytes. The same effect was observed on B-CLL cells isolated from 3 patients treated with pro-apoptotic compounds, suggesting an involvement of MSCs in drug-resistance. Finally, chemotaxis tests showed the ability of MSCs to produce molecules promoting migration and localization of neoplastic B cells in bone marrow.
Taken together, these findings suggest that MSCs derived from patients with B-CLL, despite an apparent normal phenotype and normal differentiation ability, provide survival signals to neoplastic cells extending their lifespan and producing chemotattic factors favouring their accumulation in the bone marrow.La leucemia linfatica cronica di tipo B (LLC-B) è la forma più comune di leucemia nell’adulto ed è caratterizzata dall'accumulo clonale di piccoli linfociti B CD5+ nel sangue periferico, nel midollo osseo e negli organi linfatici, dovuto sia ad un aumento della proliferazione che ad un difetto dei meccanismi di morte cellulare programmata. La resistenza all’apoptosi in questi linfociti favorisce la progressione della malattia attraverso un’aumentata sopravvivenza del clone neoplastico e l’induzione della resistenza ai farmaci citostatici. Tali alterazioni sono imputabili sia a fattori intrinseci che a fattori estrinseci derivanti dal microambiente. Poiché l’aumentata sopravvivenza ed il progressivo accumulo del clone linfocitario risultano selettivamente favoriti dall'interazione con cellule accessorie non tumorali presenti nel microambiente in cui esso risiede, in questa tesi abbiamo focalizzato l’attenzione sulle cellule mesenchimali staminali (MSC), allo scopo di valutare il loro ruolo nella sopravvivenza e nella compartimentalizzazione del clone B leucemico. Le MSC costituiscono una frazione esigua (inferiore allo 0,01%) della popolazione di cellule midollari, sono cellule staminali multipotenti in grado di differenziare in diversi tessuti di origine mesenchimale; sono inoltre dotate di proprietà immunomodulatorie verso linfociti B, T, Natural Killer e cellule dendritiche. In questa tesi le MSC sono state isolate dal sangue midollare di 47 pazienti affetti da LLC-B e sono state caratterizzate fenotipicamente e funzionalmente mediante analisi citofluorimetrica (positività per CD73, CD90 e CD105, negatività per CD31, CD34 e CD45) e colture differenziative (adipociti ed osteociti) confrontandole con MSC di donatori sani. Successivamente si sono allestite co-colture di linfociti B di pazienti affetti da LLC e MSC allo scopo di valutare l’effetto delle MSC sul clone neoplastico di LLC. Le MSC ottenute dai pazienti non hanno presentato alterazioni dal punto di vista fenotipico né funzionale rispetto alle MSC di donatori sani, tuttavia esse hanno sviluppato interazioni capaci di favorire la sopravvivenza del clone leucemico. Gli esperimenti di co-coltura hanno dimostrato infatti che le MSC esercitano un effetto anti-apoptotico sui linfociti B neoplastici, documentato da un aumento significativo della sopravvivenza delle cellule B di LLC dopo 7 giorni di coltura, effetto verificatosi anche con MSC di donatori sani e invece molto meno marcato nei linfociti B normali. Tale attività anti-apoptotica si è osservata, seppur di minore intensità, anche nei linfociti B di pazienti sottoposti a trattamento chemioterapico in vivo con Fludabarina e Ciclofosfamide, suggerendo che le MSC possano essere implicate anche nei meccanismi di chemio resistenza del clone di LLC. Infine l’analisi della migrazione cellulare dei linfociti B patologici in presenza di terreno condizionato derivante dalle colture di MSC ha dimostrato la capacità delle MSC di produrre stimoli chemiotattici in grado di richiamare in sede midollare il clone maligno, ma non i linfociti B normali. I dati riportati suggeriscono che le MSC nei pazienti affetti da LLC-B, sebbene non mostrino alterazioni dal punto di vista fenotipico e funzionale, svolgono un ruolo attivo nel favorire la sopravvivenza e la compartimentalizzazione delle cellule B neoplastiche a livello midollare.
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Boscaro, Elisa. « Fattori prognostici nella leucemia linfatica cronica di tipo B ». Doctoral thesis, Università degli studi di Padova, 2010. http://hdl.handle.net/11577/3427364.
Texte intégralRésumé :
B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults and it is characterized by the accumulation of monoclonal small CD5+ B lymphocytes, in peripheral blood, bone marrow and lymphoid organs. The clinical course encompasses indolent to aggressive disorders, the latter requiring intensive therapeutic intervention.
In the past, several clinical and biological prognostic factors have been proposed, including clinical stage, lymphocyte doubling time, bone marrow infiltration, percentage of prolymphocytes, serum β2 microglobulin, tymidine kinase and soluble CD23 levels. Even if these factors correlate with the clinical outcome of the CLL, they were not able to predict the evolution of the disease in patients at the earliest stages of disease. For this reason novel prognostic factors able to predict at diagnosis the clinical evolution of the disease and stratifying patients into groups with a different risk degree have been recently identified.
During the three years of this project we collected pheripheral blood samples from 247 patients affected by B-CLL referring to our Hematology and Clinical Immunology Unit and we evaluated the prognostic role of some new factors, including: somatic hypermutations of the Ig variable region genes (SHM), BCR VH repertoire, expression of CD38, CD305 and ZAP-70 in leukemic cells.
By flow cytometry, we compared two techniques for ZAP-70 analysis: the isotype control and the ratiometric method. Between the two methods we selected the second one because it was indipendent of the operator and more reproducible. Then we standardized this method for our laboratory instruments. We optimized threshold value for ZAP-70 expression and we selected the cut-off that had greatest sensitivity and specificity. Finally we compared the results obtained from 4 different monoclonal antibodies (MoAb) anti-ZAP-70, identifying two MoAb for the detection of ZAP-70: the anti-ZAP70 Alexa Fluor 488, Caltag Laboratories and anti-ZAP70 FITC, Upstate Cell Signaling Solution.
The analysis of LAIR-1 showed that it was reduced in CLL patients (41% ± 32) with respect to in healthy subjects (84% ± 1) and, in particular high-risk patients (stage 3 and 4) had less protein expression than lower-risk group (stage 0-2).
Our data confirmed the prognostic role of SHM in CLL: the median survival times for mutated and unmutated patients were 260 and 99 months, respectively (p<0,001). The evaluation of the VH repertoire highlighted a prevalent expression of the gene families VH3 (58% of the patients), VH1 (18% of the sample) and VH4 (18%). The expression of VH1 genes was associated with an unmutated IgVH status (58% of CLL patients); the expression of VH4 family was associated to a mutated status (SHM≥2%) and to a median global survival of 220 months, significantly higher when compared to the average of the whole sample (p<0,001).
We also demostrated a prognostic role for CD38 and ZAP-70 expression: the median overall survival for CD38 negative and positive patients was 123 and 250 months, respectively (p<0,01); the median survival for the ZAP-70 positive and negative patients was 135 and 220 months (p<0,01).
We analyzed the correlations between these prognostic factors. Statistical analysis showed a significant correlation between CD38 expression and the unmutated IgVH status (p<0,01) and between ZAP-70 expression and the absence of hypersomatic mutation (p<0,05). LAIR-1 was less expressed in both SHM negative patients and in CD38 positive patients.
Our data confirm the utility of new prognostic factors as far as they may predict the clinical evolution of the disease. However, the mutational status of variable heavy chain Ig genes at present represents the most reliable and mandatory prognostic factor. ZAP-70 evaluation by flow cytometry tecnology is promising but every laboratory should standardize appropriate methods according to the instruments and reagents available in their setting.La leucemia linfatica cronica di tipo B (LLC-B) è la forma più comune di leucemia dell'adulto ed è caratterizzata dall’accumulo nel sangue periferico, nel midollo osseo e negli organi linfatici di piccoli linfociti B monoclonali esprimenti il marcatore CD5. È una patologia eterogenea, la cui evoluzione varia da un decorso clinico indolente, che non necessita di alcuna terapia, ad una rapida progressione che richiede un trattamento. L’identificazione di fattori che permettano di stratificare pazienti a prognosi differente fin dalle fasi iniziali della malattia è uno dei principali obiettivi degli studi riguardanti la LLC-B. Negli anni sono stati definiti fattori di prognosi classici (il tempo di raddoppiamento linfocitario, l’infiltrazione del midollo osseo, la percentuale di prolinfociti, i livelli di β2 microglobulina, di timidina chinasi e di CD23 solubile), e, più recentemente, fattori prognostici correlati a caratteristiche molecolari del clone leucemico, tra i quali la presenza di alterazioni citogenetiche, lo stato mutazionale dei geni della catena pesante delle immunoglobuline (SHM), l’espressione dell’enzima telomerasi e di molecole quali CD38 e ZAP-70. Un possibile fattore prognostico, ancora in fase di valutazione, è infine il leucocyte-associated Ig-like receptor-1 (LAIR-1 o CD305), un recettore inibitorio, espresso sulla superficie delle cellule B, che può indurre la defosforilazione di diverse chinasi. Il progetto di ricerca sviluppato nei tre anni di dottorato mirava a definire il valore di alcuni fattori prognostici di recente definizione (CD38, CD305, ZAP-70 e SHM) e le possibili correlazioni esistenti tra essi. In particolare, poiché le modalità di determinazione dell’espressione della chinasi ZAP-70 sono oggetto di discussione a livello internazionale, una parte rilevante del triennio di questo dottorato di ricerca è stata dedicata alla valutazione ed alla comparazione di diversi metodi sperimentali, al fine di identificare un procedimento affidabile e ripetibile per la quantificazione di questa proteina. L’individuazione di un metodo affidabile e riproducibile per l’analisi di ZAP-70 mediante analisi citofluorimetrica ha portato alla scelta del metodo raziometrico, che valuta l’intensità media di fluorescenza di ZAP-70 nei linfociti B patologici in rapporto all’intensità media di fluorescenza della proteina nei linfociti T. Il metodo si è rivelato infatti più indipendente dall’operatore rispetto alle altre metodiche analizzate. Una volta stabilito il metodo più appropriato, abbiamo adeguato la metodica alla strumentazione del nostro laboratorio di Ematologia e Immunologia Clinica. Abbiamo quindi stabilito il valore soglia che meglio distingueva tra pazienti positivi e negativi e che ci permetteva di ottenere le maggiori specificità e sensibilità e abbiamo infine confrontato i dati ottenuti dall’utilizzo di diversi anticorpi monoclonali in grado di riconoscere la proteina ZAP-70 dimostrando che i due anticorpi che davano risultati maggiormente riproducibili e più simili tra loro erano l’anticorpo anti-ZAP70 Alexa Fluor 488, Caltag Laboratories e l’anticorpo anti-ZAP70 FITC, Upstate cell signaling solution. Per quanto riguarda gli altri fattori prognostici esaminati, abbiamo innanzitutto confermano il ruolo prognostico delle SHM nei 247 pazienti da noi analizzati e afferenti all’Unità operativa di Ematologia e Immunologia Clinica. Infatti il valore medio di sopravvivenza globale per i pazienti con SHM≥2% rispetto alle sequenze germline è risultato pari a 260 mesi e 99 mesi rispettivamente (p<0,001). La valutazione del repertorio VH ha evidenziato una prevalente espressione della famiglia VH3 (58% del campione). Le altre famiglie VH più rappresentate erano la famiglia VH1 (18% del campione) e VH4 (18%). L’espressione della famiglia VH1, era associata ad un’elevata probabilità di avere uno stato mutazionale <2% delle IgVH (58%). L’espressione della famiglia VH4, invece, si associa ad uno stato mutato (≥2%) delle IgVH (67%) e ad una sopravvivenza globale media di 220 mesi, significativamente superiore rispetto alla media dell’intero campione (p<0,001). Anche CD38 e ZAP-70 hanno dimostrato un ruolo prognostico importante: la sopravvivenza globale media per i pazienti CD38 positivi e negativi era pari rispettivamente a 123 mesi e 250 mesi (p=0,002); la sopravvivenza globale media per i pazienti ZAP-70 positivi e negativi era pari a 135 e 220 mesi (p=0,009). Lo studio dell’espressione di LAIR-1 ha dimostrato che questo recettore è espresso mediamente in quantità minore (41%±32) rispetto ai soggetti sani (84%±1), ed in particolare i pazienti ad alto rischio (stadio 3 e 4) avevano un’espressione minore della proteina rispetto al gruppo a minor rischio (stadio 0-2). Abbiamo valutato l’esistenza di correlazioni tra i diversi fattori prognostici. Abbiamo così rilevato una correlazione statisticamente significativa tra l’espressione di CD38 e l’assenza di ipermutazioni somatiche (p<0,01). Analogamente, abbiamo osservato una correlazione tra la positività di espressione di ZAP-70 e la mancanza di SHM (p<0,05). Per quanto riguarda LAIR-1, il recettore risulta espresso in quantità minore sia nei pazienti con SHM<2% sia in quelli CD38 positivi, mentre non è emersa alcuna differenza quando si sono considerati i pazienti per l’espressione di ZAP-70. I risultati ottenuti confermano l’efficacia dei fattori prognostici innovativi nel predire fin dal momento della diagnosi il possibile decorso clinico della malattia. Lo stato mutazionale rimane il fattore prognostico di riferimento e attualmente non sostituibile. Per quanto riguarda la proteina ZAP-70, promettente per la praticità e la rapidità della metodica impiegata per la sua valutazione, va sottolineato che ogni laboratorio deve standardizzare la metodica adeguandola agli strumenti ed ai reagenti in dotazione.
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Muraro, Elena. « IGHV1-69 as a promising candidate for the development of a shared immunotherapy to B-cell lymphomas ». Doctoral thesis, Università degli studi di Padova, 2013. http://hdl.handle.net/11577/3423387.
Texte intégralRésumé :
B-cell Non-Hodgkin Lymphomas (B-NHL) are a heterogeneous group of cancers, broadly diffused worldwide and often relapsing after standard treatment and rituximab. Therapeutic vaccines targeting B-NHL idiotype (Id) represent a promising approach to maintain the complete response induced by standard treatments. However, customized idiotypic vaccination still remains a non-approved, experimental therapeutic option, mostly due to the personalized use and penalized by the lack of reliable clinical or biological markers of patient eligibility and responsiveness. Nevertheless, the molecular characterization of different lymphoid tumor histotypes revealed a set of stereotyped immunoglobulins among distinct B-cell lymphoma types. On this ground, we focused our attention on the IGHV1-69 protein, frequently expressed in HCV-associated lymphomas, chronic lymphocytic leukaemia, and auto-immunity related lymphoproliferations, and we characterized the ex vivo immunogenicity of this protein.
Seventy IGHV1-69 sequences obtained from patients affected by different B-NHLs or pre-malignant lymphoproliferations were compared to design an optimized sequence characterized by the highest degree of similarity among studied cancers, and thus CDR3 hypervariable region free. Within this “immunogenically” optimized sequence, we identified 13 potential HLA class-I cytotoxic T lymphocyte (CTL) epitopes and synthesized the corresponding pentamers (Pent). We assessed by flow cytometry the presence and extent of epitope-specific T-cell responses in peripheral blood of patients with IGHV1-69+ B-cell lymphoproliferative disorders and healthy donors, and validated these data in IFN-γ ELISPOT (Enzyme-linked immunosorbent spot) assays. Finally, we boosted in vitro IGHV1-69-specific responses by stimulating peripheral blood lymphocytes (PBL) from donors and patients with different protocols for the generation of epitope-specific CTL cultures.
Interestingly, the IGHV1-69 Pent+ population observed in patients’ samples was generally larger than in donors, supporting the existence of spontaneous memory T-cell responses against IGHV1-69, at least for some HLA-restrictions. Surprisingly, in patients’ samples, IGHV1-69-recognizing T cells displayed higher IFN-γ release in ELISPOT assays compared to viral-specific T cells. Moreover, we obtained peptide-specific CTL lines, which showed a weak but specific lysis against peptide-pulsed targets, especially when derived from patients’ PBLs. In addition, we were able to generate IGHV1-69-epitope specific CTL clones from healthy donors CD8+ T cells, employing synthetic artificial APC, developed to elicit and expand low-avidity tumor-directed human CTL lines. Finally, IGHV1-69-induced CTL lines showed specific lysis also towards an IGHV1-69 naturally expressing cell line, suggesting that IGHV1-69 memory T-cell responses could be boosted for therapeutic purposes.
These results show that IGHV1-69 constitutes a potential target for the development of a subset-specific Id vaccine. Furthermore, multimer (tetramers and pentamers) and ELISPOT immune-monitoring may partially overcome the main limitations of current Id-targeting vaccinations and further improve their clinical efficacy.I Linfomi Non-Hodgkin a cellule-B (B-NHL) rappresentano un gruppo eterogeneo di patologie, ampiamente diffuse nel mondo e caratterizzate da frequenti ricadute in seguito a trattamenti standard o terapia con rituximab. Vaccini terapeutici che hanno come bersaglio l’Idiotipo (Id) dei B-NHL, costituiscono un approccio promettente nel mantenere la risposta completa indotta con trattamenti standard. Tuttavia, i vaccini idiotipici personalizzati rappresentano ancora un approccio terapeutico sperimentale e non approvato su larga scala, principalmente perché paziente-specifici e perché privi di marcatori attendibili per l’identificazione di pazienti elegibili e di risposta alla terapia. Ciononostante, la caratterizzazione molecolare di differenti istotipi di tumori di origine linfoide, ha rivelato la presenza di una serie di immunoglobuline stereotipate anche fra linfomi di diverso tipo. Su questi presupposti, abbiamo focalizzato la nostra attenzione sulla proteina IGHV1-69, frequentemente espressa in linfomi associati all’infezione da HCV, nella leucemia linfatica cronica (CLL) e in linfoproliferazioni associate ad auto-immunità, e abbiamo valutato in vitro l’immunogenicità di questa proteina. Inizialmente, abbiamo confrontato 70 sequenze relative alla proteina IGHV1-69 e ottenute da pazienti affetti da differenti B-NHLs o linfoproliferazioni pre-maligne, allo scopo di ideare una sequenza ottimizzata, caratterizzata dal maggior grado di similarità fra i tumori presi in esame, e pertanto priva della regione ipervariabile CDR3. All’interno di questa nuova sequenza, abbiamo identificato 13 epitopi potenzialmente riconoscibili da linfociti T citotossici (CTLs) nell’ambito di 7 alleli HLA di classe I, e abbiamo sintetizzato i corrispondenti pentameri (Pent). Tramite citofluorimetria a flusso abbiamo quindi valutato la presenza di risposte T-cellulari specifiche per gli epitopi derivati da IGHV1-69, in campioni di sangue periferico ottenuti da pazienti affetti da linfoproliferazioni esprimenti IGHV1-69 e da donatori sani. Abbiamo inoltre validato questi dati tramite saggi ELISPOT (Enzyme-linked immunosorbent spot) per l’identificazione del rilascio di IFN-γ. Infine abbiamo stimolato in vitro le risposte specifiche per IGHV1-69, inducendo i linfociti del sangue periferico (PBLs) di donatori sani e pazienti, attraverso diversi protocolli per la generazione di colture CTL epitopo-specifiche. E’ stato interessante osservare come nei campioni ottenuti da paziente la popolazione di linfociti T CD8+ positiva ai pentameri specifici per gli epitopi di IGHV1-69 sia risultata generalmente più numerosa della corrispondente popolazione osservata in donatori sani. Questo dato supporta l’esistenza di risposte memoria T cellulari nei confronti di IGHV1-69, almeno in alcune restrizioni HLA. Inoltre, nei campioni ottenuti da paziente le cellule T specifiche per gli epitopi di IGHV1-69 hanno rivelato in saggi ELISPOT un maggior rilascio di IFN-γ rispetto ai linfociti T specifici per epitopi virali. In aggiunta, stimolando parallelamente PBLs di donatori sani e pazienti, abbiamo ottenuto linee CTL peptide-specifiche, in grado di riconoscere debolmente, ma in modo specifico target caricati con il peptide d’interesse, soprattutto quando derivate da PBLs di pazienti. Inoltre, tramite l’utilizzo di antigen-presenting cells artificiali, prodotte allo scopo di indurre ed espandere linee CTL caratterizzare da bassa affinità nei confronti di antigeni tumorali, abbiamo anche generato cloni CTL specifici per un epitopo di IGHV1-69 a partire da linfociti T CD8+ di donatori. Infine, si è evidenziato che colture CTLs indotte in seguito a stimolo con epitopi derivanti da IGHV1-69, sono in grado di riconoscere in modo specifico una linea cellulare naturalmente esprimente IGHV1-69, suggerendo in questo modo che le risposte memoria T-cellulari specifiche per IGHV1-69, possano essere stimolate ed espanse a scopi terapeutici. Questi risultati dimostrano che IGHV1-69 costituisce un target potenziale per lo sviluppo di un vaccino Id applicabile su un sottogruppo di linfomi a cellule B. Inoltre, l’immunomonitoraggio tramite marcatura con multimeri (tetrameri o pentameri) e saggi ELISPOT potrebbe eludere almeno parzialmente i principali limiti degli attuali vaccini idiotipici, al fine di incrementare ulteriormente la loro efficacia clinica.
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Paderi, Francesca. « Bone metabolism involvement in acute lymphocytic leukemia : the receptor Activator Nuclear Factor Kappa B Ligand pathway ». Doctoral thesis, Università degli studi di Padova, 2015. http://hdl.handle.net/11577/3424235.
Texte intégralRésumé :
This study begins with the clinical observation of muscolo-skeletal involvement in leukaemia.
Bone metabolism alterations have been reported before diagnosis, and persist during therapy and follow up. The Receptor Activator Nuclear Factor Kappa B Ligand (RANKL), also known as CD254, represents the major pathway that regulates bone metabolism. This ligand can exist either as a soluble form either as membrane form (CD254). The ligand is expressed mainly by bone forming cells osteoblasts (OBs) and its receptor RANK is expressed by bone resorbing cells osteoclasts (OCs). Upon the binding of the ligand to its receptor osteoclasts precursor are induced to fuse into a multinucleate cell, able to resorb bone substrates. Flow cytometry analysis showed that membrane CD254 was up regulated in B ALL patients at diagnosis compared with control patients (Stop therapy and maintenance).
Co-colture of CD14+ osteoclast precursors have been performed in order to assess the ability of CD14+ to fuse into multinucleate cells and eventually to resorb bone substrate. We evaluated the ability of a leukaemia cell line SEM, showing CD254 expression to influence CD14+ cells to differentiate and digest bone. Subsequently we co-coltured primary bone marrow cells from patients at diagnosis and controls and the ability to induce multinucleation of CD14+ cells were evaluated. Gene expression profile (GEP) was performed in order to see if RANKL involved pathways were altered in patients at diagnosis. We found that osteoclastogenic pathway, and osteoclast specific genes involved in osteopetrosis were down regulated.
In this context of interaction we decided to focus on the cell communication through circulating membrane vesicles. Known with the generic term of extracellular vesicles (EVs), those can be isolated from the peripheral and bone marrow plasma. Here they have been isolated and analysed by flow cytometer for specific B leukemic (CD19), platelets (CD61) and bone (CD254) markers. The results showed that the overall number of EVs in peripheral blood plasma from diagnosis was reduced compared to the controls. Only few CD19+ vesicles were present in the peripheral blood plasma of diagnosis.
In conclusion this study highlights the importance of the interaction between blasts cells and the bone metabolism, suggesting leukaemia can actively influence osteoclasts precursors.Lo studio parte dall’osservazione che i pazienti pediatrici affetti da leucemia, presentano un interessamento osseo ancora prima della diagnosi e che persiste durante e dopo la terapia. La principale via regolatrice del metabolismo osseo è quella del Receptor Activator Nuclear Factor Kappa B Ligand (RANKL), anche noto come CD254. Questo ligando esiste sia in forma solubile sia di membrana (CD254). Il CD254 è espresso soprattutto dagli Osteoblasti (OBs), le cellule responsabili della formazione dell’osso, mentre il suo recettore, RANK, dagli Osteoclasti (OCs), le cellule deputate al riassorbimento. Gli osteoclasti degradano l’osso dopo l’attivazione attraverso il legame del RANKL. Altre cellule possono esprimere il RANKL e l’alta espressione del RANKL è associata alla capacità delle cellule di indurre osteolisi. L’analisi al citofluorimetro ha dimostrato che l’espressione della forma di membrana CD254 è up-regolata nei pazienti all’esordio B LLA Common rispetto ai controlli fuori terapia o a fine mantenimento. Mediante esperimenti di co-cultura è stata studiata la capacità dei blasti di influenzare il differenziamento dei precursori degli osteoclasti. E’ stata valutata quindi la capacità dei precursori CD14+ di fondersi a formare una cellula multinucleata, l’osteoclasto maturo, il quale in seguito diventa attivo e in grado di degradare la matrice ossea. La capacità di degradazione dell’osso è stata valutata usando una linea cellulare leucemica (SEM) esprimente il CD254, messa in co coltura con i CD14+. Le cellule coltivate in un terreno contenente frammenti di osso sono state in grado di degradare il substrato osseo. E’ stata poi valutata la capacità di multinucleazione da parte dei blasti da BM degli esordi ed esprimenti CD254 rispetto a quella dei controlli. Si è visto che l’alta espressione del RANKL sui blasti CD19+ dei pazienti alla diagnosi induce multinucleazione dei CD14+. Inoltre studi di Gene Expression Profile (GEP) sono stati fatti per valutare se ci fosse un’alterazione dei geni coinvolti nell’osteoclastogenesi e nell’osteopetrosi e alcuni di questi sono risultati down regolati in modo significativo. In questo network d’interazioni cellulari abbiamo voluto studiare un aspetto della comunicazione cellulare che riguarda le Microvescicole circolanti o “Extracellular Vesicles” (EVs). Le EVs sono state caratterizzate al citometro per l’espressione di marcatori di leucemia (CD19), piastrine (CD61) e per il metabolismo osseo (CD254). I risultati indicano che la produzione di EVs negli esordi dei pazienti B ALL è down regolata e che solo poche vescicole esprimono il CD19. Nel complesso questi dati suggeriscono che esiste un coinvolgimento diretto dei blasti nella via che regola il metabolismo osseo e che i blasti possono influenzare gli osteoclasti.
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United States. Federal Highway Administration., dir. Testing Of New Bridge Rail And Transition Designs... Volume III : Appendix B BR27D Bridge Railing... Publication No. FHWA-RD-93-060... U.S. Department Of Transportation... June 1997. [S.l : s.n., 1997.
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Bastos, Rui Calçada. Rui Calçada Bastos : Rua Conde das Antas 53-B, 1070-069 Lisboa. Lisboa : Documenta, 2020.
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Bailey, Allen A. Oral history interview with Allen Bailey, [date unknown] : Interview B-066, Southern Oral History Program Collection (#4007). [Chapel Hill, N.C.] : University Library, UNC-Chapel Hill, 2006.
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Neil, Henderson J., et Vesperi Maria D, dir. The Culture of long term care : Nursing home ethnography. Westport, Conn : Bergin & Garvey, 1995.
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Razali, Azhar Rhafsah bin, 1953- et Indonesia. Kejaksaan Negeri (Banda Aceh), dir. Surat dakwaan no. perk. 06/SUBV/B. ACEH/3/1991, nama lengkap Azhar Rhafsah bin Razali ... [Banda Aceh] : Kejaksaan Negeri Banda Aceh, 1991.
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International Workshop Ontology Based Modelling in Humanities (1st 2006 Universität Hamburg). First International Workshop Ontology Based Modelling in Humanities : 7-8 April 2006, University of Hamburg : FBI-HH-B-264/06. Sous la direction de Hahn Walther von 1942- et Vertan Cristina. Hamburg : Universität Hamburg, Bibliothek des Departments Informatik, 2010.
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budget, Cameroon Direction du. Circulaire no 2985 MINFI/B du 06 juillet 1990 : Portant instructions relatives à l'exécution et au contrôle de l'exécution du budget de l'Etat pour l'exercice 1990/1991. [Yaounde?] : Le Ministère, 1990.
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H, Peden Ann, dir. Comparative health information management. 2e éd. Australia : Delmar Learning, 2005.
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E, Ambrose Stephen. Wild blue : 741 Squadron, on a wing and a prayer over occupied Europe. London : Pocket Books, 2002.
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1959-, Ollila Eeva, dir. Making a healthy world : Agencies, actors, and policies in international health. Helsink : Stakes, 1997.
Trouver le texte intégralChapitres de livres sur le sujet "B-060"
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Wright, Jacob L. « Christopher B. Hay, Death In The Iron Age II And In First Isaiah ». Dans Perspectives on Hebrew Scriptures IX, sous la direction de Ehud Ben Zvi et Christophe Nihan, 677–80. Piscataway, NJ, USA : Gorgias Press, 2014. http://dx.doi.org/10.31826/9781463235635-060.
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Delvig, A. A., L. I. Krasnoproshina, V. I. Kuvakina et B. A. Dmitriev. « Protective activity of detoxified lipooligosaccharides of Neisseria meningitidis serogroups A and B in mice ». Dans Neisseriae 1990, sous la direction de Mark Achtman, Peter Kohl, Christian Marchal, Giovanna Morelli, Andrea Seiler et Burghard Thiesen, 331–36. Berlin, Boston : De Gruyter, 1991. http://dx.doi.org/10.1515/9783110867787-060.
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Nawangsih, Eka Noneng, Apen Apgani et Bintari Rizkia Sekar Tirani. « The Effect of Inulin and Sucrose Addition on the Number of Colonies L. acidophilus and B. bifidum in the Soyghurt After the Freeze-Drying Process ». Dans Proceedings of The 13th Annual Scientific Conference of Medical Faculty, Universitas Jenderal Achmad Yani (ASCMF 2022), 65–75. Dordrecht : Atlantis Press International BV, 2022. http://dx.doi.org/10.2991/978-94-6463-060-2_11.
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« B. Missbrauchsverbot ». Dans Handbuch Vorstand und Aufsichtsrat, 1014–31. RWS Verlag, 2023. http://dx.doi.org/10.15375/9783814558745-060.
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« john work ». Dans B Jenkins, 83. Duke University Press, 2020. http://dx.doi.org/10.1515/9780822392675-060.
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« John Work ». Dans B Jenkins, 83. Duke University Press, 2010. http://dx.doi.org/10.1215/9780822392675-060.
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« Kapitel 24 (617 b 16–617 b 19) ». Dans Historia animalium, 827–29. De Gruyter, 2019. http://dx.doi.org/10.1515/9783110526073-060.
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« Appendix B : JPPI Brainstorming Participants ». Dans Rise and Decline of Civilizations, 380–81. Boston, USA : Academic Studies Press, 2019. http://dx.doi.org/10.1515/9781618112774-060.
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« B Ethischer Kompass der Gesellschaft für Informatik ». Dans Gewissensbisse - Fallbeispiele zu ethischen Problemen der Informatik, 204–7. transcript Verlag, 2023. http://dx.doi.org/10.1515/9783839464632-060.
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« Appendix B : Alternate Table of Contents by Theme ». Dans A Black Philadelphia Reader, 345–46. Penn State University Press, 2024. http://dx.doi.org/10.1515/9780271098265-060.
Texte intégralActes de conférences sur le sujet "B-060"
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Miesbach, WA, K. Meijer, M. Coppens, P. Kampmann, R. Klamroth, R. Schutgens, G. Castaman et al. « AMT-060 Gene Therapy in Adults with Severe or Moderate-Severe Hemophilia B Confirms Stable FIX Expression and Sustained Reductions in Bleeding for up to 5 Years ». Dans 65th Annual Meeting of the Society of Thrombosis and Haemostasis Research. Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0041-1728089.
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Miesbach, W., M. Recht, N. Key, K. Sivamurthy, E. P. Monahan et W. S. Pipe. « Durability of Factor IX activity and bleeding rate in people with severe or moderately severe haemophilia B after long-term follow-up in the phase 1/2 Study of AMT-060, and phase 2b and phase 3 studies of etranacogene dezaparvovec (AMT-061) ». Dans GTH Congress 2023 – 67th Annual Meeting of the Society of Thrombosis and Haemostasis Research – The patient as a benchmark. Georg Thieme Verlag, 2023. http://dx.doi.org/10.1055/s-0042-1760526.
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« Session 06-B TCAD : Applications II ». Dans 2010 International Conference on Simulation of Semiconductor Processes and Devices (SISPAD 2010). IEEE, 2010. http://dx.doi.org/10.1109/sispad.2010.5604560.
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Kokro, Aspa P., Raju Datla et Muhammad Hajj. « Ocean Wave Harvesting for Supplemental Powering of a Small Autonomous Boat ». Dans SNAME Maritime Convention. SNAME, 2023. http://dx.doi.org/10.5957/smc-2023-060.
Texte intégralRésumé :
This study presents the concept of a small autonomous catamaran for operation in remote offshore areas for long duration. The relative linear motion between the hulls and the main deck is converted into a rotational motion of an electrical generator to harvest wave energy for supplemental powering and improving the overall energy efficiency of the craft. The design of “DavLab” catamaran is optimized by matching the natural undamped frequency of the system to the frequency of dominant waves for a top referenced heaving absorber. In addition, numerical simulation results showed that increasing the design waterline reduces vertical motion, and the hull responses increase with increasing length to beam ratio and decreasing beam to draft ratio. Consequently, the combined motion at the power take-off system positions were increased by selecting a slender body with L/B = 5.88 and large draft B/T = 1.89 for large motion at operating conditions. In head seas, the required power for a 1/3 scale model at Froude number equal to 0.6 is predicted about 3.5 W. For supplemental powering with wave energy harvesting, the wave run predictions in head seas for a dominant period of 2 seconds and significant wave height of 0.2 m were evaluated at two model speeds, namely Vm0 = 0 m/s and Vm1 = 2.66 m/s corresponding to Froude number 0 and 0.6. Predictions for maximum generated power are 4.7 W and 12.7 W at Vm0 and Vm1 respectively. Therefore, the 1/3 scale model of the Catamaran suspension is to be built and tested in Davidson Laboratory Towing Tank #3 in regular and irregular head seas.
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Bernusky, Haley, Phil Tibbo, Fakir Yunus, Patricia Conrod, Matthew Keough, Kara Thompson, Marvin Krank et Sherry Stewart. « Does Anxiety Mediate the Relationship Between Cannabis Use and Psychotic-Like Experiences in Emerging Adults ? Investigating a Conditional Process Model in a Multi-Site University Sample ». Dans 2022 Annual Scientific Meeting of the Research Society on Marijuana. Research Society on Marijuana, 2022. http://dx.doi.org/10.26828/cannabis.2022.02.000.15.
Texte intégralRésumé :
Background/Aim: Cannabis is commonly used by Canadian emerging adults (ages 18-25 years), many of whom attend post-secondary institutions. Frequent cannabis use has been linked with psychotic-like experiences (PLEs); however, the exact nature of this complex relationship remains to be fully understood. Anxiety is a prevalent mental health concern in emerging adults and university students, and anxiety has been independently linked with both cannabis use and PLEs. Males and females use cannabis and experience mental health differently: females tend to be more anxious while males tend to use more cannabis and are at higher risk for psychotic-like experiences. In this first of two studies for my Masters, I evaluated whether anxiety mediated the relationship between cannabis use frequency and PLEs in emerging adult undergraduates. I then tested the impact of moderation by biological sex by assessing if the mediation model held statistical significance across sexes. Hypotheses: H1) Consuming cannabis more frequently will be associated with more anxiety which, in turn, will be associated with greater PLEs in emerging adults, H2) the anxiety mediation pathway will be statistically stronger for females; and H3) males will have a stronger direct association between cannabis use and PLEs. Method: A sample of 1,507 first- and second-year emerging adult university students (mean [SD] age = 19.2 [1.52] years; 67% female) were recruited. Cross-sectional, self-report survey data were collected throughout fall 2021 from five Canadian universities as part of the UniVenture substance misuse prevention trial. Validated measures capturing demographics, cannabis use frequency, anxiety, and PLEs were administered. Results: The mediation model with cannabis use frequency as the predictor, PLEs as the outcome, and anxiety as the mediator was tested, followed by testing a moderated mediation (conditional process) model with biological sex moderating the paths from cannabis use frequency to anxiety and from cannabis use frequency to PLEs using the PROCESS macro for SPSS. Bootstrapped 95% confidence intervals showed evidence of a significant indirect effect of cannabis use on PLEs through anxiety for emerging adults (a-path p < .001; b-path p < .001; 95% CI [.016, .048]), supporting H1. No direct effect was found (c’-path p = .946) suggesting that the relationship between frequent cannabis use and PLEs may be fully mediated by anxiety. In the second model, significant moderated mediation was found (95% CI [.005, .060]). More frequent cannabis use was associated with increased anxiety among females only. Conditional indirect effects showed significant mediation through anxiety for females (95% CI [.020, .056]), but not males (95% CI [-.015, .028]), consistent with H2. No significant sex moderation was found for conditional direct effects of cannabis on PLEs for either males (p = .667) or females (p = .907), contrary to H3. Conclusion: Assuming replication in prospective research, results highlight anxiety as an important intervention target in frequent female cannabis users to potentially prevent the development or worsening of PLEs. Understanding differential trajectories from frequent cannabis use to PLEs is important for informing individualized prevention and programming and encouraging health equity.
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Costa, Gabriel Galete. « NOVA TERAPIA GÊNICA PROMISSORA PARA HEMOFILIA B : ETRANACOGENE DEZAPARVOVEC/AMT-061 ». Dans Congresso Brasileiro de Pesquisas e Análises Clínicas On-line. Revista Multidisciplinar em Saúde, 2023. http://dx.doi.org/10.51161/conaclil/17063.
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Thies, Katie A., Anisha M. Hammer, Sarah A. Steck, Manjusri Das, Raleigh D. Kladney, Steven T. Sizemore, Michael C. Ostrowski et Gina M. Sizemore. « Abstract P6-06-06 : Platelet derived growth factor-b (PDGFB) promotes breast cancer progression ». Dans Abstracts : 2019 San Antonio Breast Cancer Symposium ; December 10-14, 2019 ; San Antonio, Texas. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.sabcs19-p6-06-06.
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Miesbach, W., G. Castaman, N. S. Key, S. Lattimore, F. G. Leebeek, S. Zelenkofske, M. Recht et S. W. Pipe. « HOPE-B : Study Design of a Phase III trial of an Investigational Gene Therapy AMT-061 in Subjects with Severe or Moderately Severe Hemophilia B ». Dans 63rd Annual Meeting of the Society of Thrombosis and Haemostasis Research. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1680217.
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Antonios, J., T. Barak, B. Gultekin, K. Yalcin, A. Chamberlain, R. Hebert, C. Matouk et M. Gunel. « O-068 Regulatory B cell and adjunctive immune population drives intracranial aneurysm rupture in patient population ». Dans SNIS 20th Annual Meeting Abstracts. BMA House, Tavistock Square, London, WC1H 9JR : BMJ Publishing Group Ltd., 2023. http://dx.doi.org/10.1136/jnis-2023-snis.68.
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Yan, H., S. Viswanadhapalli, M. Fernandez, C. Rivera, G. Sareddy, P. Casali et R. Vadlamudi. « Abstract P4-06-15 : Role of B lymphocytes and B cell-produced IL-27 in breast cancer progression and drug resistance ». Dans Abstracts : 2018 San Antonio Breast Cancer Symposium ; December 4-8, 2018 ; San Antonio, Texas. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-p4-06-15.
Texte intégralRapports d'organisations sur le sujet "B-060"
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Kiss, F., J. Potvin, M. Coyle et M. McLeod. Magnetic first vertical derivative map, 21G/06 a,b, New Brunswick. Natural Resources Canada/ESS/Scientific and Technical Publishing Services, 2002. http://dx.doi.org/10.4095/213421.
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Ilas, Germina, Ian C. Gauld, Robert Michael Westfall et Marco T. Pigni. Evaluation of Hanford B Reactor Experiments (PTA-069 and PTA-084) for Code and Data Benchmarking. Office of Scientific and Technical Information (OSTI), juin 2014. http://dx.doi.org/10.2172/1134648.
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Coyle, M. Residual total magnetic field, Southampton Island aeromagnetic survey, Mount Scotch Tom / Post River, NTS 46 B/05 and 46 B/06, Nunavut. Natural Resources Canada/ESS/Scientific and Technical Publishing Services, 2008. http://dx.doi.org/10.4095/225213.
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Coyle, M. First vertical derivative of the magnetic field, Southampton Island aeromagnetic survey, Mount Scotch Tom / Post River, NTS 46 B/05 and 46 B/06, Nunavut. Natural Resources Canada/ESS/Scientific and Technical Publishing Services, 2008. http://dx.doi.org/10.4095/225228.
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Shen, Gianetto et Tyson. L52342 Development of Procedure for Low-Constraint Toughness Testing Using a Single-Specimen Technique. Chantilly, Virginia : Pipeline Research Council International, Inc. (PRCI), décembre 2011. http://dx.doi.org/10.55274/r0010687.
Texte intégralRésumé :
Pipelines from remote frontier regions are increasingly required to have adequate resistance to large deformations such as that caused by ground movement. In response to this, �strain-based design"� has been developed to enable assessment of imperfections at applied strains beyond yield. In addition, it is proposed to take advantage of the increased apparent toughness of pipe under low constraint, such as girth weld imperfections under axial tension, compared with the high-constraint toughness measured in conventional tests such as ASTM E1290 [1]. Application of low-constraint testing has been dvantageously applied in assessment of toughness for offshore pipeline projects. Also in the pipeline industry, demands on new pipeline projects include low design temperatures as well as high strain capacity. At the same time, increased strength is specified, which increases the level of required toughness. These factors make it increasingly important to assure weldment toughness, in particular to ensure that the failure mode remains ductile. It is well known that brittle cleavage is especially sensitive to constraint, and the availability of a toughness test that would reproduce field conditions would enable more rational development and acceptance of candidate welds and, in particular, enable more appropriate testing of weld heat-affected zones. This work was performed for specific application to surface circumferential cracks in pipe under strain-based design, for which the best constraint matching has been found to occur for clamped single-edge tension (SE(T)) specimens with H/W=10. For this geometry, a test procedure similar to that of ASTM E1820-06 for single-edge bend (SE(B)) and compact tension (C(T)) specimens was developed for J-resistance tests using a single-specimen technique. All the equations used in the procedure, including those for evaluation of J-integrals from the area under load/plastic crack mouth opening displacement (CMOD) curves, and evaluation of crack length from unloading compliance including rotation correction, were developed using finite element analysis (FEA) with a range of crack depths, focusing on a/W= 0.2 to 0.5 which is of most practical interest. The present procedure is compared with that of E1820 for SE(B) testing regarding evaluation of J-integral with crack growth correction, crack length evaluation, and correction of compliance for rotation.