Journal articles on the topic 'DAC Report'
To see the other types of publications on this topic, follow the link: DAC Report.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'DAC Report.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Rodriguez, María Victoria, Estefanía Butassi, Matías Funes, and Susana A. Zacchino. "Synergism between Terbinafine and a Neo-clerodane Dimer or a Monomer Isolated from Baccharis flabellata against Trichophyton rubrum." Natural Product Communications 14, no. 1 (January 2019): 1934578X1901400. http://dx.doi.org/10.1177/1934578x1901400101.
Full textAbstract:
The new neo-clerodane dimer (DACD) likely formed by a [4+2] photo-cycloaddition between two molecules of ent-15,16-epoxy-19-hydroxy-1,3,13(16),14-clerodatetraen-18-oic acid (DAC), both isolated from Baccharis flabellata Hook et Arn. var. flabellata (Asteraceae), were tested in combination with terbinafine (Terb) against Trichophyton rubrum. The interactions were assessed with different methodologies such as 3D CombiTool software, Loewe Combination Index (CI) and isobolograms. Results showed that the monomer DAC as well as its dimer DACD act synergistically with Terb against T. rubrum. DAC/Terb and DACD/Terb showed eight and twelve synergistic mixtures respectively in the CombiTool graphics thus suggesting that DACD/Terb was more synergistic with Terb than DAC. These results were corroborated by the CI values and the isobolograms of the detected combinations. DACD/Terb showed much lower CIs (0.34-0.47) than DAC/Terb (0.57-1.15) at the different inhibition percentages tested. Concomitantly, DACD/Terb isobolograms were more concave than for DAC/Terb at the different inhibition percentages. This is the first report showing antifungal synergistic interactions of neo-clerodanes dimers and add new evidences that neo-clerodanes monomers interact synergistically with Terb against T. rubrum.
2
Obermeier, Fred W. "A report on DAC-87." ACM SIGDA Newsletter 17, no. 3 (September 1987): 39. http://dx.doi.org/10.1145/378916.378944.
Full text
3
Saba, Hussain, Craig Rosenfeld, Jean-Pierre Issa, John DiPersio, Azra Raza, Virginia Klimek, James Slack, Carlos de Castro, Karl Mettinger, and Hagop Kantarjian. "First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome (MDS)." Blood 104, no. 11 (November 16, 2004): 67. http://dx.doi.org/10.1182/blood.v104.11.67.67.
Full textAbstract:
Abstract MDS is a disease of the elderly marked by dysplasia of hematopoetic cell lines resulting in cytopenias and AML progression. There is currently no treatment approved to alter the natural history of the disease. Aberrant methylation associated with cancer is a potential target for pharmacologic therapy, and DacogenTM (decitabine) for injection (SuperGen, Inc.), a cytosine analogue, indirectly depletes methylcytosine after incorporation into DNA with subsequent inactivation of DNA methyltransferases. We report the results of a Phase III trial of decitabine (DAC) vs. supportive care (Supp.Care) in adult MDS patients with IPSS Intermediate (Int)-1 (31%), Int-2 (44%) and high risk disease (26%). Secondary MDS (14%) and previously treated (27%) MDS patients were not excluded. Bone marrows were assessed by a blinded, independent pathologist. 170 patients (accrued from July 2001 through April 2003 at 23 centers) were randomized 1:1 to either Supp.Care or DAC (a 3 hr infusion of 15mg/m2/hr every 8 hrs on 3 consecutive days every 6 wks for up to 10 cycles. The groups were comparable for numerous risk factors, including time from diagnosis (median 29 weeks for DAC and 35 weeks for Supp.Care). Kaplan Meier (KM) curves for time to AML progression or death showed early and clinically meaningful separation (consistent with clinical benefit) in favor of DAC in all patients (intent to treat; ITT), Int-2/High Risk, and High Risk patients. Using the Cox proportional hazards model for the ITT population, the probability of progression to AML or death was 1.68-fold greater for Sup.Care than for DAC (p=0.023). Median Time to AML or Death (Days) MDS group (n) DAC Supp.Care p-value 1Protocol specified test. 2Preferred test for analysis of early separation of KM curves. n=89 n=81 Wilcoxon1,2 Log rank1 All Patients (170) 338 263 0.046 0.204 Int-2/High Risk (118) 334 189 0.005 0.040 High Risk (44) 260 79 0.001 0.006 Treatment naïve (124) 354 189 0.005 0.034 Figure Figure Investigator reported response rate by International Working Group criteria was 25% (10% CR, 15% PR) for DAC vs. 0% for Supp.Care (p< 0.001), with responses equally distributed across baseline subgroups. Time to response was 100 days and median duration was estimated at >9 months. Responders (CR and PR) vs. non-responders had a median survival of 678 days vs. 406 days (p= 0.038 Wilcoxon). There were no treatment related deaths. As expected, grade 3–4 toxicity (including hematologic toxicity, febrile neutropenia) occurred in more DAC patients than in Supp.Care patients. Most patients tolerated treatment well. DAC appears a promising therapy for MDS with manageable toxicity. Final results of independently reviewed response rates and clinical benefit (transfusion independence; Quality of Life) will be presented.
4
Kashimura, Hiroshi, Takashi Inoue, Kuniaki Ogasawara, and Akira Ogawa. "Preoperative Evaluation of Neural Tracts by Use of Three-dimensional Anisotropy Contrast Imaging in a Patient with Brainstem Cavernous Angioma: Technical Case Report." Neurosurgery 52, no. 5 (May 1, 2003): 1226–30. http://dx.doi.org/10.1093/neurosurgery/52.5.1226.
Full textAbstract:
Abstract OBJECTIVE AND IMPORTANCE We describe a case of brainstem cavernous angioma in which the neural tracts were evaluated before surgery by three-dimensional anisotropy contrast (3-DAC) magnetic resonance imaging. CLINICAL PRESENTATION A 64-year-old man presented with a cavernous angioma located intrinsically in the brainstem and manifesting as gait ataxia. 3-DAC imaging demonstrated that the lesion was located outside the left inferior cerebellar peduncle and inside the middle cerebellar peduncle. INTERVENTION The intact brain surface was incised, and the lesion was removed successfully on the basis of the preoperative 3-DAC images. The patient exhibited temporary exacerbation of his gait ataxia, but the symptom improved 3 months after surgery. Postoperative 3-DAC imaging demonstrated resection of the lesion and preservation of the left inferior and middle cerebellar peduncles. CONCLUSION 3-DAC imaging may provide essential information about the neural tracts for the planning of brainstem surgery.
5
Shizu, Katsuyuki, Jiyoung Lee, Hiroyuki Tanaka, Hiroko Nomura, Takuma Yasuda, Hironori Kaji, and Chihaya Adachi. "Highly efficient electroluminescence from purely organic donor–acceptor systems." Pure and Applied Chemistry 87, no. 7 (July 1, 2015): 627–38. http://dx.doi.org/10.1515/pac-2015-0301.
Full textAbstract:
AbstractThermally activated delayed fluorescence (TADF) emitters are third-generation electroluminescent materials that realize highly efficient organic light-emitting diodes (OLEDs) without using rare metals. Here, after briefly reviewing the principles of TADF and its use in OLEDs, we report a sky-blue TADF emitter, 9-(4-(benzo[d]thiazol-2-yl)phenyl)-N3,N3,N6,N6-tetraphenyl-9H-carbazole-3,6-diamine (DAC-BTZ). DAC-BTZ is a purely organic donor–acceptor-type molecule with a small energy difference between its lowest excited singlet state and lowest triplet state of 0.18–0.22 eV according to fluorescence and phosphorescence spectra of a DAC-BTZ-doped film. In addition, the doped film exhibits a high photoluminescence quantum yield of 0.82. Time-resolved photoluminescence measurements of the doped film confirm that DAC-BTZ emits TADF. An OLED containing DAC-BTZ as an emitter exhibits a maximum external quantum efficiency (EQE) of 10.3%, which exceeds those obtained with conventional fluorescent emitters (5–7.5%). TADF from DAC-BTZ makes a large contribution to the high EQE of its OLED.
6
Long, Huei, Chi-Tan Hu, and Ching-Feng Weng. "Antrodia Cinnamomea Prolongs Survival in a Patient with Small Cell Lung Cancer." Medicina 55, no. 10 (September 26, 2019): 640. http://dx.doi.org/10.3390/medicina55100640.
Full textAbstract:
Introduction: Antrodia cinnamomea (AC) is an extremely rare medicinal fungus native to forested regions of Taiwan. It possesses numerous biological activities, especially anti-tumor effects shown in various in vitro cancer cells and in vivo animal models. However, there are few clinical reports about AC as a treatment for cancer patients. This report attempts to demonstrate the therapeutic effect of dish-cultured AC (DAC) on a small cell lung cancer (SCLC) patient taken orally for an extended duration. Patient concerns: An 88-year-old male with a history of diabetes mellitus and hypertension visited the outpatient department with the symptoms of dyspnea and a cough for two weeks. After a diagnosis of SCLC, the patient declined both chemotherapy and radiotherapy because of the side effects and only accepted supportive care without additional therapy. Diagnosis: Limited-stage SCLC (T4N2M1a, stage IV) after the chest radiograph, computed tomography-guided biopsy, and pathological diagnosis. Interventions: The patient was prescribed DAC with an increasing dosage, from 5 g/d up to 10 g/d DAC, for six months, without radiation or chemotherapy treatment. Outcomes: DAC caused the tumor to shrink substantially. Surprisingly, the patient survived for 32 months without relapse after six months of DAC treatment. Laboratory examinations indicated that the patient’s health had improved significantly, reverting to near normal levels. Notably, he had a good quality of life with a high Barthel index score. Unfortunately, this patient died of septic shock caused by acute cholangitis. Conclusion: DAC may exert an anti-cancer effect, which can lead to tumor regression. This is supposed to be achieved by the combined DAC’s immunomodulatory, anti-angiogenic, anti-metastatic, anti-proliferative, and pro-apoptotic effects mediated through multiple signaling pathways. We propose that DAC can be used as a complementary medicine to prolong the life expectancy and improve the life quality of SCLC patients.
7
Foster, Harry, Rob Oshana, Jorg Henkel, and Vivek De. "Report on the Design Automation Conference (DAC 2021)." IEEE Design & Test 39, no. 1 (February 2022): 97–99. http://dx.doi.org/10.1109/mdat.2021.3138609.
Full text
8
Chen, Ping, William Blum, Josephine Aimiuwu, Vijayasarathi Upadhyayula, Zhongfa Liu, Shujun Liu, Jiuxia Pang, et al. "Quantification of Intracellular Decitabine-Triphosphate with A Novel, Highly Sensitive and Specific LC-MS/MS Assay in Acute Myeloid Leukemia Patients Treated with Low Dose Decitabine." Blood 114, no. 22 (November 20, 2009): 3782. http://dx.doi.org/10.1182/blood.v114.22.3782.3782.
Full textAbstract:
Abstract Abstract 3782 Poster Board III-718 Low doses (5-20 mg/m2/day) of the azanucleoside decitabine (DAC) have been shown to be active in AML likely through DNA hypomethylation and re-expression of otherwise epigenetically silenced, hypermethylated genes, including tumor suppressors. Following cellular uptake, DAC rapidly undergoes phosphorylation to its active metabolite, DAC-triphosphate (DAC-TP), which is incorporated into the newly synthesized DNA, covalent binds to and sequesters DNA methyltransferases that mediate aberrant enzymatic-DNA hypermethylation. Measurement of DAC-TP remains critically important in understanding and monitoring the effect of drug treatment in order to design more effective treatment schedules. In contrast to the well-established methods for measurement of triphosphates of other nucleoside analogs (e.g. cytarabine), development of a reliable method of intracellular DAC-TP quantification has proven to be rather challenging and as yet no such method for DAC-TP has been reported. Here, we developed a non-radioactive, sensitive, and specific HPLC-MS/MS method to quantify intracellular DAC-TP that is readily applicable to intracellular quantification of DAC-TP in marrow mononuclear cells (MNCs) and peripheral blood mononuclear cells (PBMCs) from DAC-treated patients. This method uses an internal standard (IS) of 2-chloroadenosine-5'-triphosphate (ClATP), against which DAC-TP is measured; we tested the method first in vitro in DAC treated myeloid leukemia K562 cells. K562 cells were treated with 2 μM DAC for 1, 4, and 24 hours and DAC-TP, deoxynucleotides (dNTPs), and the spiked ClATP were extracted with methanol precipitation and separated through a gradient elution on a Supelcogel ODP-50 column. An ion trap mass spectrometer in a negative ion electro-spray mode was then used for detection. The multiple reaction monitor at m/z 467.1→369.0 allowed specific detection and separation of DAC-TP from other dNTPs and quantification against a known, spiked amount of ClATP. Linearity of the assay was demonstrated between 10 nM and 10 μM in K562 cell lysate with 50 nM being the lower limit of quantification (LLOQ). The within-day coefficients of variation (CVs) were found to be between 14.2-19.9% at LLOQ and 4.7-7.0% for higher concentrations. The within-day accuracy values were 83.7-115.6% for DAC-TP. Following 0.2 μM DAC treatment in K562 cells for 4 hr, the accumulation of DAC-TP peaked (∼2 pmol/106 cells) at 4 hr and was detectable at 24 hr. Next, the assay was then successfully applied to patient samples. We quantified DAC-TP in marrow MNCs collected within 3 hours from patients treated DAC at 20mg/m2 intravenously over 1 hour; we were able to detect for the first time in in vivo treated cells DAC-TP levels (0.08∼0.7 pmol/106 cells). Additionally, we were able to measure DAC-TP levels in PBMC in selected patients (0.13-1.92 pmol/106 cells). Correlation of intracellular DAC-TP with DNA hypomethylation and gene re-expression is ongoing. In conclusion, we report the first highly sensitive and specific HPLC-MS/MS analytic method for in vivo quantification of DAC-TP. This method can readily be applied for correlative studies of intracellular DAC-TP with DAC plasma pharmacokinetics, DAC-induced DNA hypomethylation/gene re-expression, and clinical outcome, and utilized for future trials based on biochemical modulation of DAC administered alone or in combination with other drugs. Supported by R01CA102031 U01-CA76576, OSU BioMedical Mass Spectrometry Laboratory and N01-CM-62207. Disclosures: Blum: Celgene: Research Funding.
9
DeZern, Amy E., Amer M. Zeidan, John Barnard, Wesley Hand, Najla Al Ali, Francis Brown, Cassie Zimmerman, et al. "Differential Response to Hypomethylating Agents Based on Sex: A Report on Behalf of the MDS Clinical Research Consortium (MDS CRC)." Blood 126, no. 23 (December 3, 2015): 2889. http://dx.doi.org/10.1182/blood.v126.23.2889.2889.
Full textAbstract:
Abstract Background The standard first-line therapy for higher-risk myelodysplastic syndromes (MDS) are the hypomethylating agents (HMA). While clinical characteristics, molecular markers, and karyotype can contribute to predicting prognosis in MDS, these parameters have not identified differential response rates between the HMAs decitabine (DAC) and azacitidine (AZA). Gender differences have been associated with varied outcomes in multiple cancers, and are thought to be related to differences in disease biology, treatment response, or adherence to therapy. Relevant to MDS, gender can effect expression of cytidine deaminase, which inactivates the HMAs. Male have increased levels compared to females. The impact of gender on response to HMAs is not established. Methods A dataset from the MDS CRC database was analyzed. Patients (pts) were diagnosed with higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High) and per 2008 WHO criteria and were treated with AZA or DAC as first-line therapy. Response was assessed per International Working Group (IWG) criteria (2006). The IPSS and its revision (IPSS-R) were calculated at presentation. Missing data were multiply imputed 100 times using the mice approach. Differences among variables were evaluated by the chi-square test and Mann-Whitney U test for categorical and continuous variables, respectively, with continuous variables summarized by median and range. Overall survival (OS) was calculated from presentation date to date of death or last follow up. Propensity scores were calculated for DAC vs AZA using all variables available pre-treatment. Propensity weighted Cox proportional analysis and log-rank tests were used to model and test OS. Results Of 625 higher-risk MDS pts, 33.7% were women (Table 1). The median OS for the cohort was 16.9 months (95% CI 15.6-18.2); 17.8 months for men (95% CI 16.4-19.2) and 15.0 months for women (95% CI 12.1-18.6). Approximately one third of pts received DAC as front line HMA in both gender groups. While most variables had similar distributions between DAC and AZA within genders, two variables showed differences between HMA treatments in both genders: bone marrow blast percentage at diagnosis and IPSS-R cytogenetic category, with blast percentage consistently higher in the DAC treated set. In addition, DAC-treated females were on treatment longer than AZA-treated females There was no difference in median OS across gender (p=0.33). DAC-treated pts had marginally better OS than AZA pts (p=0.043), (median OS of 18.7 months vs 16.3 months), but the difference varied strongly by gender (Figure 1). Female DAC pts had much better OS than female AZA pts (p=0.0014), with a median OS of 21.2 months (95% CI 16.1-27.9) versus 13.1 months (95% CI 10.7-15.9). Males showed no significant difference (p=0.59), with a median OS of 18.3 months (95% CI 14.9-22.2) compared to 17.6 years (95% CI 16.0-19.5). Female DAC survival improvement remained significant in a Cox PH analysis after adjusting for cytogenetic category and bone marrow blast % at diagnosis. (Figure 1) Conclusion Women with higher-risk MDS may live longer when treated with DAC than with AZA. While factoring in gender as a variable in therapeutic choice between the HMAs remains premature, future prospective investigations of both drugs in men and women are warranted. Table 1. Patient characteristics by Sex FemaleN=210, 33.7% MaleN=415, 66.3% Parameter DAC AZA P-value DAC AZA P-value N=7234.3% N=138 65.7% N=130 31.3% N=285 68.7% Age, years 67.4 35-84 68.9 36-91 0.222 70.0 38-89 70.8 31-99 0.641 ANC X 109 L 1.06 0.04-27.7 0.83 0.10-20.4 0.085 1.04 0.02-44.9 1.01 0.01-42.6 0.900 Platelets X 109 L 57.8 2.0-412.4 59.4 4.9-655.2 0.820 55.6 3.0-654 66.2 2.5-451.3 0.095 Hemoglobin g/dL 9.53 4.38-12.90 9.27 4.91-14.04 0.271 9.40 4.10-13.93 9.13 3.00-15.91 0.086 Bone marrow blasts % 13.0 0.27-29 10.0 0-84 <0.001 13.1 0-29.1 9.9 0-83 <0.001 Time on HMA (months) 6.0 0.16-30.1 4.2 0.14-41.3 0.055 4.7 0.10-38.8 5.4 0.03-55.0 0.840 IPSS-R CategoryLow/Very LowIntermediateHighVery High 0.3 12.5 36.9 50.4 0.1 10.2 29.5 60.2 0.496 0.1 11.8 33.6 54.5 1.8 9.5 35.3 53.3 0.567 IPSS-R Cytogenetic CatVery PoorPoorIntermediateGood/Very Good 47.3 3.2 21.1 29.7 43.1 21.6 16.9 18.8 0.0011 42.4 8.1 18.5 31.0 42.4 11.7 25.3 20.6 0.086 Progression to AML (Y) 46.5 47.4 0.936 44.8 43.1 0.803 Figure 1. Overall survival by HMA and Sex (and breakdown by HMA) from Time of Presentation to CRC Institution Figure 1. Overall survival by HMA and Sex (and breakdown by HMA) from Time of Presentation to CRC Institution Disclosures Komrokji: Incyte: Consultancy; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau; Celgene: Consultancy, Research Funding. Steensma:Celgene: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.
10
Ma, Yunju, Changju Qu, Haiping Dai, Sining Liu, Qingya Cui, Wei Cui, Jia Yin, et al. "Decitabine in Combination with Fludarabine and Cyclophosphamide As Lymphodepletion Regimen Followed By CD19/CD22 Bispecific Targeted CAR-T Therapy Significantly Improves Survival in Relapsed/Refractory B-ALL Patients: A Pilot Study." Blood 138, Supplement 1 (November 5, 2021): 1754. http://dx.doi.org/10.1182/blood-2021-152041.
Full textAbstract:
Abstract Background: CD19/CD22 bispecific targeted chimeric antigen receptor T cell (CAR-T) therapy has achieved impressive progress in patients with relapsed/refractory B cell acute lymphoblastic leukemia (R/R B-ALL), with high rates of complete remission (CR). However, T cell exhaustion caused by de novo DNA methylation restricts the capacity of CAR-T. Decitabine (DAC), a DNA methyltransferase inhibitor, has been demonstrated to reverse exhaustion-associated DNA-methylation programs, promote the rejuvenation of CAR-T cells and enhance anti-leukemic effect of CAR-T cells in vitro. To date, there are limited reports about the use of DAC as a part of lymphodepletion therapy before CAR-T cell therapy. Here, we report efficacy and safety of DAC in combination with fludarabine and cyclophosphamide (FC) regimen followed by CD19/CD22 CAR-T cell therapy for patients with R/R B-ALL. Method:We conducted a phase 1/2 clinical trial to investigate the efficacy and safety of CD19/CD22 CAR-T in the treatment of R/R B-ALL (NCT03614858). Fourteen patients were treated with DAC (total dose 100mg/m 2 in 3 days) followed by FC regimen (fludarabine 30mg/m 2 × 3d and cyclophosphamide 300mg/m 2 × 3d) (DAC group), while twelve patients received FC regimen prior to CAR-T cell infusion (CON group). A total of 1 or 2 × 10 7 CAR-T cells/kg were infused at dose escalation. Results: Baseline characteristics of patients in both groups had no significant differences except previous hematopoietic stem cell transplantation (HSCT). There were more patients with relapse after HSCT in DAC group (42.9% versus 0%, P=0.017). All patients did not achieve remission before lymphodepletion. The day 28 CR rates were 100% in DAC group and 91.7% in CON group. Furthermore, minimal residual disease (MRD) negative CR rates were 71.4% and 58.3%, respectively (P = 0.683). There was no significant difference in the proportion of nontransplant patients after CAR-T treatment between two groups. Among the nontransplant patients after CAR-T infusion in DAC group, 16.7% (1/6) of patients relapsed at 4 months. However, among 4 nontransplant patients in CON group, 1 patient achieved NR after CAR-T therapy and 3 patients relapsed at 1.5, 5, and 10 months. There were significant differences in overall survival (OS) and leukemia-free survival (LFS) between two groups: 3-year OS, 88.9% (DAC) versus 33.3% (CON), P = 0.01 and 3-year LFS, 92.3% (DAC) versus 21.8% (CON), P = 0.002. Multivariable analysis showed that addition of DAC to the lymphodepletion regimen was associated with better OS (hazard ratio [HR] 0.107, [95% CI, 0.013-0.875], P = 0.037) and LFS (HR 0.081, [95% CI, 0.01-0.65], P = 0.018). Cytokine release syndrome was observed in all patients. Conclusion: In summary, DAC in combination with FC regimen followed by CD19CD22 CAR-T cells was feasible and well tolerated. Our study demonstrated DAC combined with FC was an independent prognostic factor correlated with better survival in relapsed/refractory B-ALL patients. Disclosures No relevant conflicts of interest to declare.
11
Jabbour, Elias J., Nicholas J. Short, Xuelin Huang, Abhishek Maiti, Tapan M. Kadia, Naval Daver, Gautam Borthakur, et al. "A Randomized Phase II Study of Low-Dose Decitabine Versus Azacitidine in Patients with Low- or Intermediate-1-Risk Myelodysplastic Syndromes: A Report on Behalf of the MDS Clinical Research Consortium." Blood 128, no. 22 (December 2, 2016): 226. http://dx.doi.org/10.1182/blood.v128.22.226.226.
Full textAbstract:
Abstract Background: The outcome of patients (pts) with lower-risk myelodysplastic syndrome (MDS) is heterogeneous, with some pts having a particularly poor prognosis. Low doses of hypomethylating agents (HMAs) have been shown to be active in lower-risk MDS. We evaluated the relative safety and efficacy of low-dose decitabine (DAC) and azacitidine (AZA) in pts with lower-risk MDS. Methods: Adult pts with de novo or secondary low- or intermediate-1-risk MDS, CMML or MDS/MPN were eligible for this study. Pts with prior HMA exposure were excluded. Pts were randomized in a Bayesian adaptive design to receive either AZA 75 mg/m2 IV/SC daily or DAC 20 mg/m2 IV daily for 3 consecutive days on a 28-day cycle; pts were more likely to be assigned to the better performing treatment arm. The primary efficacy outcome was the overall improvement rate (OIR) defined as the composite of complete remission (CR), marrow CR, and hematologic improvement. Secondary outcomes included safety profile, cytogenetic response, conversion to transfusion independence, event-free survival (EFS), and overall survival (OS). EFS was defined as the time to HMA failure, progressive disease, transformation to acute myeloid leukemia (AML) or death from any cause. Results: Between 11/2012 and 2/2016, 113 pts with lower-risk MDS have been treated, 40 (39%) with AZA and 73 (71%) with DAC. The median age of the entire cohort was 70 years (range, 44-88 years), and the majority of pts (81%) were intermediate-1-risk by IPSS. Baseline characteristics of the 2 treatment groups were well-balanced and are summarized in Table 1. The median number of cycles received was 9 (range 1-41 cycles). Of the 39 pts in the AZA arm and 70 pts in the DAC arm who have received at least 2 cycles of therapy and were evaluable for response, the OIR was 53% in both groups. The CR rate with AZA and DAC was 38% and 29%, respectively (P=0.29). Among pts with abnormal karyotype at baseline, complete or partial cytogenetic response was observed in 24% of pts in the AZA arm and in 63% of pts in the DAC arm (P=0.01); the rate of complete cytogenetic response was 6% and 26% in the two groups, respectively (P=0.09). Of the 18 pts in the AZA arm and the 38 pts in the DAC arm who were transfusion dependent at baseline and evaluable for response, 17% and 32% achieved transfusion independence, respectively (P=0.24) The median duration of follow-up for the entire cohort was 20 months (range, 2-42 months). Twenty four pts in the AZA arm (60%) and 23 pts in the DAC arm (32%) have come off study due to lack of response or progressive disease. There was a trend toward prolonged EFS with DAC compared to AZA (median EFS: 19.6 months vs. 13.7 months; 1-year EFS rate: 73% vs. 57, respectively; P=0.15; Figure 1A). Twelve pts in the AZA arm (30%) and 17 pts in DAC arm (23%) have died. The median OS was similar between DAC and AZA (median OS not reached for both; 1-year OS rate: 87% vs. 84%, respectively; P=0.80; Figure 1B). Progression to AML occurred in 5 pts (13%) in the AZA arm and 6 pts (8%) in the DAC arm. Both agents were overall well-tolerated. Cycle delays were required in 23% and 37% of pts and dose reductions were required in 5% and 12% of pts treated with AZA and DAC, respectively. Infection or neutropenic fever occurred 2 pts (5%) treated with AZA and in 5 pts treated with DAC (7%). No grade 4 adverse events were observed in either treatment arm. Conclusions: Low-dose AZA and DAC are effective and well-tolerated in pts with lower-risk MDS. Early results suggest that low-dose DAC may result in superior EFS compared to low-dose AZA. A randomized trial comparing low-dose AZA, low-dose DAC, AZA x 5 days, and best supportive care in lower-risk MDS is ongoing. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Ariad: Research Funding; Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; Karyopharm: Honoraria, Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding.
12
Brady, Casper, Mark E. Davis, and Bingjun Xu. "Integration of thermochemical water splitting with CO2 direct air capture." Proceedings of the National Academy of Sciences 116, no. 50 (November 21, 2019): 25001–7. http://dx.doi.org/10.1073/pnas.1915951116.
Full textAbstract:
Renewable production of fuels and chemicals from direct air capture (DAC) of CO2 is a highly desired goal. Here, we report the integration of the DAC of CO2 with the thermochemical splitting of water to produce CO2, H2, O2, and electricity. The produced CO2 and H2 can be converted to value-added chemicals via existing technologies. The integrated process uses thermal solar energy as the only energy input and has the potential to provide the dual benefits of combating anthropogenic climate change while creating renewable chemicals. A sodium–manganese–carbonate (Mn–Na–CO2) thermochemical water-splitting cycle that simultaneously drives renewable H2 production and DAC of CO2 is demonstrated. An integrated reactor is designed and fabricated to conduct all steps of the thermochemical water-splitting cycle that produces close to stoichiometric amounts (∼90%) of H2 and O2 (illustrated with 6 consecutive cycles). The ability of the cycle to capture 75% of the ∼400 ppm CO2 from air is demonstrated also. A technoeconomic analysis of the integrated process for the renewable production of H2, O2, and electricity, as well as DAC of CO2 shows that the proposed scheme of solar-driven H2 production from thermochemical water splitting coupled with CO2 DAC may be economically viable under certain circumstances.
13
Gillaspie, A. G., and S. A. Ghabrial. "First Report of Peanut Stunt Cucumovirus Naturally Infecting Desmodium sp." Plant Disease 82, no. 12 (December 1998): 1402. http://dx.doi.org/10.1094/pdis.1998.82.12.1402a.
Full textAbstract:
Plant species in the genus Desmodium (Fabaceae) are used as forage and cover crops and include a number of common weeds such as beggarweed (D. tortuosum) and beggarlice (D. intortum). Accessions of the genus are part of the plant genetic resources collection maintained at Griffin, GA. Peanut stunt cucumovirus (PSV) was detected in naturally infected plants of Desmodium sp. PI 322505 (from Brazil) in a germ plasm regeneration plot by a direct antigen coating-enzyme-linked immunosorbent assay (DAC-ELISA) with an antiserum against PSV strain ER (subgroup I) originally isolated from cowpea in Georgia. The infected plants showed mild mosaic symptoms. Indicator host studies in the greenhouse revealed symptoms characteristic of PSV on Nicotiana tabacum cv. Burley 21 (ringspots and oak leaf pattern), Chenopodium album subsp. amaranticolor (chlorotic local lesions), and Vigna unguiculata (chlorotic spots followed by systemic mild mosaic). These symptomatic indicator plants tested positive for PSV by DAC-ELISA. Greenhousegrown plants of D. incanum (kaimi-clover) and D. uncinatum (Spanish tick-clover) were inoculated with the field isolate and the plants were tested for PSV by DAC-ELISA (10 infected of 10 tested and 3 infected of 9 tested, respectively). The PSV isolate infecting Desmodium spp. was found to contain satellite RNA and it generated the predicted products in reverse transcription-polymerase chain reactions (RT-PCRs) with primers based on specific PSV-ER sequences. The RT-PCR products were confirmed by restriction-enzyme digestion (1). This is the first report of PSV naturally infecting a member of the genus Desmodium. Because some members of this genus may grow as perennial weeds near peanut, cowpea, or other host crops, this genus may serve as an alternate/overwintering host for the virus. Reference: (1) R. A. Naidu et al. Phytopathology 85:502, 1995.
14
Lübbert, Michael, Hartmut Bertz, Björn H. Rüter, Roland H. Mertelsmann, and Jürgen Finke. "Non-Intensive AML/MDS Treatment with Low-Dose Decitabine Prior to Reduced-Intensity Conditioning (RIC) and Allogeneic Blood Stem Cell Transplantation of Older Patients." Blood 108, no. 11 (November 16, 2006): 5257. http://dx.doi.org/10.1182/blood.v108.11.5257.5257.
Full textAbstract:
Abstract Patients (pts) undergoing allogeneic stem cell transplantation for AML or high-risk MDS usually receive standard induction chemotherapy first, with the goal of achieving a complete remission (CR) or at least best response to conventional chemotherapy. This disease control is often necessary to bridge the time needed for identifying an unrelated donor in case no sibling donor is available, although CR is no absolute prerequisite for successful allografting following RIC (Bertz et al., J Clin Onc21:1480, 2003). Recently, non-intensive treatment with low-dose azanucleosides has been developed for older pts with high-risk MDS. Low-dose Decitabine (DAC) shows a particularly interesting activity in inducing cytogenetic remissions (38%) in MDS pts with poor-risk cytogenetics. The role of DAC prior to allografting has not yet been determined. Here we report our single-center experience of 10 consecutive pts treated with low-dose DAC for MDS (n=5), CMML (n=2) or AML (n=3). The median number of DAC courses given was 3 (range 1–13), with CR and PR as best response in 4 and 1 pt respectively, stable or persistent disease in 4 and 1 pt, resp. Allografting was either done as consolidation at time of best response (n=4) or as salvage for relapsed/refractory disease (n=6). Median age at time of allografting was 65 years (range 63–71). After conditioning with either FBM (n=8) or Flu/2 Gy (n=2), pts were transplanted from either matched sibling (n=3) or unrelated donor (n=7). One pt died before engraftment on day +13 due to infection. The other 9 pts engrafted, and no unexpected toxicities were noted. 6/9 pts have died either due to relapse (n=3) or infection in CR (n=3). Three pts are alive in CR at the time of this report (+1, +10, +26 months following transplant). Prior to transplantation two of them were in PR and CR following 2 and 8 courses of DAC, respectively, one had progression of CMML after 5 courses. In conclusion, we show that RIC and allografting in older pts with myeloid neoplasia following DAC treatment is feasible, and no unexpected toxicities have occurred. DAC pretreatment can induce improvement or even remission with negligible nonhematopoietic toxicity, thus bridging the time period of donor search prior to allografting. The allogeneic option in these pts should be explored more often and response to DAC and transplant risk-assessment (comorbidities, performance status etc.) will likely be major determinants of optimal timing of allografting in this setting.
15
Suino-Powell, Kelly, Yong Xu, Chenghai Zhang, Yong-guang Tao, W. David Tolbert, S. Stoney Simons, and H. Eric Xu. "Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by Deacylcortivazol." Molecular and Cellular Biology 28, no. 6 (December 26, 2007): 1915–23. http://dx.doi.org/10.1128/mcb.01541-07.
Full textAbstract:
ABSTRACT A common feature of nuclear receptor ligand binding domains (LBD) is a helical sandwich fold that nests a ligand binding pocket within the bottom half of the domain. Here we report that the ligand pocket of glucocorticoid receptor (GR) can be continuously extended into the top half of the LBD by binding to deacylcortivazol (DAC), an extremely potent glucocorticoid. It has been puzzling for decades why DAC, which contains a phenylpyrazole replacement at the conserved 3-ketone of steroid hormones that are normally required for activation of their cognate receptors, is a potent GR activator. The crystal structure of the GR LBD bound to DAC and the fourth LXXLL motif of steroid receptor coactivator 1 reveals that the GR ligand binding pocket is expanded to a size of 1,070 Å3, effectively doubling the size of the GR dexamethasone-binding pocket of 540 Å3 and yet leaving the structure of the coactivator binding site intact. DAC occupies only ∼50% of the space of the pocket but makes intricate interactions with the receptor around the phenylpyrazole group that accounts for the high-affinity binding of DAC. The dramatic expansion of the DAC-binding pocket thus highlights the conformational adaptability of GR to ligand binding. The new structure also allows docking of various nonsteroidal ligands that cannot be fitted into the previous structures, thus providing a new rational template for drug discovery of steroidal and nonsteroidal glucocorticoids that can be specifically designed to reach the unoccupied space of the expanded pocket.
16
Wilms, Anna Lena, and Roman Seer. "Tax Transparency in the European Union Regarding Country by Country Reporting (BEPS Action 13)." EC Tax Review 25, Issue 5/6 (November 1, 2016): 325–34. http://dx.doi.org/10.54648/ecta2016032.
Full textAbstract:
One goal of the fight against aggressive tax planning is to improve tax transparency of the globalized activities of Multinational Entities (MNE). The OECD Action Plan No. 13 does not only recommend a unilateral implementation of a Country-by-Country- Reporting (CbCR), but also an additional implementation package composed of a Multilateral Competent Authority Agreement (MCAA) and bilateral agreements. In line with the Organisation for Economic Co-operation and Development (OECD) tax policy the European Union (EU) has already amended again the Council Directive 2011/16/EU (hereinafter ‘DAC 1’) by the Council Directive 2016/881/EU of 25 May 2016 (so-called DAC 4) implementing the OECD-CbCR-standard also on the EU-level. However, this action will respect, in general, the international tax secrecy (see Article 16 paragraph 4 DAC 1) as well as the business secrets of Article 17 paragraph 4 DAC 1. Furthermore, the EU commission has issued a proposal for a Directive amending Directive 2013/34/EU as regards disclosure of income tax information by certain undertakings and branches, COM (2016) 198 of 12 April 2016 (so-called Report on Income Tax Information – RITI). In contrast to DAC 4, the RITI will make the CbCR data public. This article will ask for legal consistency, a mismatch of legislative competence and the protection of business interests during the CbCR process.
17
Issa, J., H. M. Kantarjian, and H. I. Saba. "Cytogenetic responses to the hypomethylating agent, decitabine (DAC), in a phase III trial of DAC vs supportive care (SC) in patients (pts) with myelodysplastic syndromes (MDS)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 6501. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.6501.
Full textAbstract:
6501 Background: Clonal cytogenetic abnormalities are detected in 40%-70% of cases of de novo MDS and 95% of cases of therapy-related MDS, and the incidence increases with poor risk. DAC is a cytosine analog that reverses aberrant DNA methylation, leading to re-expression of silenced tumor suppressor genes. In this analysis, we asked whether the hypomethylating agent DAC leads to cytogenetic response in MDS. Methods: We report cytogenetic response data from a Phase III randomized, open-label trial of DAC vs SC in 170 MDS pts. Eligibility requirements included confirmed MDS (de novo or secondary) fitting any of the recognized French-American-British classifications and an International Prognostic Scoring System (IPSS) score of 0.5 or more as determined by complete blood count, cytogenetics, and bone marrow assessment. Cytogenetics was assessed as a secondary endpoint, whereas primary endpoints were response rate (CR+PR) and time to AML or death. For pts with clonal abnormalities at baseline, follow-up cytogenetic evaluations at study end were available for 26 pts in the DAC arm and 21 pts in the SC alone arm. Results: As previously reported, overall response rate according to International Working Group MDS criteria was 17% (15/89) for DAC vs 0% for SC (p<0.001). Responses occurred in all IPSS groups and were also seen in pts with 5q and 7 deletions. Response rate was 13% (2/16) in pts with 5q deletions and 21% (4/19) in pts with 7 deletions. In pts without 5q or 7 deletions, response rates were 16% (11/67) and 14% (9/64), respectively. Complete cytogenetic responses were observed in 35% (9/26) of DAC pts vs 10% (2/21) of SC pts (p=0.08, Fisher’s exact). Also, 1 pt receiving DAC had a minor cytogenetic response. 10/10 DAC pts with cytogenetic response had clinical benefit (6 CR, 2 PR, 1 hematologic improvement, and 1 with normalization of marrow blast count). The primary toxicity was myelosuppression. Conclusion: DAC induces a substantial rate of cytogenetic responses in pts with MDS, suggesting that the clinical improvements induced by this agent are related to elimination of the neoplastic clone rather than to pure differentiation effects. [Table: see text]
18
Duchmann, Matthieu, Thorsten Braun, Olivier Kosmider, Aline Renneville, Uwe Platzbecker, Lionel Ades, Marie Sebert, et al. "A Two-Gene Classifier for Chronic Myelomonocytic Leukemia (CMML) Patients Treated with Hypomethylating Agents (HMA): A Report By the GFM." Blood 126, no. 23 (December 3, 2015): 2872. http://dx.doi.org/10.1182/blood.v126.23.2872.2872.
Full textAbstract:
Abstract Context : Mutations in epigenetic regulators such as TET2 or ASXL1 predict response but do not appear to impact overall survival (OS) in MDS patients (pts) treated with HMA. Somatic mutations are highly frequent in CMML, where ASXL1 confers independent poor prognosis (GFM score; JCO,2013;31:2428). Both azacitidine (AZA) and decitabine (DAC) are active in CMML. The prognostic value of gene mutations in CMML pts treated with HMA has not been analyzed so far. Methods : Retrospective analysis of advanced CMML pts treated with AZA (within EMA label) or DAC (in GFM trials) in GFM centers and Dresden University. Screening for mutations was based on Sanger sequencing (JCO, 2013;31:2428). All statistical analyses were stratified on HMA. Results : Mutation status was available for 79 pts (M/F: 57/22, median age 71y), prior to onset of AZA (n= 46) or DAC (n= 33). Median time from diagnosis to HMA onset was 8 months. At HMA onset, WHO diagnosis was CMML-1, CMML-2 and CMML having progressed to AML in 47%, 39% and 14%, respectively (resp). Pts received a median of 9 cycles for both drugs (range: 1-55). Median follow-up was 50 months. Compared to AZA pts, DAC pts had poorer cytogenetic risk according to CMML Prognostic Scoring System (CPSS, Such Blood 2013: DAC: fav/int/poor in 49/21/30% vs AZA: 78/9/13%, p=0.009), and higher WBC (median 20.6 vs 13.4 G/L p=0.06). The most frequently mutated genes were ASXL1 (47%), SRSF2 (47%), TET2 (40%), NRAS (20%), RUNX1 (19%), KRAS (10%) and CBL (10%). The mutation spectrum was similar in AZA and DAC groups. Overall Response Rate (ORR) was 58% (AZA: 61%, DAC: 55%, p=NS), including CR in 26% and 15%, resp. (p=NS) according to IWG 2006 criteria. In univariate analysis, no single mutation significantly affected ORR, but KRAS-mutated pts tended to have higher ORR than KRAS -wildtype (wt) pts (88 vs 55%, p=0.08). Mutation in either KRAS or NRAS conferred significantly higher CR rate (36%, vs 14% in pts with NRAS/KRAS -wt, p=0.04). Median OS was 27.5 months. In univariate analysis, ASXL1 (HR=2.10, p=0.008), SRSF2 (HR=2.97, p=0.008), RUNX1 (HR=2.40, p=0.01) and to a lesser extent CBL (HR=2.22, p=0.054) mutations conferred poorer OS. TET2 mutations had no prognostic impact. The higher CR rate in pts with KRAS/NRAS mutations did not translate into prolonged OS. There was a significant interaction between ASXL1 and SRSF2 status (p=0.0009). A two-gene classifier could stratify patients with significantly different 3y-OS estimates of 80.8%, 44.1%, and 23.6% in pts with neither, either, or both ASXL1/SRSF2 mutated (Figure; p<0.0001). Other variables associated with worse OS in univariate analysis were age, WBC, peripheral immature myeloid cells (IMC), peripheral blasts, and high risk cytogenetics by CPSS. Splenomegaly, Hb and Plt levels, transfusion dependency (TD) or marrow blast % (hence WHO category) had no impact. CPSS, which includes cytogenetics, WBC, TD and WHO, had thus significant but relatively limited prognostic value, with worse outcome in high vs low risk pts (p=.04), but no difference between low and int-1 or int-2 pts (both p>.2). GFM risk system which includes ASXL1 and WBC, Hb and Plt, also had prognostic value restricted to high vs low risk comparison (p=0.04). In multivariate analysis, the two-gene classifier retained significant prognostic impact (1 mutation: HR=3.5, p=.05; 2 mutations: HR=9.4, p=.001), together with increasing IMC (HR=1.05, p=.04), independently of age, WBC, peripheral blasts and cytogenetic risk. The classifier also had prognostic value independent of CPSS (p=.001). Median OS was 18.4 vs 32.3 months in DAC vs AZA treated pts (p=0.01), but this difference was not significant after adjusting for CPSS cytogenetic risk (p=0.19). Heterogeneity analyses did not identify any significant interaction with the type of HMA independent of cytogenetics or WBC, suggesting no genotype predicted better outcome with one HMA over the other. Conclusion : In this retrospective cohort of CMML pts treated with AZA or DAC, response to HMA could not be predicted by frequently mutated genes, except for a higher CR rate in RAS -mutated pts. Treatment with HMA did not abrogate the poor prognostic value of ASXL1 mutations in CMML. A two-gene classifier based on ASXL1 and SRSF2 could stratify the prognosis of CMML treated with HMA independently of clinical variables. Finally, there was no evidence that genotype should influence the choice of HMA (AZA vs DAC) in CMML. Figure 1. Figure 1. Disclosures Off Label Use: Decitabine off label to treat CMML. Platzbecker:GlaxoSmithKline: Honoraria, Research Funding; Amgen, Inc.: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Park:Hospira: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. De Botton:Agios Pharmaceuticals: Research Funding. Fenaux:JANSSEN: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding. Itzykson:Oncoethix: Research Funding.
19
Smith, Alyssa D., Chunwan Lu, Daniela Payne, Amy V. Paschall, John David Klement, Priscilla S. Redd, Mohammed Ibrahim, et al. "Autocrine IL6 activates the STAT3-DNMT axis to silence the TNFa-RIP1 necroptosis pathway to sustain myeloid-derived suppressor cell survival and accumulation." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 164.10. http://dx.doi.org/10.4049/jimmunol.204.supp.164.10.
Full textAbstract:
Abstract Accumulation of myeloid-derived suppressor cells (MDSCs) is a hallmark of cancer. However, the underlying mechanism of MDSC accumulation in the tumor microenvironment (TME) remain incompletely understood. We report that MDSC accumulation is regulated by the TNFα-RIP1-mediated necroptosis. We determined that inhibition of DNMTs with Decitabine (DAC) abolished MDSC accumulation and increased activation of antigen-specific cytotoxic T lymphocytes (CTLs) in tumor-bearing mice. DAC-induced decrease of MDSC accumulation is correlated with increased IRF8 expression in MDSCs. However, DAC also abolished MDSC-like cell accumulation in IRF8 KO mice, indicating that DNA methylation does not regulate MDSC lineage differentiation but mediates MDSC accumulation at post differentiation stage. We determined that DAC decreased MDSC accumulation through increasing cell death and identified RIP1-dependent necroptosis as target of DNA methylation in MDSCs. Genome-wide DNA bisulfite sequencing revealed that the Tnf promoter is hypermethylated in tumor-induced MDSCs in vivo. Consequently, DAC dramatically increased TNFα level in MDSCs and neutralizing TNFα significantly decreased MDSC cell death. Furthermore, recombinant TNFα induced MDSC cell death in a does- and RIP1-dependent manner. IL6 which is expressed in MDSCs in tumor-bearing mice and human colorectal cancer patients. Our data shows that the autocrine IL6 activates the STAT3-DNMT axis to epigenetically silence the TNFα-RIP1 necroptosis pathway to sustain MDSC survival and accumulation in cancer. Targeting the TNFα-RIP1 necroptosis is potentially an effective approach to supress MDSCs to activate tumor-reactive CTLs in the TME.
20
Surdu, D. "Multi-decade voltage dividers with phase regulation." Metrology and instruments, no. 1 (March 25, 2019): 14–20. http://dx.doi.org/10.33955/2307-2180(1)2019.14-20.
Full textAbstract:
Phase controlled accurate voltage divider creates two coherent AC voltages with calculated magnitude ratio using additional voltages with calculated phase control. Ratio of these voltages is calculated theoretically with high accuracy.
Digital-to-analog converters (DAC) are used to create AC additional voltages. Because of it the discreteness of the phase controlled voltage divider is equal to DACs digit divided on two. Modern DAC, depend on their operation speed, usually have 6-16 digits. Consequently, the discreteness of the relative magnitude phase control lies in the range of 3 × 10–2 –3 × 10–5. Discreteness of the DAC phase control only slightly infl uence on the accuracy of the magnitude phase control, so that only discreteness of DAC infl uences on the accuracy of measurement by phase controlled dividers.
Report describes the methods of the discreteness uncertainty reduction in voltage dividers with phase control. Two methods of the discreteness uncertainty reduction are discussed. First one use phase controlled dividers only. Other one use mixed both phase and magnitude control. The discreteness uncertainty of both methods is investigated. Possibility of the crea tion of the phase controlled divider with diff erent control low are discussed and analyzed. Decade calibration in both cases is developed and researched.
21
Hsieh, Wen-Pin, Yi-Chi Tsao, and Chun-Hung Lin. "Thermal Conductivity of Helium and Argon at High Pressure and High Temperature." Materials 15, no. 19 (September 26, 2022): 6681. http://dx.doi.org/10.3390/ma15196681.
Full textAbstract:
Helium (He) and argon (Ar) are important rare gases and pressure media used in diamond-anvil cell (DAC) experiments. Their thermal conductivity at high pressure–temperature (P-T) conditions is a crucial parameter for modeling heat conduction and temperature distribution within a DAC. Here we report the thermal conductivity of He and Ar over a wide range of high P-T conditions using ultrafast time-domain thermoreflectance coupled with an externally heated DAC. We find that at room temperature the thermal conductivity of liquid and solid He shows a pressure dependence of P0.86 and P0.72, respectively; upon heating the liquid, He at 10.2 GPa follows a T0.45 dependence. By contrast, the thermal conductivity of solid Ar at room temperature has a pressure dependence of P1.25, while a T−1.37 dependence is observed for solid Ar at 19 GPa. Our results not only provide crucial bases for further investigation into the physical mechanisms of heat transport in He and Ar under extremes, but also substantially improve the accuracy of modeling the temperature profile within a DAC loaded with He or Ar. The P-T dependences of the thermal conductivity of He are important to better model and constrain the structural and thermal evolution of gas giant planets containing He.
22
Sega, Naonori, Yuta Somei, Hiroshi Shimada, and Yoshinao Mizugaki. "Operation of a 4-bit RSFQ digital-to-analog converter based on a binary split-confluence configuration." Journal of Physics: Conference Series 2323, no. 1 (August 1, 2022): 012033. http://dx.doi.org/10.1088/1742-6596/2323/1/012033.
Full textAbstract:
Abstract One of the unique applications of single-flux-quantum (SFQ) circuitry is a digital-to-analog converter (DAC) of which the output voltage is defined by the Josephson effect. Recently, we have designed and operated rapid single-flux-quantum (RSFQ) DACs with frequency modulation of SFQ pulse sequences. In this paper, we report our design and test results of a 4-bit RSFQ-DAC based on the configuration of the “sum of selected bits sequence (Σ-SBS)”. By adjusting the timing margins, in addition to the fabrication using the Nb integration process with the critical current density as high as 10 kA/cm2, the maximum output voltage up to 260 μV was demonstrated.
23
Yu, Cuiping, Weilong Wu, Min Gao, and Yu Liu. "Modified Cellulose with BINAP-Supported Rh as an Efficient Heterogeneous Catalyst for Asymmetric Hydrogenation." Catalysts 12, no. 1 (January 12, 2022): 83. http://dx.doi.org/10.3390/catal12010083.
Full textAbstract:
Asymmetric catalysis is the preferred method for the synthesis of pure chiral molecules in the fine chemical industry. Cellulose has long been sought as a support in enantioselective catalysis. Dialdehyde cellulose (DAC) is produced by the selective oxidation of cellulose and is used to bind 5,5′-diamino Binap by forming a Schiff base. Here, we report the synthesis of modified cellulose-supported Rh as a novel biomass-supported catalyst and the characterization of its morphology, composition, and thermal stability. DAC-BINAP-Rh was a very effective catalyst in the asymmetric hydrogenation of enamides and could be easily recycled. This work provides a novel supported catalyst that broadens the applications of cellulose in asymmetric catalysis.
24
Majumder, S., and V. K. Baranwal. "First Report of Garlic common latent virus in Garlic from India." Plant Disease 93, no. 1 (January 2009): 106. http://dx.doi.org/10.1094/pdis-93-1-0106c.
Full textAbstract:
Garlic (Allium sativum L.) is one of the most important culinary herbs in the Indian subcontinent. Several viruses belonging to genera Potyvirus, Carlavirus, and Allexivirus are known to infect garlic (2,3). Garlic accessions grown on the research farm of the Indian Agricultural Research Institute, New Delhi, were tested for the presence of Onion yellow dwarf virus (OYDV), Shallot latent virus (SLV), and Garlic common latent virus (GarCLV). Leaves showing mild to severe mosaic symptoms were collected in January of 2008 from five accessions of garlic (Pusa Selection-34, G-1, Selection-17, G-282, and PGS-14) from the experimental plots. Direct antigen coated (DAC)-ELISA was performed with antisera to OYDV, GarCLV (Bioreba, Reinach, Switzerland), and Garlic latent virus (GarLV) (synonym for SLV) obtained from D. E. Lesemann, (Braunschweig, Germany). Total RNA was extracted from 100 mg of leaves with the RNeasy Plant Mini kit (Qiagen, Maryland) according to the manufacturer's protocol. Reverse transcription (RT)-PCR and DAC-ELISA confirmed the presence of OYDV and SLV in all selection lines, both of which were reported previously from garlic in India (1). The occurrence of GarCLV was confirmed by DAC-ELISA and RT- PCR using a primer pair 5′-AAATGTTAATCGCTAAACGACC-3′ and 5′-CTTTGTGGATTTTCGGTAAG-3′ designed from the conserved region of open reading frame (ORF) 5 (coat protein) and ORF 6 (nucleic acid binding protein) of GarCLV (GenBank Accession Nos. AB004566, X81138, and X81139). Expected amplicons of ∼500 bp for GarCLV were obtained from all garlic lines tested, confirming that all five garlic lines had mixed infections of OYDV, SLV, and GarCLV. The amplicons obtained from Pusa Selection-34 were directly sequenced and the 536-bp nucleotide sequence (GenBank Accession No. FJ154841) showed a sequence identity of 87% compared with GarCLV (GenBank Accession No. AB004566). To our knowledge, this is the first report of GarCLV in garlic cultivars in India. Our study demonstrates that GarCLV occurs frequently in mixed infections with OYDV and SLV and the potential impact of these mixed infections on garlic production needs to be evaluated. References: (1) S. Majumder et al. J. Plant Pathol. 90:369, 2008. (2) P. Van Dijk. Acta Hortic. 358:299, 1994. (3) D. G. A. Walkey and D. N. Antill. J. Hortic. Sci, 64:53, 1989.
25
Englisch, Joachim, and Nevia Cicin-Šain. "DAC 7: An Entire New Framework for Joint Audits in the EU: How Do the Taxpayers Fare?" Intertax 50, Issue 1 (January 1, 2022): 7–27. http://dx.doi.org/10.54648/taxi2022002.
Full textAbstract:
Joint audits have the potential to facilitate tax collection and at the same time enhance tax certainty for taxpayers. However, the several European Union (EU) pilot projects initiated by certain Member States made it evident that a better regulatory framework was urgently needed. The EU legislator therefore used the opportunity of the sixth amendment of the Directive on administrative cooperation, known as DAC 7, to devise a new legal framework for joint audits. In this contribution the authors discuss this latest development. They analyse some key clarifications and novelties to be found in the new Article 12a DAC regarding joint audits. The article furthermore highlights the remaining open issues and inadequacies of the joint audit provisions in DAC 7, with a particular focus on taxpayer rights. Among the issues that are analysed in depth in this article are the initiation of joint audits at the taxpayer’s request, the possibility to conduct a joint audit without the taxpayer’s consent, and the legal instruments at the disposal of the taxpayer against the initiation of a joint audit or certain audit activities. Further issues concerning the applicable law, data protection standards as well as legal instruments against the findings ensuing from a joint audit are also part of the analysis. Joint audits, DAC 7, taxpayer rights, tax secrecy, data protection, final report.
26
Feinberg, B. A., J. Gilmore, W. Hawke, and T. Gondesen. "Changing the treatment paradigm for patients with MDS: How the development of therapeutics influences population-based care in community oncology, the Georgia Cancer Specialists Outcomes Database experience." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 7080. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7080.
Full textAbstract:
7080 Background: Clinical trials that lead to approval of new cancer therapeutics are based upon rigorous studies of safety & efficacy in a highly-restricted pt population. Community oncology practices are evolving to contribute to our understanding of the population- based effectiveness of these therapeutics by capturing and analyzing outcomes data. Georgia Cancer Specialists, a group practice of 41 hematologists/oncologists has been routinely tracking outcomes data since 1999. We now report outcomes for pts with MDS from our database. MDS was selected since this is a Medicare population, has typically been treated with supportive care only, and 3 new agents, 5-azacytadine (VID), lenalidomide (REV) and decitabine (DAC) have recently been approved allowing assessment of their impact on this cancer population. Methods: The Georgia Cancer Specialists Outcomes Database is an integrated electronic medical records and billing database that captures over 45 parameters on every pt visit at 31 sites. This study is a retrospective, observational study using de-identified pt-level information. Results: We followed 824 MDS pts from Jan-Oct, 2006, with 63% women; mean age 71 yrs; 61% Medicare/Medicaid. Only 7% of pts received at least one MDS-indicated chemotherapeutic. Of these, 44% received VID; 36% REV, and 43% DAC and 18% received at least two. At initial therapy, more REV pts (73%) were transfusion-dependent than VID (20%) and DAC (55%) (p=0.034). Average duration of observed therapy ranged from 2.3–3.25 cycles. A greater proportion of DAC pts (93%) had an improvement in RBC count within the first 4 cycles when compared to VID (44%) and REV (62.5%) (p<0.01). The treatment response profile for platelets was similar for VID and DAC. Conclusions: Practice patterns of elderly pts with MDS are changing as new therapies are adopted in community oncology practice. DAC appears to be very active, with the shortest time to initial response. Rigorous population based outcomes analyses at the practice level is an important component of quality cancer care and must supplement information generated by randomized clinical trials. No significant financial relationships to disclose.
27
Pusic, Iskra, Jaebok Choi, Noel Bernabe, Camille N. Abboud, Peter Westervelt, Ravi Vij, Amanda F. Cashen, Geoffrey L. Uy, Keith E. Stockerl-Goldstein, and John F. Dipersio. "Maintenance Therapy With Decitabine After Allogeneic Hematopoietic Stem Cell Transplantation For Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome." Blood 122, no. 21 (November 15, 2013): 4638. http://dx.doi.org/10.1182/blood.v122.21.4638.4638.
Full textAbstract:
Introduction Disease recurrence is the major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Graft-versus-host disease (GVHD) is the major cause of non-relapse morbidity and mortality after alloHSCT. Decitabine (DAC) is a hypomethylating agent that irreversibly binds to and inhibits DNA methyltransferase-1, leading to loss of DNA methylation. DAC maintenance may help eradicate minimal residual disease and facilitate a graft-versus-leukemia effect. Lower DAC doses are expected to be better tolerated after alloHSCT and equally effective in promoting hypomethylation. Additionally, DAC maintenance may have a favorable effect on the incidence of GVHD by enhancing the effect of T-regulatory lymphocytes (Choi et al, Blood, 2012). Methods Patients (pts) with AML/MDS in complete remission (CR) after alloHSCT, with ANC> 1,500/mm3, platelets> 50,000/mm3, and without grade III-IV acute GVHD were eligible to receive DAC, starting between day +50 and +100 after alloHSCT. We investigated 4 DAC doses: 5, 7.5, 10 and 15 mg/m2/day IV x 5 days of a 6-week cycle, for a total of 8 cycles. Each cohort contained 4-8 evaluable patients. The Maximum Tolerated Dose (MTD) was defined as the maximum dose at which< 20% of patients experience hematologic or non-hematologic dose limiting toxicities (DLT) during the 1st cycle of treatment. GVHD prophylaxis was at the physician discretion. Results 19 pts were enrolled to date; the median age was 60 y (22-66); 14 pts had AML and 5 MDS. All conditioning regimens were myeloablative; 14 donors were unrelated and 5 related. 3 cohorts have been completed and a final 4th cohort is currently enrolling. Median follow-up from alloHSCT is 24 mo (7-36). 8 pts (44%) completed all 8 cycles: 7 pts remain in CR with stable counts and full donor chimerism and 1 pt developed CNS-only relapse 26 mo after alloHSCT. 9 pts went off study before cycle 6: 1 pt for poor compliance after 6 cycles, 3 pts for relapsed disease (after 1, 2 and 5 cycles, respectively), 2 pts for sepsis, and 2 pts after physician decision. 6 pts have died: 3 from relapse, 2 from sepsis after 3 cycles of DAC (they were not neutropenic at a time), and 1 form sepsis >1 y after getting off study. 2 pts are still on study passed 3rd cycle. DAC maintenance was well tolerated. Associated hematological toxicities were mostly grade I/II leukopenia and thrombocytopenia. There was one occurrence of hematological DLT. No MTD has been reached. Non-hematological toxicities were grade I/II nausea, fatigue, neuropathy, and transaminase elevation. 2 pts had grade I-II acute GVHD prior to starting DAC and both resolved while on DAC; 1 pt developed grade IV gut GVHD coinciding with first cycle of DAC that completely resolved on DAC; 1 pt developed late acute GVHD of skin and liver around 6th cycle of DAC that resolved after few wks. 2/8 pts who completed 8 cycles of DAC developed very mild skin and oral chronic GVHD not requiring any systemic therapy, 1/8 pt developed late acute GVHD responding to therapy, and 1 pt developed overlap GVHD syndrome. 4/7 pts who went off study prior cycle 6, and did not have an early relapse, developed severe chronic GVHD requiring intensive immunosuppressive therapy. Conclusion To our knowledge this is the first report of DAC as maintenance therapy after alloHSCT. DAC at the dose of 15 mg/m2 for 5 days every 6 weeks is safe and can be administered in heavily pretreated pts in the post-alloHSCT setting. Approximately 43% of pts were able to receive all 8 cycles. The lack of toxicities and low incidence of GVHD indicate that a longer period of administration should be investigated. Although there is a trend of increased FOXP3 expression, results were not statistically significant. Further correlative studies, including genome-wide methylation studies, are ongoing. Disclosures: Off Label Use: Decitabine maintenance after alloHSCT.
28
Lübbert, Michael, Pierre W. Wijermans, and Björn H. Rüter. "Re-Treatment with Low-Dose 5-Aza-2′-Deoxycytidine (Decitabine) Results in Second Remissions of Previously Responsive MDS Patients." Blood 104, no. 11 (November 16, 2004): 1447. http://dx.doi.org/10.1182/blood.v104.11.1447.1447.
Full textAbstract:
Abstract At low doses, azanucleosides with DNA methyltransferase inhibitory activity like 5-azacytidine and 5-aza-2′-deoxycytidine (DAC) have significant single-agent activity in MDS and AML. However, the optimal treatment duration is still a matter of debate: while at least two consolidating courses after best response are usually performed, the response to treatment with these drugs after a relapse of MDS has not been systematically studied. We report on 22/91 patients (pts) with MDS (24%) having received DAC both initially and, at relapse, as re-treatment. Median age was 71 years (range, 51–81). Characteristics of MDS at time of initial treatment according to FAB: 3 RA, 10 pts with RAEB, 8 pts with RAEB-t (i.e. AML according to WHO) and 1 pt with CMML. According to the IPSS at time of initial treatment, 5/22 (23%) pts were intermediate-1 (int-1), 4/22 (18%) pts int-2 and 13/22 (59%) pts were high-risk. Patients had initially received a median of 6 DAC courses (range, 2–6), in 12/22 (55%) pts resulting in a complete remission (CR), in 6/22 (27%) pts in a partial remission (PR) and in 4/12 (18%) pts in hematologic improvement (HI). 6/12 pts. with hematologic CR had also had a complete cytogenetic response. Re-treatment of relapse with DAC started a median 11 months (range, 3–27) after the last course of initial treatment. Characteristics of MDS at time of re-treatment: 1 pt RA, 13 pts RAEB, 6 pts RAEB-t and 2 pts sAML. During re-treatment, pts received a median of 3 courses (range, 1–6), with 10/22 (45%) responses: 1 CR, 2 PR (all 3 had CR at initial treatment) and 7 HI (2 CR at initial treatment, 4 PR, 1 HI). 12/22 (55%) pts did not show objective responses to re-treatment, including 3 with primary resistance to the first re-treatment course. Median survival of all pts (n=22) from start of first DAC course was 28 months (range, 15–50+) 13/22 (59%) pts transformed to AML. Median time from second response to relapse was 4 months (range, 1–16), thus three times shorter than first response. The pt with CR both at initial treatment (9 months duration) and at re-treatment (5 months duration) received a second re-treatment with 3 courses of DAC (total of 15 courses), without achieving another response. Compared to pts not achieving a second response, responders to DAC re-treatment were less frequently in the IPSS high-risk group (40% versus 83%), and had lower median sLDH at re-treatment start (197 U/L versus 282 U/l). Age, FAB subtype at retreatment, previous response to DAC (including response duration and achievement of a cytogenetic remission) did not differ between both groups. In conclusion, re-treatment resulted in objective responses in 45% of previously DAC-responsive patients. However, quality and duration of second remissions were inferior, implying that DAC-responsive patients might benefit more from continuation of the initial treatment than from re-treatment. Ongoing multi-institutional trials allow continuation of initial DAC treatment beyond 6 courses.
29
Holowiecki, Jerzy, Sebastian Grosicki, Andrzej Hellmann, Aleksander Skotnicki, Tadeusz Robak, Wieslaw W. Jedrzejczak, Lech Konopka, Kazimierz Kuliczkowski, Slawomira Kyrcz-Krzemien, and Beata Stella-Holowiecka. "Improved Survival in Acute Myeloid Leukaemia Patients Aged over 40 Given Cladribine in Combination with Standard Remission Induction (DA 3+7) and Consolidation Treatment (HD AraC). Seven Year Follow-Up of Prospective, Cooperative PALG Study." Blood 108, no. 11 (November 1, 2006): 2003. http://dx.doi.org/10.1182/blood.v108.11.2003.2003.
Full textAbstract:
Abstract The aim of this study was to evaluate long-term outcome of acute myeloid leukemia (AML) patients treated within the PALG 1999 DAC vs. DA Study. [b][Within 3 years (1999–2002) 445 patients, aged 18–60, were randomized 1:1 to the induction treatment DAC-7: daunorubicin 60 mg/m2/d iv 1–3; cytarabine 200 mg/m2/d ci d 1–7; cladribine (2-CdA) 5 mg/m2 2h inf. iv d 1–5 and standard DA-7 regimen (the same therapy excluding cladribine). Patients achieving CR received two courses of subsequent intensive consolidation: HAM (HD AraC, mitoxantrone) HD AraC with or without cladribine in the DAC-7 or DA-7 arm, respectively. In case of PR after the first induction course the same regimen was repeated, Post-consolidation therapy was comparable in both arms with following proportions of autoHCT, alloHCT and maintenance: DAC-7 17%, 14%, 69%; DA-7 21%, 14%, 65%, respectively. As previously reported, a single course of DAC-7 induction resulted in 17% higher CR rate compared to the DA-7 treatment (p=0,0008). The difference was particularly pronounced in patients: aged >40 years and with initial WBC >100x109/L. In the latter subgroup also the overall CR rate (achieved after entire induction program) was higher in the DAC-7 arm (71% vs. 43%). [Leukemia.2004;18:989–97] In the present report we analyzed seven-year long-term outcome (median follow-up 5 yrs) in the whole study population and in subgroups stratified according to age, initial WBC, cytogenetics, sex, FAB subtype, and preceding myelodysplasia. In the whole group the overall survival (OS) rate equaled 29,5% for DAC-7 and 24% for DA-7 arm (p=NS) and leukemia free survivall (LFS) 30% vs. 28% (p=NS), respectively. Of note, in patients aged >40 years, the therapy containing cladribine was associated with improved OS (26% vs. 14,5%, p=0.03), and LFS (28% for DAC-7 vs. 18,5% for DA-7, p=0.02). Other subgroup analyses revealed higher probability of the OS in patients with initial WBC ≥ 50 G/l assigned to DAC-7 compared to DA-7 arm (32% vs. 20,5%, p=0.04). The LFS rate equaled 35% and 27% (p=NS), respectively. In women receiving DAC-7 induction therapy in comparison with those treated in arm without 2-CdA reached higher OS: 29% vs. 19,5%, p=0,03, respectively. LFS in these subgroups was comparable: 25% vs. 22%, p=NS, respectively. We conclude that addition of cladribine to induction and consolidation therapy of AML improves long-term outcome in patients: older than 40 y, as well as in those with high tumour burden. The better outcome in older patients results mainly from reduced risk of relapse, whether that in cases with high WBC seems to be linked to a higher CR rate.
30
Holowiecki, Jerzy, Sebastian Grosicki, Tadeusz Robak, Slawomira Krzemien, Sebastian Giebel, Andrzej Hellmann, Aleksander Skotnicki, et al. "Addition of Cladribine to the Standard AML Treatment Improves Long-Term Outcome in High Tumor Burden and Older Than 40 Years Acute Myeloid Leukemia Patients. Five-Year Follow-Up of the Polish Adult Leukemia Group (PALG 1999 DAC vs. DA Study)." Blood 104, no. 11 (November 16, 2004): 1795. http://dx.doi.org/10.1182/blood.v104.11.1795.1795.
Full textAbstract:
Abstract The goal of the study was to evaluate long-term outcome of acute myeloid leukemia (AML) patients treated within the PALG 1999 DAC vs, DA Study. Between 1999–2002, 445 patients, aged 18–60 years, were randomized to the induction DAC-7: daunorubicin 60 mg/m2/d iv 1–3; cytarabine 200 mg/m2/d ci 1–7; cladribine 5 mg/m2 2h inf. iv d 1–5 or standard DA-7 regimen (the same regimen without cladribine). Patients achieving CR received two courses of subsequent intensive consolidation: 1) HAM (HD AraC, mitoxantrone) 2) HD AraC with or without cladribine in the DAC-7 or DA-7 arm, respectively. In case of PR after the first induction course the same regimen was repeated, NR patients received CLAG (2-CDA, HD-AraC, G-CSF), regardless the randomization arm. Post-consolidation therapy was in both arms comparable. As previously reported, a single course of DAC-7 induction resulted in 17% higher CR rate compared to the DA-7 treatment. The difference was particularly pronounced in a population of patients >40 years and for those with initial WBC >100x109/L. In the latter subgroup also the overall CR rate (achieved after >=1 induction course) was higher in the DAC-7 arm (71% vs. 43%). [Leukemia. 2004 May;18(5):989–97] In the present report we analyzed long-term outcome (median follow-up 3.2 years) in the whole study group and in pre-defined subgroups taking into account initial tumor burden, age, cytogenetics, FAB subtype, and preceding myelodysplasia. At five years the overall survival (OS) rate equaled 31% for DAC-7 and 25% for DA-7 arm (p=0.42) and leukemia free survivall (LFS) 32% vs. 29% (p=0.38), respectively. The subgroup analysis revealed higher probability of the OS in patients with initial WBC ≥100 G/l assigned to DAC-7 compared to DA-7 arm (39% vs. 11%, p=0.02). The LFS rate and the probability of relapse equaled 50% and 32% (p=NS) and 36% and 68% (p=0.0497), respectively. In patients aged >40 years, the therapy containing cladribine was associated with improved LFS (30% for DAC-7 vs. 20% for DA-7, p=0.01), and a tendency to improved OS (28% vs. 18%, p=0.09). In this subgroup DAC-7 therapy resulted in reduced relapse incidence (60% vs. 69%, p=0.04).We conclude that addition of cladribine to induction/consolidation therapy of AML may improve long-term outcome in higher age ranges patients and in those with high tumor burden. The improvement results mainly from reduced risk of relapse, and, in patients with high initial WBC, from higher CR rate.
31
Savona, Michael R., Olatoyosi Odenike, Philip C. Amrein, David P. Steensma, Wael A. Harb, Amy E. DeZern, Laura C. Michaelis, et al. "Results of First in Human (FIH) Phase 1 Pharmacokinetic (PK) Guided Dose-Escalation Study of ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with Oral Decitabine in Subjects with Myelodysplastic Syndromes (MDS)." Blood 126, no. 23 (December 3, 2015): 1683. http://dx.doi.org/10.1182/blood.v126.23.1683.1683.
Full textAbstract:
Abstract Introduction: Patients with International Prognostic Scoring System (IPSS) intermediate (Int) and high risk (HR) MDS benefit from therapy with hypomethylating agents (HMAs). Treatment with the HMAs decitabine (DAC) and azacitidine (AZA) requires 5 or 7 daily parenteral doses respectively every month with some patients remaining on treatment for extended periods. An orally administered HMA would provide significant patient convenience, potentially enhance adherence to treatment, and may allow exploring extended treatment schedules with lower doses of DAC. Neither DAC nor AZA is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin in preclinical models. We report here the first Phase 1 results of a PK-guided FIH dose escalation trial of ASTX727 (the combination of oral DAC and E7727). Methods: Adult patients with Int or HR MDS or Chronic Myelomonocytic Leukemia (CMML) were enrolled in this dose-escalating trial with a 3+3 design. In addition to assessing the safety of the combination, the primary PK objective was to achieve a mean AUC of DAC following oral ASTX727 comparable to that achieved by IV DAC at the approved dose of 20 mg/m2. In the first cycle, each patient received an IV DAC dose of 20 mg/m2 on Day 1 as an internal comparator followed by oral ASTX727 on Days 2-5 escalated by cohort. Subsequent cycles were given with oral ASTX727 on Days 1-5 at the same dose of Cycle 1. Cycles were 28 days in length. Pharmacodynamics (PD) were evaluated by LINE-1 DNA methylation in peripheral blood. A data safety review committee evaluated safety, PK and PD on patients in each completed cohort and determined dosing for each component of ASTX727 at the next cohort. Only one component at a time was escalated in each cohort and oral doses were not adjusted for weight or body surface area. Responses were assessed using the International Working Group (IWG) criteria for response (Cheson et al, 2006). Results: The Phase 1 portion of the trial completed dosing of 4 cohorts with 6 subjects each (24 subjects). The median age was 71 years (range 59-85), 15/24 (63%) were male, and median time from diagnosis was 307 days (range 5-3024). Prior therapies were administered to 10 patients including five who had received prior HMA. In cohorts 1-3 ASTX727 was given as a fixed oral DAC dose of 20 mg with escalating doses of oral E7727 at 40, 60, and 100 mg respectively. In cohort 4, the oral DAC dose was escalated to 40 mg while E7727 was kept at 100 mg. The Day 1 AUC for IV DAC 20 mg/m2 over all 4 cohorts had a mean (SD) value of 193(82) ng*hr/mL. After oral ASTX727 on Days 2-5, the mean DAC AUC as % of IV DAC AUC was 17, 19, 32, and 98% on Day 2 and 31, 41, 58 and 148% on Day 5, in cohorts 1-4 respectively (Figure). DAC AUC variability after oral ASTX727 was acceptable (CV% 35-53 across 4 cohorts). DAC Cmax values after oral ASTX727 approached IV (87%) in Cohort 4 on Day 5. Mean % LINE-1 demethylation on cycle 1 Day 8±SE was 6.8%±2.7; 8.6%±2.7; 9.5%±3.3; and 15.3%±3.4 from baseline for cohorts 1-4 respectively. No Dose Limiting Toxicities (DLTs) or Grade ≥ 3 drug-related non-hematologic AEs were observed in any patient. The most common Grade ≥ 3 AEs regardless of relationship to the drug were thrombocytopenia (37.5%), anemia (33.3%), neutropenia (29.2%) and febrile neutropenia (16.7%). Twenty patients remain on therapy, and at least 5 so far have experienced objective clinical responses (including 1 Complete Response (CR), 1 marrow CR, 1 Partial Response and 2 Hematologic Improvement). Conclusions: ASTX727 (the combination of oral DAC and oral CDAi E7727 administered concomitantly) achieved the primary PK objective of reaching (at Day 2) or exceeding (at Day 5) IV DAC 20 mg/m2 AUC levels at the doses of 40 mg DAC and 100 mg E7727 with an excellent safety profile. Day 8 LINE-1 demethylation in Cohort 4 is consistent with that historically reported following DAC 20 mg/m2 IV for 5 days. Clinical responses have been observed. The trial will explore lower doses of oral DAC and will proceed to dose expansion followed by randomized phase 2 portion comparing IV DAC to oral ASTX727 in previously untreated Int or HR MDS and CMML patients. Figure 1. Mean DAC AUC after IV DAC 20 mg/m2 (D1) and oral ASTX727 (D2 and D5) for cohorts 1-4 Figure 1. Mean DAC AUC after IV DAC 20 mg/m2 (D1) and oral ASTX727 (D2 and D5) for cohorts 1-4 Disclosures Savona: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Astex Pharmaceuticals, Inc: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Michaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. Faderl:JW Pharma: Consultancy; Karyopharm: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Astellas: Research Funding; Celator: Research Funding; Ambit: Research Funding; Onyx: Speakers Bureau; BMS: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Oganesian:Astex Pharmaceuticals, Inc.: Employment. Dua:Astex Pharmaceuticals, Inc.: Employment. Nawabi:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment.
32
Canuti, Marta, Joost T. P. Verhoeven, Hannah J. Munro, Sheena Roul, Davor Ojkic, Gregory J. Robertson, Hugh G. Whitney, Suzanne C. Dufour, and Andrew S. Lang. "Investigating the Diversity and Host Range of Novel Parvoviruses from North American Ducks Using Epidemiology, Phylogenetics, Genome Structure, and Codon Usage Analysis." Viruses 13, no. 2 (January 28, 2021): 193. http://dx.doi.org/10.3390/v13020193.
Full textAbstract:
Parvoviruses are small single-stranded DNA viruses that can infect both vertebrates and invertebrates. We report here the full characterization of novel viruses we identified in ducks, including two viral species within the subfamily Hamaparvovirinae (duck-associated chapparvovirus, DAC) and a novel species within the subfamily Densovirinae (duck-associated ambidensovirus, DAAD). Overall, 5.7% and 21.1% of the 123 screened ducks (American black ducks, mallards, northern pintail) were positive for DAC and DAAD, respectively, and both viruses were more frequently detected in autumn than in winter. Genome organization and predicted transcription profiles of DAC and DAAD were similar to viruses of the genera Chaphamaparvovirus and Protoambidensovirus, respectively. Their association to these genera was also demonstrated by subfamily-wide phylogenetic and distance analyses of non-structural protein NS1 sequences. While DACs were included in a highly supported clade of avian viruses, no definitive conclusions could be drawn about the host type of DAAD because it was phylogenetically close to viruses found in vertebrates and invertebrates and analyses of codon usage bias and nucleotide frequencies of viruses within the family Parvoviridae showed no clear host-based viral segregation. This study highlights the high parvoviral diversity in the avian reservoir with many avian-associated parvoviruses likely yet to be discovered.
33
Almstedt, Maika, Dietmar Pfeifer, and Michael Lubbert. "Cancer Testis Antigens Residing on the X-Chromosome Are Preferentially Derepressed in Myeloid Leukemic Cells by the DNA Demethylating Agent 5-Aza-2’-Deoxycytidine (DAC)." Blood 112, no. 11 (November 16, 2008): 2247. http://dx.doi.org/10.1182/blood.v112.11.2247.2247.
Full textAbstract:
Abstract Introduction: Azanucleoside DNA demethylating agents upregulate large sets of genes in vitro. Cancer testis antigens (CTAs) are a growing group of immunogenic proteins that provide attractive targets for cancer-specific immunotherapy in solid tumors. In contrast, only a very limited number of studies has been performed on epigenetic regulation of CTAs in myeloid leukemia. A single report suggested specific in vivo induction of CTA mRNAs in blasts from AML and MDS pts treated with intermediate-dose Decitabine (DAC; Sigalotti et al., Blood101:4644–6, 2003). We wished to extend this finding by examining kinetics and spectrum of CTA and leukemia-associated antigen (LAA) regulation by DAC in myeloid cell lines and primary AML blasts. Materials and Methods: Myeloid cell lines were treated over 72 hrs with 50–200 nM DAC. RNA was isolated from peripheral blood blasts of AML pts treated with DAC (135mg/m2 over 72 hours within the 00331 phase II trial) before and during early phase of the treatment (= days 2, 5 from start of DAC) when circulating blasts were still >40% (mean 75%). Expression analyses were performed by Western Blot (NY-ESO-1), qPCR (NY-ESO-1, MAGEA1, MAGEA3, Myeloblastin), and by HG-U133plus 2.0 mRNA microarray. Results: The five myeloid cell lines Kasumi-1, U937, HL60, K562 and NB4 did not express NY-ESO-1 protein. Upon treatment with DAC, NY-ESO-1 was markedly de-repressed in 3/5 cell lines (Kasumi-1, U937, HL60). Induction of expression was dose- and time-dependent, with maximum induction at day 6, and reversible with prolonged culturing up to day 21. No derepression was seen when U-937 and HL-60 were treated with equitoxic low concentrations of cytarabine (not a Dnmt inhibitor). MAGEA1, MAGEA3 and the LAA Myeloblastin (MBN) were also induced by DAC in Kasumi-1, with the strongest effect observed for NY-ESO-1 and the least for MBN (high baseline expression). Expression analyses were extended to all 67 CTAs present on the U133plus array (45 located on the X-chromosome, 22 autosomally), of which 11/67 (17%) were induced >2 fold in Kasumi-1. Notably, all 11 CTA genes were X-chromosomal, whereas 0/22 autosomal CTAs showed reinduction (p= 0.008 by Fisher-Exact test). 2/9 LAA genes (22%) were also reinduced. In primary AML blasts from 9 pts, DAC treatment resulted in >2fold induction of 3 CTAs and 5 LAAs. qPCR demonstrated NY-ESO-1 upregulation in 2/5 patients, with a maximum at day 5 from start of treatment. Conclusions: Marked derepression of NY-ESO-1 and other CTAs by treatment of myeloid cell lines with an azanucleoside DNA demethylating agent occurred preferentially with genes residing on the X chromosome, in line with a major role of DNA methylation for their regulation. Derepression by DAC was also observed in vivo, albeit less marked and occurring early during treatment. One of the therapeutic effects of low-dose DNA demethylating agents on leukemic myeloid blasts may be mediated via upregulation of antigens rendering the malignant cells more immunogenic.
34
Zeidan, Amer M., Maya Ridinger, Peter J. P. Croucher, Errin Samuëlsz, Mark Erlander, Katherine L. Ruffner, and Eunice S. Wang. "Predictive Biomarkers of Response to the Polo-like Kinase 1 (PLK1) Inhibitor, Onvansertib, in Combination with Decitabine in Relapsed or Refractory Acute Myeloid Leukemia (R/R AML)." Blood 138, Supplement 1 (November 5, 2021): 3431. http://dx.doi.org/10.1182/blood-2021-145129.
Full textAbstract:
Abstract Background: PLK1 is a serine/threonine kinase master regulator of the cell cycle, overexpressed in AML blasts. Onvansertib (ONV) is an oral, highly selective next-generation PLK1 inhibitor that demonstrated anti-tumor activity in AML preclinical models. The safety and efficacy of ONV in combination with decitabine (DAC) in patients with R/R AML is under study in an ongoing phase 1b/2 clinical trial (NCT03303339). Here we report results of correlative studies to identify molecular predictors of response to the ONV-DAC combination. Methods: R/R AML patients were treated for 5 days with ONV (orally) and DAC (20 mg/m 2 IV qd x 5d) in 21- or 28-day cycles. Patients who completed at least 1 cycle of treatment were considered evaluable for efficacy. At baseline, bone marrow (BM) samples were collected for targeted next-generation sequencing (Myeloid VariantPlex, Archer) and blood samples for RNA-sequencing. Results: As of July 7, 2021, 23 patients were treated with ONV (12 - 90 mg/m 2) + DAC in Phase 1b and 32 patients with ONV 60 mg/m 2 + DAC in Phase 2. Nine (20%) of the 46 patients that were evaluable for efficacy achieved a complete remission with or without complete hematologic recovery (CR/CRi) as their best response (7 CR and 2 CRi). Another 6 patients had ≥50% BM blast decrease from baseline at one point on trial therapy. Those 6 patients plus the 9 patients who achieved CR/CRi are referred to as BM responders (n=15). RNA-seq was performed on blood collected from 32 patients, including 12 BM responders. Differential gene expression, gene-set, and machine learning analyses of BM responders versus non-responders identified a gene expression signature predictive of response to the ONV-DAC combination. No association between the ONV-DAC signature and DAC response was observed after applying the ONV-DAC signature to gene expression profiles from patients treated with DAC as a single agent in a multicenter Phase 2 study (NCT00866073), indicating that the gene signature is specific to the combination. The ONV-DAC signature was also applied to the BeatAML cohort (n=399) and identified 241 predicted responders. Mutation analysis of the BeatAML cohort revealed a positive association between predicted ONV-DAC response and mutations in splicing factors (SF) such as SRSF2, suggesting that SF mutations may serve as a response biomarker for the ONV-DAC combination. Indeed, genomic analysis of baseline BM samples from patients evaluable for efficacy in our Phase 1b/2 (n=46), showed a significant increase in clinical responses in patients with SRSF2 and SF3B1 mutations versus patients with other alterations (Figure 1 and Table 1). In addition, biomarkers reported to be positively correlated with DAC responses (TP53 and TET2 mutations, high fetal hemoglobin expression) were not associated with ONV-DAC clinical responses (Figure 1). Conclusion: We identified a gene expression signature associated with clinical response to the ONV-DAC combination, that did not predict response to DAC single agent. The ONV-DAC predictive signature was found to be correlated with SF mutations in the BeatAML cohort. In our cohort, we confirmed the association between clinical response to ONV-DAC and SF mutations. These analyses support further investigation of the ONV-DAC combination in R/R AML patients with SF mutations and the potential use of ONV-DAC for other hematological diseases with high prevalence of SF mutations such as myelodysplastic syndrome and chronic myelomonocytic leukemia. Figure 1 Figure 1. Disclosures Zeidan: Janssen: Consultancy; Astellas: Consultancy; Astex: Research Funding; Genentech: Consultancy; Daiichi Sankyo: Consultancy; Aprea: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Epizyme: Consultancy; BeyondSpring: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Pfizer: Other: Travel support, Research Funding; BioCryst: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Geron: Other: Clinical Trial Committees; Kura: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Incyte: Consultancy, Research Funding; AstraZeneca: Consultancy; Jasper: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Jazz: Consultancy; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Ridinger: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Croucher: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Samuëlsz: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Erlander: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Ruffner: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company; ALX Oncology: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company; Anthem INC: Current equity holder in publicly-traded company; Cardinal Health: Current equity holder in publicly-traded company; Change Healthcare: Current equity holder in publicly-traded company; CVS Health Corp: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Organon: Current equity holder in publicly-traded company. Wang: GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.
35
Inten Meutia. "Analysis of GRI Reporter." Think India 16, no. 2 (August 15, 2013): 40–54. http://dx.doi.org/10.26643/think-india.v16i2.7822.
Full textAbstract:
This paper reports the characteristic of GRI Reporters. GRI Reporters are corporates that make a sustainability reporting based on GRI guideline and report their reporting to GRI. This paper provides descriptions about the type of corporation, sector of corporation, the region and country, membership of country (OECD and DAC), and application level of corporation of the GRI reporters. From the descriptive analysis, we get information that more companies have the awareness to publish sustainability reports. In this paper, we do analysis on some interesting phenomenons; those are: indication that sustainability reporting has been the concern of SMEs as well as other corporations, financial services sector is the largest sector of the GRI reporter, and in fact many GRI Reporters come from developing countries, instead of developed countries.
36
Holowiecki, Jerzy, Sebastian Grosicki, Slawomira Kyrcz-Krzemien, Janusz Kloczko, Kazimierz Sulek, Andrzej Hellmann, Aleksander Skotnicki, et al. "Prospective, Randomized, Multicenter Phase III, Polish Adult Leukemia Group (PALG) Study Comparing DAF (DNR+AraC+Fludarabine), DAC (DNR+AraC+Cladribine), and Standard DA Regimen in Induction of Untreated Acute Myeloid Leukemia Patients - First Report." Blood 106, no. 11 (November 16, 2005): 4616. http://dx.doi.org/10.1182/blood.v106.11.4616.4616.
Full textAbstract:
Abstract The goal of this study is to compare the efficacy and safety of an original DAF regimen: daunorubicine (DNR) 60 mg/m2/d iv, days 1–3; cytarabine (AraC) 200 mg/m2/d ci, d 1–7, and fludarabine 25 mg/m2 2h inf. iv d 1–5 versus previously studied DAC regimen* (DNR, AraC, Cladribine), and versus standard DA in de novo acute myeloid leukemia (AML) patients below 60. Primary objective is complete remission (CR) rate after single course of induction and overall survival, secondary objectives - overall CR rate, toxicity, leukemia-free survival rate, assessment of lymphocyte subpopulations levels and survival in patients submitted to bone marrow allotransplantation (alloBMT) immediately after CR assessment. Patients achieving CR and did not submit to alloBMT received two courses of subsequent intensive consolidation: 1) HAM (HD AraC, mitoxantrone) 2) HD AraC. In case of partial remission (PR) after the first induction course the same regimen was repeated, Patients with no remission (NR) or PR/NR after 2 induction courses were withdrawn with the study. We are planning to enrol to the study 600 patients in 3 years. Between 09.2004 and 07.2005, 147 adult AML patients, aged 48 (19–60)y, sex: male 57, female 90, treated in 16 co-operating Polish Adult leukemia Group (PALG) centres were randomised to either DAF (n=44), DAC (n=49) or DA (n=54) arm. PML/RAR alfa positive - FAB M3 cases were excluded. Both study groups were well balanced in respect of age, sex, FAB subtype, and WBC. The final CR rate and CR rate after the first induction course equalled: for DAF 65% and 60%, for DAC 70% and 60%, and for DA 55% and 47%, respectively (p=NS). The median times to ANC recovery > 0.5 G/L, and PLT >50 G/L in each arms were similar (22–26 d.) (p=NS). All patients developed WHO grade IV thrombocytopenia and agranulocytosis. The frequency and severity of infections, mucositis, vomiting, diarrhea, alopecia, polyneuropathy as well as of cardiac, liver or kidney failure were comparable in each treatment arms. Early death was noted in 6% (n=2) in DAF, in 9% (n=3) in DAC, and in 13% (n=5) in DA group, because of bacterial sepsis in every cases. In conclusion, this original study proves that the addition of fludarabine to the standard DNR+AraC regimen (DAF) comparing to DAC and DA regimen is a potent antileukemic treatment without increased toxicity.
37
Hofmeister, A. M. "Infrared Microspectroscopy in Earth and Planetary Science: Recent Developments, Including In Situ High-Pressure, High-Temperature Techniques." Microscopy and Microanalysis 3, S2 (August 1997): 857–58. http://dx.doi.org/10.1017/s143192760001117x.
Full textAbstract:
Vibrational spectroscopy is used in Earth science for both quantitative and qualitative analysis. This report focuses on infrared (IR) spectroscopy, although similar efforts are on-going in Raman spectroscopy.Qualitative studies utilize the fact that the vibrational spectrum is a characteristic of a material: hence comparison to a set of standards allows for identification of the phase. Most of these types of studies in Earth science involve macrosamples, but measurements of microsamples from meteorites are on interest in order to identify the structure of SiC inclusions and the type of organic compounds in interplanetary dust. As most of these samples are micron sized, which is below the diffraction limit for the mid-IR, the approach has been to compress the sample using a diamond anvil cell (DAC) into a disk of sub-micron thickness, adhere the sample to a KBr plate, and to subsequently remove the disk from the DAC and obtain spectra with the aid of an FTIR microscope.
38
Wegscheider, W. "Report of the Study Group ”Quality Assurance and Accreditation" to the DAC-FECS." Accreditation and Quality Assurance 7, no. 1 (January 1, 2002): 24. http://dx.doi.org/10.1007/s00769-001-0415-1.
Full text
39
Mouly, Enguerran, Emilie Rousseau, Cecile Planquette, and Remi Delansorne. "Inecalcitol and Decitabine Synergize to Inhibit Cell Proliferation and to Induce Differentiation of Human Acute Myeloid Leukemia Cell Lines." Blood 132, Supplement 1 (November 29, 2018): 5234. http://dx.doi.org/10.1182/blood-2018-99-118125.
Full textAbstract:
Abstract Decitabine (DAC) is a hypomethylating agent indicated as front-line therapy for de novo or secondary acute myeloid leukemia (AML) in newly diagnosed patients aged 65 years or older unfit for standard induction chemotherapy (Kantarjian et al., 2012, Malik & Cashen, 2014, Nieto et al., 2016, He et al., 2017). Its mechanism of action at the DNA level mostly results in inhibition of cell proliferation. Cellular differentiation can also be involved in some extent in a fraction of the leukemic cell population, as reported in initial pharmacological studies (Creusot et al., 1982; Pinto et al., 1984). Overall survival advantage is nevertheless limited to several more months and the next challenge is to combine DAC with other drugs to improve it further (Kubasch & Platzbecker, 2018). Inecalcitol (INE: 14epi-,19nor-,23yne-,1,25dihydroxy-cholecalciferol) is a vitamin D receptor agonist characterized by potent anti-proliferative and pro-differentiating general properties on cancer cells and by a low calcemic potential (Okamoto et al., 2012; Ma et al., 2013; Medioni et al. 2014), and especially on AML cell lines (AACR 2017, 2018). INE is currently being tested in combination with DAC in this category of elderly AML patients unfit for standard chemotherapy. The aim of the present report was to look for synergies in vitro between DAC and INE on four non-APL human AML cell lines (MOLM-13, U-937, THP-1, OCI-AML2) both on inhibition of proliferation and induction of differentiation. After 72 hours of incubation, cells were counted and labeled for CD11b and CD14 at the cell surface as biomarkers of monocytic/macrophagic differentiation. The range of DAC concentrations had to adapted to each cell line to avoid maximal cytotoxicity: 1.2 nM to 100 nM on MOLM-13, 3 nM to 250 nM on U-937 and THP-1, and 31 nM to 500 nM on OCI-AML2. The same range of 0.12 to 10 nM INE concentrations was tested on each cell line. Each concentration of INE was tested in combination with each concentration of DAC. Synergy was calculated as the excess over the highest single agent (HSA) using the open source Combenefit software (Di Veroli et al., 2016). The highest concentration of DAC alone (MOLM-13: 100 nM, U-937 and THP-1: 250 nM; OCI-AML2: 500 nM) induced a decrease in cell count of 30% of THP-1 cells, 50% of OCI-AML2 cells, 65% of U-937 cells and 80% of MOLM-13 cells. The highest concentration of INE alone (10 nM) induced a decrease in cell count of 20% of U-937 and THP-1 cells, 60% of OCI-AML2 cells and 70% of MOLM-13 cells. The antiproliferative effects of DAC and INE were at least additive in all combinations tested. Significant HSA synergy indexes were found for the decrease in cell number in all four cell lines, ranging from 12% to 23% depending on cell lines and combinations of concentrations. The highest concentration of DAC alone had no (U-937, THP-1) or limited activity (<+12% of labeled MOLM-13 or OCI-AML2 cells) to induce either CD11b or CD14 on the cell surface. By contrast, the highest concentration of INE alone (10 nM) stimulated the expression of CD11b and CD14 in up to 70% to 95% of the cells depending on the cell line (except the CD14 labeling of U-937 cells which remained < 8%). The respective EC50 of INE for CD11b and CD14 induction was 1 and 3 nM on THP-1 cells, 4 and 3 nM on MOLM-13 cells, 3 and 3 nM on OCI-AML2 cells and 1 nM on U-937 cells (50% not reached for CD14). There was no antagonistic effect of DAC towards the pro-differentiating properties of INE. A significant HSA synergy index in the 16% to 26% range was observed for both CD11b and CD14 in MOLM-13 cells and for CD14 in OCI-AML2 cells. A very high HSA synergy index of 75% was observed for the stimulation of CD14 in U-937 cells. In summary, DAC exerted more antiproliferative activity than INE which was more potent to induce monocytic/macrophagic differentiation of four non-APL human AML cell lines. The combination of DAC and INE systematically resulted in a synergy to inhibit cell proliferation, and the strong stimulation of cell differentiation induced by INE alone was in some cases boosted by DAC. These in vitro results provide the mechanistic basis for the potential interest of treating elderly AML patients with INE in addition to DAC in the ongoing double-blind placebo-controlled Phase II clinical trial (NCT02802267). Disclosures Mouly: Hybrigenics: Employment. Rousseau:Hybrigenics: Employment. Planquette:Hybrigenics: Employment, Equity Ownership, Patents & Royalties: inventor, but no royalties. Delansorne:Hybrigenics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: inventor, but no royalties.
40
Claus, Rainer, Dietmar Pfeifer, Maika Almstedt, Björn Hackanson, Manuela Zucknick, Christoph Plass, and Michael Lübbert. "Decitabine (DAC) Treatment Induces Very Early In Vivo DNA Methylation and Transcriptome Changes in Primary AML Peripheral Blood Blasts." Blood 118, no. 21 (November 18, 2011): 1360. http://dx.doi.org/10.1182/blood.v118.21.1360.1360.
Full textAbstract:
Abstract Abstract 1360 Background: The in vitro effects of the DNA hypomethylating agents 5-aza-C (5-azacytidine) and 5-aza-dC (DAC) upon the epigenome and transcriptome of AML cell lines have been investigated by numerous groups, demonstrating induction of gene-specific and global hypomethylation, as well as up- and downregulation of multiple genes. However, their in vivo mechanisms of action are not well-studied, with only very sparse data on primary blasts from patients (pts) with myeloid neoplasias treated with these compounds (Daskalakis et al., Blood 2002, Yang et al., Cancer Research 2006, Fandy et al., Blood 2009). This is primarily due to the substantial methodological challenges of obtaining sufficient cell numbers of bona fide malignant cells during treatment. To study very early in vivo effects, we isolated and analyzed primary cells from AML pts with high numbers of peripheral blood blasts treated with the hypomethylating agent DAC. Patients, Materials and Methods: Of 48 consecutive pts aged >60 years with newly diagnosed AML treated with DAC as described (Lübbert et al., 2011) at a single centre within a multicenter phase II study (trial 00331), successful sequential sampling of peripheral blood blasts in sufficient numbers and purity was feasible in 8 pts. The median WBC at AML diagnosis was 18,400/μl (range 4,800–241,000), the median age was 80 years, and 6/8 had cytogenetic abnormalities. The methylation state of LINE1 and 35 genes (5' regions, represented by a total of 635 evaluable CpG dinucleotides) was quantified by MALDI-TOF mass spectrometry. Gene selection criteria were based on previous identification as potentially silenced tumor suppressors in genome-wide methylation analyses, and on reports as epigenetic targets in myeloid neoplasia. Transcriptional changes were assessed by array-based transcriptome profiling using the HG-U133plus 2.0 GeneChip array. Results: Isolation and purification of sufficient numbers of blasts was done both immediately before and at day 6 (median, range 4–7) after start of DAC infusion. Methylation quantification of pre-treatment blasts yielded patterns clearly distinguishing them from CD34-positive normal hematopoietic precursors of healthy donors (n=10). Specifically, P73, P15 and CDH1 exhibited the strongest and most consistent methylation gains (9–18%, p<0.015) in the malignant vs. normal cells. Early after DAC treatment, a striking decrease in LINE1 methylation was noted in 7/8 pts (p = 0.02), the most consistent effect among all investigated genomic regions. Overall, DAC-induced methylation changes (hypo- and/or hypermethylation) occurred in all eight pts. Hypomethylation was observed in the CpG islands of PBX1 (median 11%, range 5.5–25%, p<0.069), ESR1 (median 1.5%, range 0–9%, p<0.1) and MPO (median 4.3%, range 1–19%, p<0.1). For P73 and TLX3, substantial hypomethylation was observed in a subset of patients (maximum changes of 36% and 34% respectively), while other pts showed unchanged or increased DNA methylation levels. Unsupervised hierarchical clustering revealed that the highest similarities were intra- but not inter-individual. When interrogating unbiased methylation changes at all 635 CpGs, significant hypomethylation was induced in 4/8 pts, significant hypermethylation in 1/8 pts, and non-significant methylation changes seen in 3/8 pts. DAC-induced mRNA expression changes also occurred in all eight pts, without clear correlations between hypomethylation and restored expression. Conclusions: DAC administered at a clinically effective dose and schedule resulted in a consistent and pronounced in vivo decrease of LINE1 methylation already at early time points after treatment start, with significant hypomethylation events in 50% of the pts This might be indicative of effective, early Dnmt1 depletion. Induction of multiple transcriptional changes (but up- and downregulation) was also noted in all pts. This is, to the best of our knowledge, the first report of an integrated methylation/transcriptome analysis in primary leukemia cells isolated at very early time points during therapy with hypomethylating agents, i.e. before clonal selection or even replacement and the occurrence of secondary events. Our observations are compatible with a mechanism of action of DAC that is distinct from those of a non-hypomethylating cytosine analogues such as cytarabine, in line with in vitro results (Flotho et al, Leukemia 2009). Disclosures: No relevant conflicts of interest to declare.
41
Garcia-Manero, Guillermo, Olatoyosi Odenike, Philip C. Amrein, David P. Steensma, Amy E. DeZern, Laura C. Michaelis, Stefan Faderl, et al. "Successful Emulation of IV Decitabine Pharmacokinetics with an Oral Fixed-Dose Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with Oral Decitabine, in Subjects with Myelodysplastic Syndromes (MDS): Final Data of Phase 1 Study." Blood 128, no. 22 (December 2, 2016): 114. http://dx.doi.org/10.1182/blood.v128.22.114.114.
Full textAbstract:
Abstract Introduction: Patients with International Prognostic Scoring System (IPSS) intermediate 1 and 2 (Int) and high risk (HR) MDS benefit from therapy with hypomethylating agents (HMAs) decitabine (DAC) and azacitidine (AZA). Treatment requires 5 or 7 daily parenteral doses every month while the patient is benefitting. An oral HMA taken at home would provide patient convenience, and potentially enhance adherence to treatment particularly for long-term responders. Neither DAC nor AZA is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin in preclinical models. We report here the final results of a Phase 1 study including an extension arm of a PK-guided first in human dose escalation trial of ASTX727 (the combination of oral DAC and E7727). Methods: Adult patients with Int or HR MDS or Chronic Myelomonocytic Leukemia (CMML) were enrolled in this dose-escalating trial. In addition to assessing the safety of the combination, the primary PK objective was to achieve a mean AUC of DAC following oral ASTX727 comparable to that achieved by IV DAC at the approved daily dose of 20 mg/m2. In the first cycle, each patient received an IV DAC dose of 20 mg/m2 on Day 1 as an internal comparator followed by oral ASTX727 on Days 2-5 escalated by cohort. Subsequent cycles were given with oral ASTX727 on Days 1-5 at the same dose of Cycle 1. Cycles were 28 days in length. Only one component at a time was escalated in each cohort and oral doses were not adjusted for weight or body surface area. Intrapatient dose escalation was permitted. Pharmacodynamics (PD) were evaluated by LINE-1 DNA methylation in peripheral blood. Responses were assessed using the International Working Group (IWG) criteria for response (Cheson et al, 2006). Results: 43 patients were treated in 5 cohorts of 6 patients each plus a 13 patient expansion of cohort 5. The median age was 71.5 years (range 59-86), 30/43 (70%) were male, and median time from diagnosis was 273 days (range 5-3518). Prior therapies had been administered to 22/43 (51%) patients including 20 who had received prior HMA. The AUC for IV DAC 20 mg/m2 in all patients (n=43) had a mean (CV) of 171(37%) ng*hr/mL. The Cmax for IV DAC 20 mg/m2 had a mean (CV) of 179(36%) ng/mL. Doses of each component of ASTX727 were escalated as shown in Table 1. E7727 was escalated first from 40 to 100 mg in cohorts 1 to 3 then kept constant at cohorts 4 to 6. DAC doses were kept constant at 20 mg in cohorts 1 to 3 then escalated to 40 mg at cohort 4 and de-escalated to 30 mg at cohort 5. Dose dependent increases in AUC and Cmax occurred with escalating doses. DAC AUC values after oral ASTX727 approached then exceeded IV at 149% by cohort 4. DAC Cmax values after oral ASTX727 never exceeded IV in any Cohort. Mean % LINE-1 demethylation on cycle 1 Day 8±SE increased with dose escalation reaching 12.8%±3.8 by cohort 4. Lower DAC AUC and Cmax were observed after lowering the oral DAC dose from 40 to 30 mg in cohort 5 as shown in Table 1. One patient in cohort 4 had a dose limiting toxicity of thrombocytopenia and no Grade ≥ 3 drug-related non-hematologic AEs were observed in any patient. The most common ≥ Grade 3 AEs regardless of relationship to the drug were thrombocytopenia (36%), anemia (30%), neutropenia (27%), and febrile neutropenia (21%). No drug-related Grade ≥ 3 gastrointestinal AEs were reported. A median of 5 cycles (range 1-23) were administered, 11 patients remain on therapy, and 14 (32%) have experienced objective clinical responses so far, including 5 Complete Response (CR), 4 marrow CR, and 5 Hematologic Improvement. Of 23 patients initially RBC dependent, 6 (26%), became independent and of 6 who were platelet dependent, 2(33%) became independent. Conclusions: ASTX727 (the combination of E7727 and DAC administered PO concomitantly) achieved the primary PK objective of emulating IV DAC 20 mg/m2 AUC levels with a similar safety profile. Day 8 LINE-1 demethylation in Cohort 4, overall clinical response and transfusion independence rates are consistent with those historically reported following DAC 20 mg/m2 IV for 5 days, even though 47% had received prior HMA therapy. ASTX727 has now proceeded to a randomized phase 2 study comparing IV DAC 20 mg/m2 IV daily for 5 days to oral ASTX727 at the doses of 35 mg DAC and 100 mg E7727 daily for 5 days in Int or HR MDS and CMML patients. Disclosures Odenike: Geron: Research Funding; Suneisis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity's Board of Directors or advisory committees. Steensma:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Ariad: Equity Ownership; Genoptix: Consultancy; Millenium/Takeda: Consultancy. Michaelis:Incyte: Honoraria; Pfizer: Equity Ownership; Celgene: Honoraria, Speakers Bureau. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals: Employment. Oganesian:Astex Pharmaceuticals, Inc.: Employment. Zhang:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Savona:Ariad: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding.
42
Xu, Xingguang, Matthew B. Myers, Friso G. Versteeg, Bobby Pejcic, Charles Heath, and Colin D. Wood. "Direct air capture (DAC) of CO2 using polyethylenimine (PEI) “snow”: a scalable strategy." Chemical Communications 56, no. 52 (2020): 7151–54. http://dx.doi.org/10.1039/d0cc02572k.
Full text
43
Badar, Talha, Hagop M. Kantarjian, Farhad Ravandi, Elias Jabbour, Gautam Borthakur, Jorge E. Cortes, Naveen Pemmaraju, Sherry R. Pierce, Naval Daver, and Srdan Verstovsek. "Therapeutic Benefit of Decitabine, a Hypomethylating Agent, in Patients with Myeloproliferative Neoplasm in Blastic Phase/Acute Myeloid Leukemia (MPN-AML), Accelerated Phase (MPN-AP), and DIPSS-Plus High Risk Primary Myelofibrosis (PMF)." Blood 124, no. 21 (December 6, 2014): 3186. http://dx.doi.org/10.1182/blood.v124.21.3186.3186.
Full textAbstract:
Abstract Background: MPN-AML, MPN-AP, and DIPSS-plus high risk PMF are associated with a poor response to therapy and shortened survival. Several studies have shown clinical activity of hypomethylating agents (DNA methyltransferase inhibitors) in these situations. We reviewed our database to evaluate the clinical outcome of patients (pts) with MPN-AML, MPN-AP and DIPSS-plus high risk PMF who received decitabine (DAC; a hypomethylating agent) in the course of their treatment at our institution. Methods: Retrospective chart review identified 21 pts with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high risk PMF treated with DAC in our center over last 7 years. MPN- AP was defined by 10%-19% blasts in the peripheral blood or bone marrow (BM). DIPSS-plus is a prognostic model for PMF and can be applied at any point during the disease course (Gagnat et al. J Clin Oncol 2011; 29:392-7). Responses in MPN-AML were defined according to published recommendations (Mascarenhas et al. Leuk Res 2012; 36:1500-4). Responses in MPN-AP and DIPSS-plus high risk PMF were defined according to the revised IWG-MRT and ELN consensus report (Tefferi et al. Blood 2013; 122: 1395-8). Results: MPN-AML pts characteristics: median age 64 yrs (range, 45-82); initial MPN: ET 4 (19%), PV 5 (24%), PMF 10 (48%), and MPN unclassified 2 (10%) pts. The median number (no.) of prior therapies for MPN was 1 (range, 0-4). The median time for transformation from MPN to MPN-AML was 93 mo (range, 1.4-292). Thirteen (39%) pts had unfavorable cytogenetics. DAC was given as first-line therapy in 12 (57%) pts, as second-line therapy in 8 (38%), and as third-line in 1 (5%). The median no. of DAC cycles given was 2 (range, 1-15). MPN-AP pts characteristics: median age 63 yrs (range, 50-81); initial MPN: ET 2 pts (15%), PV 5 (39%), and PMF 6 (46%). The median no. of prior therapies for MPN was 2 (range, 0-5). The median time from diagnosis of MPN to DAC was 65 (0-389) mo. The median no. of DAC cycles given was 2 (range 1-37). PMF with DIPSS-plus high risk pts characteristics: median age 67 yrs (range, 55-77). Seven (64%) pts had a JAK2 mutation. The median hemoglobin (Hb) was 9.2 g/dl (range, 7.7-11.7), median WBC was 41.5 K/uL (range, 2-140), median platelet (plt) count was 69 K/uL (range, 9-860) and bone marrow blast percentage (BM BL %) was 2% (range, 0-9). The median number of DIPSS-plus risk factors was 6 (range, 4-8), and median no. of prior therapies was 1 (range, 0-4). The median time to DAC from diagnosis of PMF was 19 (3-195) mo. The median no. of DAC cycles given was 3 (range 1-8). Six (29%) MPN-AML pts responded to DAC: 3 CR, 2 CRi and 1 PR. Two pts who achieved CR, received DAC as second line after falling induction chemotherapy for AML. The median time to response was 2.6 mo (range, 1-13.5). Among non-responders; 10(48%) pts died due to disease progression, 3 (14%) pts died due to sepsis, one is alive with stable disease (SD) on therapy, and one pt died 2 months after bone marrow transplant (BMT). The median response duration (defined as time to next therapy/death/last follow up) was 7 mo (range, 2-24). One patient responding to DAC had BMT after 2 months of maintaining the response. The median OS from the time of post MPN-AML acquisition was 6.9 mo. The OS was 10.5 mo in responders vs 4 mo in non-responders (p= 0.024) (Fig. 1A). Among MPN-AP, 1 pt had clinical improvement (CI) in Hb and plt, and 7 had SD (with improvements in blood count), for overall benefit in 8 (61%) pts. The median benefit duration was 6.5 mo. (1.8-14). Four (31%) pts with SD after improvement in leukocytosis and BM BL % had BMT. The median OS from the time of MPN-AP acquisition was 9.7 mo. The OS in responders was 11.8 mo. vs 4 mo. in non-responders (p=0.28) (Fig.1B). Among non-responders 3 (23%) pts transformed to AML, one pt received next line of therapy and had BMT, one pt died due to disease progression. Nine (82%) pts with DIPSS-plus high risk PMF benefited from DAC: 1 had CI in plt, 1 had CI in spleen, and 7 had SD (with improvements in blood count). Median response duration was 9 mo (1-23). Three (27%) pts had BMT after improvement in leukocytosis and BM BL %. Both pts who did not respond, progressed to AML and died due to infectious complication. The median OS was 36.6 mo: OS in responders was 190 mo vs 4.7 mo in non-responders (p=0.027) (Fig. 1C). Conclusion: DAC is a viable therapeutic option for pts with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining DAC with other clinically active agents are needed to improve overall outcome. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
44
Koemets, Egor, Liang Yuan, Elena Bykova, Konstantin Glazyrin, Eiji Ohtani, and Leonid Dubrovinsky. "Interaction Between FeOOH and NaCl at Extreme Conditions: Synthesis of Novel Na2FeCl4OHx Compound." Minerals 10, no. 1 (January 5, 2020): 51. http://dx.doi.org/10.3390/min10010051.
Full textAbstract:
Iron(III) oxide-hydroxide, FeOOH, is abundant in the banded iron formations (BIFs). Recent studies indicate that BIFs may carry water down to the lower mantle with subducting slabs. The previous experiments investigating the properties of FeOOH at extreme pressures (P) and temperatures (T) were performed in diamond anvil cells (DACs), where it was compressed inside alkali metal halide pressure-transmitting media (2). Alkali metal halides such as NaCl or KCl are expected to be chemically inert; therefore, they are widely used in DAC experiments. Here, we report the chemical interaction between FeOOH and NaCl pressure medium at 107(2) GPa and 2400(200) K. By means of single-crystal X-ray diffraction (SC-XRD) analysis applied to a multigrain sample, we demonstrate the formation of a Na2FeCl4OHx phase and provide its structural solution and refinement. Our results demonstrate that at high P-T conditions, the alkali metal halides could interact with hydrous phases and thus cannot be used as a pressure transmitting and thermal insulating medium in DAC experiments dedicated to studies of hydroxyl or water-bearing materials at high P-T.
45
Fujita, Yoko, Linpeng Wei, Jonathan T. C. Liu, and Nader Sanai. "SURG-04. INTRAOPERATIVE HAND-HELD LINE-SCANNED DUAL-AXIS CONFOCAL MICROSCOPY FOR VISUALIZING LOW-GRADE GLIOMAS." Neuro-Oncology 21, Supplement_6 (November 2019): vi240. http://dx.doi.org/10.1093/neuonc/noz175.1005.
Full textAbstract:
Abstract BACKGROUND Extent of resection is a prognostic factor for low- and high-grade gliomas. Fluorescence guided surgery (FGS) using five-aminolevulinic acid (5-ALA) is associated with greater extent of resection in high-grade gliomas. However, for low-grade gliomas, intraoperative imaging technologies such as FGS, have not been optimized to distinguish tumor from normal tissue. Intraoperative confocal microscopy can better visualize tissue cytoarchitecture in real-time. Here we report on the feasibility of a newly-developed, hand-held, line-scanned dual-axis (LS-DAC) confocal microscope in distinguishing tumor vs. normal cells in ex vivo human low-grade glioma tissue. METHOD Ten low-grade glioma patients who underwent craniotomy were enrolled. Resected specimens were labelled with acridine orange (1mM) for one minute, and exposed surfaces were immediately imaged by our device. Subsequently, specimens were cut into sections and stained with H&E for histopathological analysis. RESULTS LS-DAC confocal microscope visualized nuclei of tumor cells vs. surrounding tissue, demonstrating clear differences in cellularity in the two compartments. Acquired images were comparable to those observed on matched H&E-stained sections. Live images provided minimal motion artifact due to the higher frame rate of 16 Hz. CONCLUSION LS-DAC confocal microscope provided real-time, high-contrast mosaic images of human low-grade glioma tissue ex vivo. The ability to distinguish tumor vs. normal tissue at the cellular level with little motion artifact, as well as the device’s hand-held design, suggests this technology merits additional investigation as an intraoperative adjunct for low-grade glioma surgery.
46
Sanna, Marco, Giovanni Caocci, Adriana Vacca, Eugenia Piras, Federica Orrù, and Giorgio La Nasa. "Daunorubicin, Cytarabine, and Cladribine Regimen Plus Radiotherapy and Donor Lymphocyte Infusion for Extramedullary Relapse of Acute Myeloid Leukemia after Hematopoietic Stem Cell Transplantation." Case Reports in Hematology 2013 (2013): 1–2. http://dx.doi.org/10.1155/2013/258028.
Full textAbstract:
Myeloid sarcoma is a rare tumor consisting of myeloid blasts that involve anatomic sites outside the bone marrow. Fatal prognosis is inevitable in patients with extramedullary relapse after hematopoietic stem cell transplantation (HSCT), and no standard treatments are available yet. We report the first case of extramedullary relapse after HSCT treated with a combination of daunorubicin, cytarabine, and cladribine (DAC) regimen plus radiotherapy and donor lymphocyte infusion (DLI). This treatment induced a new and durable remission in our patient. The favorable toxicity profile and the reduced cost make this combination worthy of further investigations.
47
Huang, Xiaomeng, Sebastian Schwind, Bo Yu, Jiuxia Pang, Ramasamy Santhanam, Kenneth K. Chan, Ramiro Garzon, et al. "Targeted Delivery of MicroRNA-29b by Nanoparticles Provides Antileukemic Activity and Increases Sensitivity to the Hypomethylating Agent Decitabine (DAC) in Acute Myeloid Leukemia (AML)." Blood 118, no. 21 (November 18, 2011): 81. http://dx.doi.org/10.1182/blood.v118.21.81.81.
Full textAbstract:
Abstract Abstract 81 Despite advances in our understanding of disease mechanisms the outcome of the majority of AML patients (pts) remains poor. Epigenetic gene silencing by DNA hypermethylation has been shown to contribute to AML. Recently we demonstrated promising results of treatment with the hypomethylating agent DAC in older AML pts. Pts with higher miR-29b expression were more likely to respond to DAC. MiR-29b targets DNA methyltransferases (DNMTs; i.e. DNMT1, DNMT3A & DNMT3B) and has hypomethylating and tumor suppressor activity in AML. Thus uncovering a method to increase intracellular miR-29b and sensitize AML blasts to DAC may be of therapeutic value. Free synthetic miRs are degraded in bio-fluid and have very limited cellular uptake. To overcome these limitations, we developed a novel non-viral delivery system for synthetic miRs. Polyethylenimine was used to capture synthetic miRs & form a polyplex core. An outside layer of lipid components, 1,2-Dioleoyl-sn-Glycero-3-Phosphoethanolamine, Linoleic acid & 1,2-Dimyristoyl-sn-glycerol, methoxypolyethylene Glycol (MW=2,000) was used to protect the miRs from degradation & clearance and facilitate their uptake. Using this approach we produced nanoparticles (NPs) encapsulating 0.4 μM synthetic miR-29b precursors (pM29b) or scramble controls (sc) [both Ambion]. Since AML blasts and cell lines overexpress the transferrin receptor, we conjugated the NPs with transferrin (Tf) to increase the uptake by targeted delivery. To evaluate the efficiency of NP uptake we encapsulated FAM-fluorescent labeled-pM29b and treated AML cell lines (i.e. Kasumi-1 & MV4-11). Tf-conjugated NP (TfNP) treated cells showed the highest uptake by confocal microscopy and flow-cytometry (mean fluorescence intensity (MFI): 21.0 & 22.9 for Kasumi-1 & MV4-11 respectively) compared to non-Tf-conjugated NPs (NP; MFI: 8.3 & 13.0). To evaluate if pM29b was processed into its mature form we measured levels of mature miR-29b in MV4-11 & Kasumi-1 by qPCR after treatment with TfNP encapsulating pM29b (TfNP29b) or NP encapsulating pM29b (NP29b). At 48h mature miR-29b increased 2000 and 2100 fold after treatment with TfNP29b but only 20 and 50 fold following treatment with NP29b in MV4-11 & Kasumi-1 respectively, compared to untreated or TfNPsc treated cells. Thus TfNPs were 40–100 times more efficient than NPs in increasing levels of miR-29b. Our observations were validated in primary blasts from 3 AML pts. At 48h miR-29b levels increase on average 400 fold in TfNP29b vs TfNPsc treated blasts. The levels of an unrelated miR (i.e. miR-140) remained unchanged in all our experiments. These results demonstrate that pM29b is efficiently delivered and processed into its mature form after TfNP delivery, leading to a specific increase of miR-29b in AML cell lines & primary blasts with otherwise low endogenous miR-29b expression. Downregulation of the miR-29b targets DNMT1, DNMT3A, and DNMT3B on RNA & protein level, determined by qPCR and western blotting respectively, was observed in both cell lines & primary AML samples at 48 hours following TfNP29b compared to TfNPsc treatment. The observed fold reduction on RNA level for DNMT1 was 0.63, 0.53 & 0.63, for DNMT3A 0.48, 0.53 & 0.58, and for DNMT3B 0.60, 0.73 & 0.53 in treated MV4-11, Kasumi-1 cells & pts blasts (mean, n=3), respectively. Increased miR-29b, following TfNP29b treatment resulted in antileukemic activity. Treatment with TfNP29b compared to TfNPsc led to 30% & 35% reduction in proliferation at day 5 and 50% & 64% decreased colony forming ability (scored after two weeks) in MV4-11 & Kasumi-1 cells, respectively. To investigate a possible sensitizing effect of miR-29b to DAC treatment, we treated MV4-11 cells and primary AML blasts with 2.5 uM DAC, which is comparable to concentrations achievable in treated AML pts. 72 hours after DAC treatment, decreased viability (measured by MTS assays) was observed in cells treated with TfNP29b (for 48h) followed by DAC compared with those treated with TfNPsc followed by DAC: 36% vs 53% (p<0.001) for MV4-11 cells and 63% vs 73% (p<0.01) for primary pts blasts. In conclusion, we report an effective nanoparticle-based delivery system for miRs. Our delivery system for pM29b showed in vitro antileukemic activity and improved response to DAC in AML cells, demonstrating that miR-29b is not only a predictor for clinical response to DAC, but may also functions as a novel therapeutic, sensitizer to hypomethylating agents in AML. Disclosures: No relevant conflicts of interest to declare.
48
Blount, A. R., R. N. Pittman, B. A. Smith, R. N. Morgan, W. Dankers, R. K. Sprenkel, and M. T. Momol. "First Report of Peanut stunt virus in Perennial Peanut in North Florida and Southern Georgia." Plant Disease 86, no. 3 (March 2002): 326. http://dx.doi.org/10.1094/pdis.2002.86.3.326c.
Full textAbstract:
In spring 2001, symptoms similar to aphid-vectored peanut stunt disease caused by Peanut stunt virus (PSV) were observed on perennial peanut (Arachis glabrata) cv. Floragraze in Jackson and Gulf counties, FL and Lowndes County, GA. Symptoms observed in commercial hay fields and at the North Florida Research and Education Center in Marianna and Quincy included malformed leaves, plant chlorosis, leaf mottling, and stunted plants, which resulted in reduced foliage yield. Leaf symptoms were visible throughout the growing season. Stunting was more common in spring and early summer. No symptoms were seen on rhizomes. Diagnosis of PSV (genus Cucumovirus) from symptomatic leaves and rhizome materials of 12 plants was confirmed by a direct antigen-coated enzyme-linked immunosorbent assay (DAC-ELISA). ELISA tests were repeated three times. Antibodies specific to the Clemson isolate, serotype E, were obtained from Clemson University, Clemson, SC. DAC-ELISA (1) values of 0.1 A405 above the healthy control for perennial peanut were considered positive for foliage and rhizome material tested. ELISA values ranged from 0.4 to 2.1. The mean ELISA value of the positive controls was 2.65. Symptomatic plants were also tested with ELISA using available antibodies from Agdia Inc., Elkart, IN, for Tomato spotted wilt virus, from ATCC for Peanut stripe virus, and from Clemson University (Cowpea isolate) for Cucumber mosaic virus, but all results were negative. To our knowledge, this is the first report of PSV on perennial peanut in Florida and southern Georgia. At this time, it is not known what role perennial peanut may play as a reservoir of the virus in the vicinity of peanut fields. Little is known about the potential for forage production loss and stand longevity. Next season, molecular detection techniques and epidemiological studies on peanut and perennial peanut will be conducted to ascertain the incidence and possible impact of PSV in Georgia and Florida. Reference: (1) A. G. Gillaspie, Jr. et al. Plant Dis. 79:388, 1995.
49
Keane, Robert G., and Howard Fireman. "Producibility in the Naval Ship Design Process: A Progress Report." Journal of Ship Production 9, no. 04 (November 1, 1993): 210–23. http://dx.doi.org/10.5957/jsp.1993.9.4.210.
Full textAbstract:
In October 1989, A Ship Design for Producibility Workshop was held by the Naval Sea Systems Command (NAVSEA) at the David Taylor Research Center (DTRC). The purpose of the workshop was "To develop the framework of a plan to integrate producibility concepts and processes into the NAVSEA Ship Design Process." The major recommendations of the workshop included initiatives related to increased training of NAVSEA design engineers in modern ship production concepts, development of producibility design tools and practices for use by NAVSEA design engineers, improved cost models, implementation of producibility strategies for ship design process improvements, modification to existing acquisition practices, and improved three-dimensional (3-D) digital data transfer. The workshop was one of NAVSEA's first Total Quality Leadership (TQL) initiatives and was subsequently expanded into the Ship Design, Acquisition and Construction (DAC) Process Improvement Project. This paper reports on the major findings and recommendations of the workshop, the near term accomplishments since the workshop, and the long range strategic plan for continuously improving producibility in the Naval Ship Design Process.
50
Ohanian, Maro, Tara L. Lin, Ellen Ritchie, Michael Craig, Apurv Agrawal, Kathleen G. Halka, Naveen Pemmaraju, et al. "Safety and Efficacy of Lower Intensity Induction Therapy with Intravenous Prexigebersen (BP1001) in Patients with High-Risk and Relapsed/Refractory Acute Myeloid Leukemia (AML)." Blood 138, Supplement 1 (November 5, 2021): 1281. http://dx.doi.org/10.1182/blood-2021-152750.
Full textAbstract:
Abstract Background: About two-thirds of AML patients harbor mutations in signaling and kinase pathways (e.g., FLT3, KRAS, NRAS, PTPN11, NF1, KIT), which utilize the growth factor receptor bound protein-2 (Grb2) to induce AML progression. Prexigebersen (BP1001), a liposome-incorporated Grb2 antisense oligonucleotide that inhibits Grb2 expression, suppresses cancer growth and survival. A Phase I/IB single center study (Ohanian, Lancet Haematol 2018) in relapsed/refractory AML patients demonstrated BP1001 safety up to 90 mg/m 2 and demonstrated CR/CRi in 3 of 6 relapsed/refractory AML patients treated with BP1001 + low dose cytarabine combination in the Phase IB portion. Preclinical studies indicated that BP1001 enhanced the inhibitory effects of decitabine (DAC), or DAC + venetoclax (VEN) against AML cells. Thus, we designed a clinical trial with three treatment arms: (1) BP1001 + DAC + VEN for newly diagnosed AML, (2) BP1001 + DAC + VEN for relapsed/refractory AML, (3) BP1001 + DAC for relapsed/refractory AML patients who are VEN-resistant or -intolerant [ClinicalTrials.gov Identifier: NCT02781883]. The study was amended to obtain safety run-in data for patients treated with BP1001 + DAC first before proceeding to safety run-in for patients treated with BP1001 + DAC + VEN. Here we report the safety run-in and efficacy data of AML patients treated with BP1001 + DAC or BP1001 + DAC + VEN. Methods: This is a multi-center open-label, Phase II study in newly diagnosed and relapsed/refractory AML patients to determine the safety and preliminary efficacy of BP1001 (given at 60 mg/m 2 over 2-3 h twice weekly for a total of 8 doses over a 28-day cycle) in combination with DAC (20 mg/m 2, once daily for 5 days) or in combination with DAC and VEN (400 mg, once daily). Eligible patients were considered unsuitable for or refused intensive chemotherapy and had ECOG performance status of 0-2. Patients treated with at least 1 cycle of therapy were evaluable for safety run-in. Results: Between April 2018 and May 2020, 6 patients (4 male: 67%) with median age 72 years (range, 51 - 76) were treated with at least 1 cycle of BP1001 + DAC combination therapy. Four patients (67%) had de novo AML and two (33%) had secondary AML. All patients in this cohort were considered high risk due to having either adverse risk status by ELN (n=5) or treated secondary AML (n=1) (transformed from myelodysplastic syndrome/myeloproliferative neoplasm after failing 4 lines of prior therapy). Adverse events (AEs) were generally consistent with those expected with DAC and/or AML and included diarrhea (67%), fatigue (50%), constipation (50%), nausea (50%), dyspnea (50%), hypoxia (50%), hypotension (50%) and pain in extremity (50%). The most frequent serious AE (SAE) was bacteremia (33%). Two de novo patients (33%) achieved a CRi and 1 treated secondary AML patient (17%) achieved a PR. Patients received a median of 2.5 cycles of therapy (range, 1 - 6); median duration of follow-up was 140 days (range, 72 - 678). Since May 2020, 6 patients (2 male: 33%) with median age 61 years (range, 44 - 81) were treated with at least 1 cycle of BP1001 + DAC + VEN combination therapy. Two (33%) had de novo AML, and four (67%) were relapsed/refractory. All patients in this cohort were adverse-risk by ELN (n=2) or relapsed/refractory (n=4). AEs were generally as expected with DAC, VEN and/or AML, including fatigue (67%), diarrhea (67%), constipation (67%), decreased appetite (67%), hypokalemia (67%), hypocalcemia (50%), edema peripheral (50%), asthenia (50%), nausea (50%), abdominal pain (50%), dysphagia (50%), hypotension (50%) and febrile neutropenia (50%). The most frequent SAEs were sepsis (33%) and febrile neutropenia (50%). Four patients (67%) achieved a CR/CRi/MLFS (n=1/2/1) and 1 (17%) achieved a PR. Of these patients, 3 were relapsed/refractory (1 CR/1 CRi/1 MLFS) and two were de novo (1 CRi/1 PR). Patients received a median of 4 cycles of therapy (range, 1 - 9); median duration of follow-up was 177 days (range, 113 - 318). Conclusions: BP1001-based combination therapy has been safely administered to high-risk and relapsed/refractory AML patients who were considered unsuitable for standard chemotherapy. Preliminary data showed the combination treatment of BP1001 + DAC or BP1001 + DAC + VEN was well-tolerated, with encouraging efficacy signals. The study will continue enrollment across all three cohorts. Drug dosing for the study will proceed as planned. Figure 1 Figure 1. Disclosures Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Ritchie: Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Speakers Bureau; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; NS Pharma: Research Funding; Protaganist: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Pemmaraju: Clearview Healthcare Partners: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; MustangBio: Consultancy, Other; Roche Diagnostics: Consultancy; Springer Science + Business Media: Other; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; LFB Biotechnologies: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Affymetrix: Consultancy, Research Funding; Blueprint Medicines: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Aptitude Health: Consultancy; CareDx, Inc.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Borthakur: Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; Protagonist: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees. Tari Ashizawa: Bio-Path Holdings, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Kantarjian: Immunogen: Research Funding; Ipsen Pharmaceuticals: Honoraria; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Aptitude Health: Honoraria; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria; NOVA Research: Honoraria; Astra Zeneca: Honoraria; Ascentage: Research Funding; BMS: Research Funding; Astellas Health: Honoraria; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; KAHR Medical Ltd: Honoraria. Cortes: Novartis: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding. Roboz: Amgen: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Blueprint Medicines: Consultancy; Glaxo SmithKline: Consultancy; Agios: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Astex: Consultancy; Bristol Myers Squibb: Consultancy; Actinium: Consultancy; Jasper Therapeutics: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Mesoblast: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy.