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101.
Nonclinical pharmacokinetics and metabolism of EPZ‐5676, a novel DOT1L histone methyltransferase inhibitor
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Aravind Basavapathruni Edward J. Olhava Scott R. Daigle Carly A. Therkelsen Lei Jin P. Ann Boriack‐Sjodin Christina J. Allain Christine R. Klaus Alejandra Raimondi Margaret Porter Scott Angelos Dovletoglou Victoria M. Richon Roy M. Pollock Robert A. Copeland Mikel P. Moyer Richard Chesworth Paul G. Pearson Nigel J. Waters 《Biopharmaceutics & drug disposition》2014,35(4):237-252
(2R,3R,4S,5R)‐2‐(6‐Amino‐9H‐purin‐9‐yl)‐5‐((((1r,3S)‐3‐(2‐(5‐(tert‐butyl)‐1H‐benzo[d]imidazol‐2‐yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran‐3,4‐diol (EPZ‐5676) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL‐rearranged leukemias. This report describes the preclinical pharmacokinetics and metabolism of EPZ‐5676, an aminonucleoside analog with exquisite target potency and selectivity that has shown robust and durable tumor growth inhibition in preclinical models. The in vivo pharmacokinetics in mouse, rat and dog were characterized following i.v. and p.o. administration; EPZ‐5676 had moderate to high clearance, low oral bioavailability with a steady‐state volume of distribution 2–3 fold higher than total body water. EPZ‐5676 showed biexponential kinetics following i.v. administration, giving rise to a terminal elimination half‐life (t1/2) of 1.1, 3.7 and 13.6 h in mouse, rat and dog, respectively. The corresponding in vitro ADME parameters were also studied and utilized for in vitro–in vivo extrapolation purposes. There was good agreement between the microsomal clearance and the in vivo clearance implicating hepatic oxidative metabolism as the predominant elimination route in preclinical species. Furthermore, low renal clearance was observed in mouse, approximating to fu‐corrected glomerular filtration rate (GFR) and thus passive glomerular filtration. The metabolic pathways across species were studied in liver microsomes in which EPZ‐5676 was metabolized to three monohydroxylated metabolites (M1, M3 and M5), one N‐dealkylated product (M4) as well as an N‐oxide (M6). Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
102.
103.
Menzel T; Rahman Z; Calleja E; White K; Wilson EL; Wieder R; Gabrilove J 《Blood》1996,87(3):1056-1063
Chronic lymphocytic leukemia (CLL) is characterized by delayed senescence and slow accumulation of monoclonal, small lymphocytes. Basic fibroblast growth factor (bFGF) is a pleiotropic cytokine that plays a role in hematopoiesis and apoptosis. Elevated bFGF levels have been detected in urine from patients with a variety of neoplastic diseases including various leukemias; however, the cellular source of the bFGF has not been determined. In this study, the intracellular bFGF level in lymphocytes of 36 patients with B-CLL and 15 normal donors was determined using an enzyme-linked immunoassay. In cells derived from patients with high-risk disease, the median level of intracellular bFGF was 381.5 pg/2 x 10(5) cells, compared with a median of 90.5 pg/2 x 10(5) cells in patients with intermediate disease. In patients with low- risk disease, the median bFGF level was 4.9 pg/2 x 10(5) cells, and in normal controls, it was 6.0 pg/2 x 10(5) cells. The difference in the bFGF levels was significant for the comparison between low- and intermediate-risk (P = .00119), low- and high-risk (P < .0001), and intermediate- and high-risk disease (P = .0001). Immunofluorescent stains of peripheral blood mononuclear cells confirmed CLL lymphocytes as a cellular source of bFGF. To evaluate the potential contribution of elevated intracellular bFGF levels to the phenotype of CLL cells, leukemic cells were cultured in vitro with an apoptotic stimulus (fludarabine). CLL cells with high intracellular levels of bFGF appeared to be more resistant to fludarabine treatment. The addition of bFGF to fludarabine-treated CLL cells resulted in a delay of apoptosis and prolonged survival. These data suggest that bFGF may contribute to the resistance of CLL cells to an apoptotic stimulus. 相似文献
104.
Higher temporal variability of forest breeding bird communities in fragmented landscapes 总被引:10,自引:0,他引:10
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Thierry Boulinier James D. Nichols James E. Hines John R. Sauer Curtis H. Flather Kenneth H. Pollock 《Proceedings of the National Academy of Sciences of the United States of America》1998,95(13):7497-7501
Understanding the relationship between animal community dynamics and landscape structure has become a priority for biodiversity conservation. In particular, predicting the effects of habitat destruction that confine species to networks of small patches is an important prerequisite to conservation plan development. Theoretical models that predict the occurrence of species in fragmented landscapes, and relationships between stability and diversity do exist. However, reliable empirical investigations of the dynamics of biodiversity have been prevented by differences in species detection probabilities among landscapes. Using long-term data sampled at a large spatial scale in conjunction with a capture-recapture approach, we developed estimates of parameters of community changes over a 22-year period for forest breeding birds in selected areas of the eastern United States. We show that forest fragmentation was associated not only with a reduced number of forest bird species, but also with increased temporal variability in the number of species. This higher temporal variability was associated with higher local extinction and turnover rates. These results have major conservation implications. Moreover, the approach used provides a practical tool for the study of the dynamics of biodiversity. 相似文献
105.
M L Pollock G A Dawson H S Miller A Ward D Cooper W Headley A C Linnerud M M Nomeir 《Journal of the American Geriatrics Society》1976,24(3):97-104
A study was made of the effects of training for 30 minutes, three days a week for 20 weeks on certain physiologic measures of sedentary men between 49 and 65 years of age. Twenty-two subjects volunteered for the experimental group, and 8 others for the control group. Exercise sessions were conducted on a quarter-mile track and consisted of continuous bouts of walking and jogging. The average daily energy expenditures progressed from 228 to 365 kilocalories between weeks 4 and 20. For the same period, average exercise heart rates (HRs) progressed from 149 beats/minute (83 per cent maximum HR) to 155 beats/minute (91 per cent maximum HR). The experimental group showed significant increases in maximum oxygen intake (VO2 max) from 2.47 to 2.90 liters/minute (18 per cent) and in maximum pulmonary ventilation (VE max) from 105 to 121 liters/minute (BTPS), and decreases in resting HR, diastolic blood pressure, body weight, skinfold fat, and abdominal girth. Serum cholesterol and triglyceride levels and heart volume remained unchanged. The control subjects showed no significant changes. Regression analysis, with use of age as a covariate, showed a small but significant inverse relationship with changes in VO2 max. It was concluded that men of the 49-65 age group respond favorably to endurance exercise and show a magnitude of change similar to that found in previous investigations of similar design with younger subjects. 相似文献
106.
TESFALDET T. MICHAEL M.D. M.P.H. OWEN MOGABGAB M.D. ERIC FUH M.D. VISHAL G. PATEL M.D. ABDALLAH EL SABBAGH M.D. MOHAMMED E. ALOMAR M.D. BAVANA V. RANGAN B.D.S. M.P.H. SHUAIB M. ABDULLAH M.D. SUBHASH BANERJEE M.D. EMMANOUIL S. BRILAKIS M.D. Ph.D. 《Journal of interventional cardiology》2014,27(1):36-43
Objective
To assess the outcomes of the “hybrid” approach to chronic total occlusion (CTO) percutaneous coronary interventions (PCIs).Background
The “hybrid approach” to CTO PCI advocates appropriate and early change of crossing strategy to maximize success, safety, and efficiency.Methods
We prospectively recorded and analyzed detailed step‐by‐step procedural data in 73 consecutive CTO PCI cases performed by a single operator between July 2011 and August 2012.Results
Technical success was achieved in 66 of 73 cases (90.4%). Mean patient age was 65 ± 7 years, and 30% had prior coronary artery bypass surgery. Dual injection was used in 78%. The primary approach was retrograde in 9 cases (12.5%) and antegrade in 64 cases (87.5%), of whom 25 cases (39.1%) underwent retrograde attempt after failed antegrade approach. The initial crossing approach was successful in 40 cases (54.8%), but 32 cases (44%) required 3.6 ± 1.4 approach changes (range 2–7). Antegrade wire escalation, antegrade dissection/reentry, and retrograde crossing were utilized in 97.2%, 46.6%, and 46.6% of cases, respectively. Among successful cases, the final CTO crossing technique was antegrade wire escalation in 50.0%, antegrade dissection/reentry in 24.2%, and retrograde in 25.8%. The mean procedure time, fluoroscopy time, and air kerma radiation exposure until CTO crossing or stopping the procedure were 66 ± 55 minutes, 25 ± 23 minutes, and 2.3 ± 1.9 Gray, respectively. Three patients (4.1%) had a major complication.Conclusion
In the “hybrid approach” to CTO PCI, changes in crossing strategy were needed in approximately half the cases, resulting in high success and low complication rates. (J Interven Cardiol 2014;27:36–43)107.
Jean Salem Ali Shamseddine Mohamad Khalife Ghina El Nounou Abdallah Abou EL Naaj Deborah Mukherji Ali Haydar Walid Faraj 《International journal of surgery case reports》2014,5(12):1162-1163
BACKGROUND
Malignant fibrous histiocytoma, a subtype of primary lung sarcoma is a very rare disease. It usually presents as a lung nodules and the final diagnosis is made by immunohistochemical studies.METHODS
A 45-year-old patient presented with progressive dyspnea, dry cough and right shoulder pain. Chest X-ray revealed complete opacification of the right hemithorax. Chest computed tomography confirmed the presence of a heterogeneous lesion occupying the whole right hemithorax causing a mass effect on the trachea. Ultrasound guided biopsy was done and final pathology was suggestive of malignant fibrous histiocytoma.CONCLUSION
Progressive dyspnea in young otherwise healthy patients should be investigated early on. In our case the presence of right shoulder pain indicates advance disease illustrated by the singular imaging findings. 相似文献108.
Karen E. Hoffman Stephanie L. Pugh Jennifer L. James Charles Scarantino Benjamin Movsas Richard K. Valicenti Andre Fortin JonDavid Pollock Harold Kim David G. Brachman Lawrence B. Berk Deborah Watkins Bruner Lisa A. Kachnic 《Quality of life research》2014,23(6):1841-1858
Purpose
The Radiation Therapy Oncology Group (RTOG) conducted a randomized, placebo-controlled trial evaluating the efficacy of GM-CSF in reducing mucosal injury and symptom burden from curative radiotherapy for head and neck (H&N) cancer.Methods
Eligible patients with H&N cancer receiving radiation encompassing ≥50 % of the oral cavity or oropharynx received subcutaneous GM-CSF or placebo. Quality of life (QoL) was assessed using the RTOG-modified University of Washington H&N Symptom Questionnaire at baseline 4, 13, 26, and 48 weeks from radiation initiation.Results
Of 125 eligible patients, 114 were evaluable for QoL (58 GM-CSF, 56 placebo). Patient demographics, clinical characteristics, and baseline symptom scores were well balanced between the treatment arms. At the end of the acute period (13 weeks), patients in both arms reported negative change in total symptom score indicating increase in symptom burden relative to baseline (mean ?18.4 GM-CSF, ?20.8 placebo). There was no difference in change in total symptom score (p > 0.05) or change in mucous, pain, eating, or activity domain scores (p > 0.01) between patients in the GM-CSF and placebo arms. Analysis limited to patients treated per protocol or with an acceptable protocol deviation also found no difference in change in total symptom score (p > 0.05) or change in domain scores (p > 0.01) between treatment arms. Provider assessment of acute mucositis during treatment did not correlate with patient-reported mucous domain and total symptom scores (p > 0.05).Conclusion
GM-CSF administered concurrently during head and neck radiation does not appear to significantly improve patient-reported QoL symptom burden. 相似文献109.
J. S. Tregoning E. S. Brown H. M. Cheeseman K. E. Flight S. L. Higham N.-M. Lemm B. F. Pierce D. C. Stirling Z. Wang K. M. Pollock 《Clinical and experimental immunology》2020,202(2):162-192
Since the emergence of COVID-19, caused by the SARS-CoV-2 virus at the end of 2019, there has been an explosion of vaccine development. By 24 September 2020, a staggering number of vaccines (more than 200) had started preclinical development, of which 43 had entered clinical trials, including some approaches that have not previously been licensed for human vaccines. Vaccines have been widely considered as part of the exit strategy to enable the return to previous patterns of working, schooling and socializing. Importantly, to effectively control the COVID-19 pandemic, production needs to be scaled-up from a small number of preclinical doses to enough filled vials to immunize the world’s population, which requires close engagement with manufacturers and regulators. It will require a global effort to control the virus, necessitating equitable access for all countries to effective vaccines. This review explores the immune responses required to protect against SARS-CoV-2 and the potential for vaccine-induced immunopathology. We describe the profile of the different platforms and the advantages and disadvantages of each approach. The review also addresses the critical steps between promising preclinical leads and manufacturing at scale. The issues faced during this pandemic and the platforms being developed to address it will be invaluable for future outbreak control. Nine months after the outbreak began we are at a point where preclinical and early clinical data are being generated for the vaccines; an overview of this important area will help our understanding of the next phases. 相似文献
110.
Jin Ma Huiling Wu Cathy Y Zhao Usha Panchapakesan Carol Pollock Steven J Chadban 《International journal of clinical and experimental pathology》2014,7(2):481-495
Inflammation and fibrosis are essential elements of diabetic nephropathy (DN). We tested the hypothesis that these elements are dependent upon Toll-like receptor 2 (TLR2) signalling by examining WT and TLR2-/- mice in an experimental model of DN. Diabetes was induced in WT and TLR2-/- mice by i.p. injection of streptozotocin. Kidney injury was assessed at 6, 12 and 24 weeks after induction of diabetes. Gene expression of TLR2, its endogenous ligands and downstream cytokines, chemokines and fibrogenic molecules were upregulated in kidneys from WT mice with streptozotocin diabetes. TLR2-/- mice were protected against the development of DN, exhibiting less albuminuria, inflammation, glomerular hypertrophy and hypercellularity, podocyte and tubular injury as compared to diabetic WT controls. Marked reductions in interstitial collagen deposition, myofibroblast activation (α-SMA) and expression of fibrogenic genes (TGF-β and fibronectin) were also evident in TLR2 deficient mice. Consistent with our in vivo results, high glucose directly promoted TLR2 activation in podocytes and tubular epithelial cells (TECs) in vitro, resulting in NF-κB activation, inflammation and TGF-β production. We conclude that TLR2 was required for the full development of inflammation, kidney damage and fibrosis in this model of DN. As TLR2 is known to be expressed by intrinsic kidney cells and as high concentration glucose stimulated podocytes and TECs in vitro to express TLR2 and TLR2 ligands, pro-inflammatory and pro-fibrotic cytokines in a TLR2 dependent manner in the present study, it appears likely that TLR2 signalling in intrinsic kidney cells contributes to the pathogenesis of diabetic nephropathy. 相似文献