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81.
82.
Phase I trial of the selective mitochondrial toxin MKT 077 in chemo-resistant solid tumours 总被引:1,自引:0,他引:1
D. J. Propper J. P. Braybrooke D. J. Taylor R. Lodi P. Styles J. A. Cramer W. C. J. Collins N. C. Levitt D. C. Talbot T. S. Ganesan A. L. Harris 《Annals of oncology》1999,10(8):923-927
Background: MKT 077 is a rhodacyanine dye analogue which preferentially accumulates in tumour cell mitochondria. It is cytotoxic to a range of tumours. In this phase I study, MKT 077 was administered as a five-day infusion once every three weeks.Patients and methods: Ten patients, median age 59 (38–70) years, with advanced solid cancers were treated at three dose levels: 30, 40 and 50 mg/m2/day for a total of 18 cycles.31 Phosphorus magnetic resonance spectroscopy (MRS) was used to evaluate the effect of MKT 077 on skeletal muscle mitochondrial function.Results: The predominant toxicity was recurrent reversible functional renal impairment (grade 2, two patients). One patient with renal cancer attained stable disease and the remainder progressive disease. There were no MRS changes in the first or second treatment cycles but one patient received 11 treatment cycles and developed changes consistent with a mitochondrial myopathy. Mean values for all pharmacokinetic parameters were at sub micromolar levels and did not exceed IC50 values (1 µM).Conclusions: Because of the renal toxicity, and animal studies showing MKT 077 causes eventual irreversible renal toxicity, further recruitment was halted. The study shows, however, that it is feasible to target mitochondria with rhodacyanine analogues, if drugs with higher therapeutic indices could be developed. 相似文献
83.
D J Propper M P Saunders A J Salisbury L Long K J O'Byrne J P Braybrooke M Dowsett M Taylor D C Talbot T S Ganesan A L Harris 《Clinical cancer research》1999,5(7):1682-1689
The cyclic AMP (cAMP)-dependent protein kinase regulatory subunit RI is overexpressed in cancer cells. 8-Chloro-cAMP (8-Cl-cAMP) is an RII site-specific analogue that down-regulates RI and inhibits the growth of a wide range of cancer cells in vitro and in vivo. We performed a Phase I trial of 8-Cl-cAMP in 32 patients with malignancies that were refractory to standard treatments. 8-Cl-cAMP was initially given in a 1-month cycle by constant infusion at 0.005 mg/kg/h for 21 days, followed by 1 week of rest. The dose was escalated to 0.045 mg/kg/h, but hypercalcemia became the dose-limiting toxicity. The length of drug administration was, therefore, reduced to 5 days per week for the first 3 weeks of the cycle, but it was not possible to increase the drug dose without producing hypercalcemia. Hence, the length of drug administration was reduced to 3 days per week for the first 3 weeks of the cycle. The maximum tolerated dose for this regimen was 0.15 mg/kg/h, and the dose-limiting toxicities were reversible hypercalcemia and hepatotoxicity. Stable disease for > or =4 months was observed in two patients treated at > or =0.045 mg/kg. cAMP-dependent protein kinase is involved in hormone- and cytokine-mediated signaling, and so representative hormone, cytokine, and peripheral lymphocyte subsets were measured. The drug had a parathyroid hormone-like effect on calcium homeostasis and significantly increased circulating luteinizing hormone and 17-hydoxyprogesterone levels (P < 0.02 and P < 0.0006, respectively). We conclude that 8-Cl-cAMP is well tolerated without attendant myelotoxicity, and in this study, it was associated with biological effects. In Phase II studies, a dose of 0.11 mg/kg/h for 3 days per week would be appropriate. 相似文献
84.
Oliver Lindner Thomas N. B. Pascual Mathew Mercuri Wanda Acampa Wolfgang Burchert Albert Flotats Philipp A. Kaufmann Anastasia Kitsiou Juhani Knuuti S. Richard Underwood João V. Vitola John J. Mahmarian Ganesan Karthikeyan Nathan Better Madan M. Rehani Ravi Kashyap Maurizio Dondi Diana Paez Andrew J. Einstein for the INCAPS Investigators Group 《European journal of nuclear medicine and molecular imaging》2016,43(4):718-728
Purpose
Nuclear cardiology is widely used to diagnose coronary artery disease and to guide patient management, but data on current practices, radiation dose-related best practices, and radiation doses are scarce. To address these issues, the IAEA conducted a worldwide study of nuclear cardiology practice. We present the European subanalysis.Methods
In March 2013, the IAEA invited laboratories across the world to document all SPECT and PET studies performed in one week. The data included age, gender, weight, radiopharmaceuticals, injected activities, camera type, positioning, hardware and software. Radiation effective dose was calculated for each patient. A quality score was defined for each laboratory as the number followed of eight predefined best practices with a bearing on radiation exposure (range of quality score 0 – 8). The participating European countries were assigned to regions (North, East, South, and West). Comparisons were performed between the four European regions and between Europe and the rest-of-the-world (RoW).Results
Data on 2,381 European patients undergoing nuclear cardiology procedures in 102 laboratories in 27 countries were collected. A cardiac SPECT study was performed in 97.9 % of the patients, and a PET study in 2.1 %. The average effective dose of SPECT was 8.0?±?3.4 mSv (RoW 11.4?±?4.3 mSv; P?<?0.001) and of PET was 2.6?±?1.5 mSv (RoW 3.8?±?2.5 mSv; P?<?0.001). The mean effective doses of SPECT and PET differed between European regions (P?<?0.001 and P?=?0.002, respectively). The mean quality score was 6.2?±?1.2, which was higher than the RoW score (5.0?±?1.1; P?<?0.001). Adherence to best practices did not differ significantly among the European regions (range 6 to 6.4; P?=?0.73). Of the best practices, stress-only imaging and weight-adjusted dosing were the least commonly used.Conclusion
In Europe, the mean effective dose from nuclear cardiology is lower and the average quality score is higher than in the RoW. There is regional variation in effective dose in relation to the best practice quality score. A possible reason for the differences between Europe and the RoW could be the safety culture fostered by actions under the Euratom directives and the implementation of diagnostic reference levels. Stress-only imaging and weight-adjusted activity might be targets for optimization of European nuclear cardiology practice.85.
Umut Disel Russell Madison Kumar Abhishek Jon H. Chung Sally E. Trabucco Asli O. Matos Garrett M. Frampton Lee A. Albacker Venkataprasanth Reddy Nuri Karadurmus Adam Benson Jennifer Webster Semra Paydas Ruben Cabanillas Chaitali Nangia M.A. Ozturk Sherri Z. Millis Sumanta K. Pal Breelyn Wilky Ethan S. Sokol Laurie M. Gay Salil Soman Shridar Ganesan Katherine Janeway Phil J. Stephens Viola W. Zhu Sai-Hong Ignatius Ou Christine M. Lovly Mrinal Gounder Alexa B. Schrock Jeffrey S. Ross Vincent A. Miller Samuel J. Klempner Siraj M. Ali 《The oncologist》2020,25(1):e39-e47
86.
87.
Marc Hens Ganesan Vaidyanathan Phil Welsh Michael R. Zalutsky 《Nuclear medicine and biology》2009,36(2):117-128
IntroductionThe monoclonal antibody (mAb) L8A4, reactive with the epidermal growth factor receptor variant III (EGFRvIII), internalizes rapidly in glioma cells after receptor binding. Combining this tumor-specific mAb with the low-energy β-emitter 177Lu would be an attractive approach for brain tumor radioimmunotherapy, provided that trapping of the radionuclide in tumor cells after mAb intracellular processing could be maximized.Materials and MethodsL8A4 mAb was labeled with 177Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A″-DTPA), 2-(4-isothiocyanatobenzyl)-diethylenetriaminepenta-acetic acid (pSCN-Bz-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (MeO-DOTA). Paired-label internalization and cellular processing assays were performed on EGFRvIII-expressing U87.ΔEGFR glioma cells over 24 h to directly compare 177Lu-labeled L8A4 to L8A4 labeled with 125I using either iodogen or N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB). In order to facilitate comparison of labeling methods, the primary parameter evaluated was the ratio of 177Lu to 125I activity retained in U87.ΔEGFR cells.ResultsAll chelates demonstrated higher retention of internalized activity compared with mAb labeled using iodogen, with 177Lu/125I ratios of >20 observed for the three DTPA chelates at 24 h. When compared to L8A4 labeled using SGMIB, except for MeO-DOTA, internalized activity for 125I was higher than 177Lu from 1-8 h with the opposite behavior observed thereafter. At 24 h, 177Lu/125I ratios were between 1.5 and 3, with higher values observed for the three DTPA chelates.ConclusionsThe nature of the chelate used to label this internalizing mAb with 177Lu influenced intracellular retention in vitro, although at early time points, only MeO-DOTA provided more favorable results than radioiodination of the mAb via SGMIB. 相似文献
88.
Myopia is the result of a mismatch between the optical power and the length of the eye, with the latter being too long. Driving the research in this field is the need to develop myopia treatments that can limit axial elongation. When axial elongation is excessive, as in high myopia, there is an increased risk of visual impairment and blindness due to ensuing pathologies such as retinal detachments. This article covers both clinical studies involving myopic children, and studies involving animal models for myopia. Atropine, a nonselective muscarinic antagonist, has been studied most extensively in both contexts. Because it remains the only drug used in a clinical setting, it is a major focus of the first part of this article, which also covers the many shortcomings of topical ophthalmic atropine. The second part of this article focuses on in vitro and animal-based drug studies, which encompass a range of drug targets including the retina, retinal pigment epithelium and sclera. While the latter studies have contributed to a better understanding of how eye growth is regulated, no new antimyopia drug treatments have reached the clinical setting. Less conservative approaches in research, and in particular, the exploration of new bioengineering approaches for drug delivery, are needed to advance this field. 相似文献
89.
Ihid C. Leao Priya Ganesan Todd D. Armstrong Elizabeth M. Jaffee 《CTS Clinical and Translational Science》2008,1(3):228-239
Vaccine‐induced CD8+ T‐cell responses can eradicate developing tumors in vivo in mouse models. Translating these successes into approved treatments for cancer patients has been challenging, since many of these models lack expression of clinically proven/relevant tumor antigens. We have shown that mesothelin is a clinically relevant CD8+ T‐cell target in human pancreas cancer, which is also highly conserved among species. Here, we utilize the murine mesothelin‐expressing pancreatic tumor model (Panc02) to identify the immune‐relevant mesothelin‐derived peptides and study interventions that enhance the antitumor response. We first screened overlapping peptides of the entire murine mesothelin protein to identify two new CD8+ mesothelin‐restricted epitopes. These peptides were then evaluated for recognition by vaccine‐induced T cells from mice treated with vaccine in sequence with low‐dose cyclophosphamide (CY) and an anti‐CD25 IL‐2Rα monoclonal antibody (PC61). These treatments are both known to deplete subpopulations of T regulatory cells (Tregs). Our findings demonstrate that combined Treg‐depleting therapies synergize to enhance vaccine efficacy. Furthermore, our data supports mesothelin as a relevant antigen in murine and clinical models and the use of Panc02 as a clinically relevant murine model of pancreatic cancer for evaluating antigen‐targeted immunotherapies in immune‐tolerant hosts. 相似文献
90.
Ganesan Venkatasubramanian Peruvumba N. Jayakumar Bangalore. N. Gangadhar Matcheri S. Keshavan 《Psychiatry Research: Neuroimaging》2008,164(3):215-222
Recent imaging studies suggest that the so-called “soft” neurological signs in schizophrenia might have neuroanatomical validity. We examined gray matter volume correlates of neurological soft signs (NSS) in antipsychotic-naive schizophrenia patients using an automated image analysis technique. NSS were assessed using a modified neurological evaluation scale with good inter-rater reliability. Magnetic resonance images of 30 schizophrenia patients and 27 age-, sex-, education- and handedness-matched healthy controls were processed using optimized voxel-based morphometry (VBM). Logistic regression analysis showed that only the Motor Sequencing Signs (MSS) sub-score was a significant predictor of subject's status among the NSS sub-scores. Optimized VBM analysis showed that the MSS sub-score had a significant negative correlation with total and regional gray matter volumes (prefrontal, posterior cingulate, temporal cortices, putamen, and cerebellum) in schizophrenia patients but not in controls. Prefrontal and temporal cortices, putamen and cerebellum had significant volume deficits in patients. Cortical and cerebellar correlates of the sub-score MSS support the concept of “cognitive dysmetria” in schizophrenia. 相似文献