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1.
Sumei Ren Paul McNamara Pernilla Royster Jae Lee Surinderjit S. Saluja David Koharski Sharon Hendershot Van Truong 《Journal of labelled compounds & radiopharmaceuticals》2007,50(7):643-648
1‐Benzyl‐4‐hydroxy[2‐14C]piperidine, a useful intermediate in labeled compound synthesis, was prepared from [14C]formaldehyde in high yield. The distribution pattern of 14C in the product is consistent with a mechanism involving reversible iminium ion formation and rapid equilibration of the iminium ion through a cationic aza‐Cope rearrangement. These steps precede the rate‐determining intramolecular cyclization step. SCH 351125 is a potent, selective CCR5 receptor antagonist with potential as a treatment for HIV infection. [14C]SCH 351125, required for metabolism studies, was prepared from 1‐benzyl‐4‐hydroxy[2‐14C]piperidine in six steps. [14C]SCH 351125 is a mixture of four atropisomers. Preparation of [14C]SCH 351125 besylate salt of the desired atropisomer pair is also described. Copyright © 2007 John Wiley & Sons, Ltd. 相似文献
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Red-cell adenosine deaminase (ADA) activity in children with Diamond-Blackfan anaemia is significantly increased (1.91 +/- 0.90 U/g Hb) compared to that seen in transient erythroblastopenia of childhood (0.80 +/- 0.16 U/g Hb) or normal individuals (0.61 +/- 0.13 U/g). These data thus further support that measurement of this purine metabolic enzyme is useful in diagnosing the cause of pure RBC aplasia in children. Of interest, however, elevated RBC-ADA activity also is seen in some children with acute leukaemia and other haematologic disorders. In children with acute lymphoblastic leukaemia (ALL), the increase in RBC-ADA activity is proportional to the degree of anaemia. However, the elevated RBC-ADA activity in this leukaemic population is not related to the fetal haemoglobin concentration. These data suggest increased RBC-ADA activity may be a non-specific manifestation of abnormal erythroid stem cell function, an alteration distinct from that seen with reactivation of fetal erythropoiesis. However, since almost all patients with Diamond-Blackfan anaemia manifest elevated RBC-ADA activity, this chemical alteration yet may reflect the specific erythroid differentiation lesion in this disorder. 相似文献
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Salnikov AV Roswall P Sundberg C Gardner H Heldin NE Rubin K 《Laboratory investigation; a journal of technical methods and pathology》2005,85(4):512-521
A pathologically elevated interstitial fluid pressure (IFP) is a characteristic of both clinical and experimental carcinoma. The soluble TGF-beta receptor type II-murine Fc:IgG2A chimeric protein (Fc:TbetaRII) lowers IFP in the KAT-4 experimental model for anaplastic thyroid carcinoma. Analyses of messenger RNA (mRNA) expressions by Affymetrix microarrays and RNase protection assays, as well as of protein expressions identified tumor macrophages as targets for Fc:TbetaRII. Treatment with Fc:TbetaRII reduced albumin extravasation, increased coverage of alpha-smooth muscle actin-positive cells and reduced expression of NG2, a marker of activated pericytes, in KAT-4 carcinoma blood vessels. Specific inhibition of interleukin-1 (IL-1), a major cytokine produced by activated macrophages, lowered carcinoma IFP to a similar degree as Fc:TbetaRII but had no significant effect on the parameters of blood vessel maturation. Neither Fc:TbetaRII nor inhibition of IL-1 changed blood vessel density. Finally, pretreatment of KAT-4 carcinomas with Fc:TbetaRII increased the antitumor efficacy of doxorubicin. Our data emphasize a potential role of tumor macrophages in carcinoma physiology and identify these cells as potential stromal targets for treatment aimed to improve efficacy of chemotherapy. 相似文献
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Pelin Sahlén Rapolas Spalinskas Samina Asad Kunal Das Mahapatra Pontus Höjer Anandashankar Anil Jesper Eisfeldt Ankit Srivastava Pernilla Nikamo Anaya Mukherjee Kyu-Han Kim Otto Bergman Mona Ståhle Enikö Sonkoly Andor Pivarcsi Carl-Fredrik Wahlgren Magnus Nordenskjöld Fulya Taylan Isabel Tapia-Páez 《The Journal of allergy and clinical immunology》2021,147(5):1742-1752
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Peter Gennemark Rasmus Jansson-Löfmark Gina Hyberg Maria Wigstrand Dorota Kakol-Palm Pernilla Håkansson Daniel Hovdal Peter Brodin Maria Fritsch-Fredin Madeleine Antonsson Karolina Ploj Johan Gabrielsson 《Journal of pharmacokinetics and pharmacodynamics》2013,40(6):651-667
Body composition and body mass are pivotal clinical endpoints in studies of welfare diseases. We present a combined effort of established and new mathematical models based on rigorous monitoring of energy intake (EI) and body mass in mice. Specifically, we parameterize a mechanistic turnover model based on the law of energy conservation coupled to a drug mechanism model. Key model variables are fat-free mass (FFM) and fat mass (FM), governed by EI and energy expenditure (EE). An empirical Forbes curve relating FFM to FM was derived experimentally for female C57BL/6 mice. The Forbes curve differs from a previously reported curve for male C57BL/6 mice, and we thoroughly analyse how the choice of Forbes curve impacts model predictions. The drug mechanism function acts on EI or EE, or both. Drug mechanism parameters (two to three parameters) and system parameters (up to six free parameters) could be estimated with good precision (coefficients of variation typically <20 % and not greater than 40 % in our analyses). Model simulations were done to predict the EE and FM change at different drug provocations in mice. In addition, we simulated body mass and FM changes at different drug provocations using a similar model for man. Surprisingly, model simulations indicate that an increase in EI (e.g. 10 %) was more efficient than an equal lowering of EI. Also, the relative change in body mass and FM is greater in man than in mouse at the same relative change in either EI or EE. We acknowledge that this assumes the same drug mechanism impact across the two species. A set of recommendations regarding the Forbes curve, vehicle control groups, dual action on EI and loss, and translational aspects are discussed. This quantitative approach significantly improves data interpretation, disease system understanding, safety assessment and translation across species. 相似文献
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Paola Bianchi Elisa Fermo Kimberly Lezon-Geyda Eduard J. van Beers Holmes D. Morton Wilma Barcellini Bertil Glader Satheesh Chonat Yaddanapudi Ravindranath Peter E. Newburger Nina Kollmar Jenny M. Despotovic Madeleine Verhovsek Mukta Sharma Janet L. Kwiatkowski Kevin H. M. Kuo Marcin W. Wlodarski Hassan M. Yaish Susanne Holzhauer Heng Wang Joachim Kunz Kathryn Addonizio Hasan Al-Sayegh Wendy B. London Oliver Andres Richard van Wijk Patrick G. Gallagher Rachael F. F. Grace 《American journal of hematology》2020,95(5):472-482
Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency. 相似文献