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V. Bafunno R. Santacroce M. Chetta F. Peyvandi F. Sessa E. Chinni V. Longo M. Margaglione 《Haemophilia》2012,18(6):1003-1007
Development of inhibitory antibodies is perhaps the most serious complication of FVIII replacement therapy, precluding efficient clinical management of patients with haemophilia A (HA). The development and function of immune system are also regulated by microRNAs (miRNAs). Mutations and changes in the level of expression of some miRNA genes have been associated with the onset and progression of immunological disorders. The aim of this study was to investigate new genetic polymorphisms in loci for miRNA and their targets to evaluate whether these SNPs may confer susceptibility to inhibitor development in patients with HA. Italian HA patients with and without inhibitors and healthy controls were recruited in this study. For SNP analysis, standard DNA sequencing method was used. We have studied four SNPs, i.e. rs36101366, rs34683807, rs1803603 and rs3024496 located in the 3′UTR of F8 and IL‐10 genes. These SNPs have been checked for their frequencies in patients with and without inhibitors, but no statistically significant differences were found. Then, we have searched for other genetic variants in loci for haematopoietic‐specific miRNAs, i.e. hsa‐mir‐150, hsa‐mir‐155, hsa‐mir‐146a, hsa‐mir‐142, hsa‐mir‐181a and in a specific miRNA, hsa‐mir‐1184, i.e. predicted to be located in the intron 22 of F8 gene. For all miRNAs selected, we did not identify any sequence variation in our study population. This is the first study to demonstrate that there was no association between selected SNPs in miRNAs and their targets and the susceptibility to inhibitor development in people affected by HA. 相似文献
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Significance of miRNA‐122 in chronic hepatitis C patients with serotype 1 on interferon therapy
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Yasuhiro Kamo Tatsuki Ichikawa Hisamitsu Miyaaki Shinjirou Uchida Tohei Yamaguchi Hidetaka Shibata Takuya Honda Naota Taura Hajime Isomoto Fuminao Takeshima Kazuhiko Nakao 《Hepatology research》2015,45(1):88-96
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miRNA‐548p suppresses hepatitis B virus X protein associated hepatocellular carcinoma by downregulating oncoprotein hepatitis B x‐interacting protein
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Xiu‐Mei Hu Xiao‐Hui Yan Yan‐Wei Hu Jin‐Lan Huang Shun‐Wang Cao Ting‐Yu Ren Yue‐Ting Tang Li Lin Lei Zheng Qian Wang 《Hepatology research》2016,46(8):804-815
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Hiroaki NEJISHIMA Noriko YAMAMOTO Mika SUZUKI Kazuyuki FURUYA Mitsuo MIMURA Shizuo YAMADA 《Lower urinary tract symptoms.》2013,5(1):44-51
Objectives: The current study was undertaken to explore novel anti‐androgens. We investigated a series of tetrahydroquinoline compounds and identified 1‐(8‐nitro‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta[c]quinolin‐4‐yl)ethane‐1,2‐diol (S‐40542). Methods: Affinity for androgen receptor of S‐40542 was evaluated in receptor binding assay. Effects of repeated treatment with S‐40542 and bicalutamide on prostate weight were examined in mice subcutaneously treated for 14days. Efficacy of S‐40542 and bicalutamide against prostate cancer was evaluated in an androgen‐dependent prostate cancer xenograft model using KUCaP‐2 cell line. Plasma concentrations of these agents in mice after oral and subcutaneous administration were measured by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) system. Results: S‐40542 displayed twofold higher affinity to androgen receptor than bicalutamide in vitro. Subcutaneous repeated administration of S‐40542 (10–100 mg/kg) significantly reduced the prostate weight. Oral repeated treatment with S‐40542 (30, 100 mg/kg) for 28 days significantly suppressed growth of KUCaP‐2 tumor. Similar administration of bicalutamide also exerted significantly anti‐tumor effect in the model. The serum prostate‐specific antigen level was little influenced by the S‐40542 treatment, while significantly decreased by bicalutamide. Oral treatment with S‐40542 resulted in a dose‐dependent elevation of the plasma concentration, and its Cmax and AUC were much lower than those of bicalutamide. The pharmacokinetic study showed that this agent had relatively short plasma half‐life and low oral bioavailability. Conclusion: S‐40542 as well as bicalutamide has shown as an anti‐androgen by reducing the prostate weight of mice. Repeated oral treatment with S‐40542 was shown to significantly suppress tumor growth in the KUCaP‐2 xenograft model. 相似文献
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P. P. Tak R. M. Thurlings C. Rossier I. Nestorov A. Dimic V. Mircetic M. Rischmueller E. Nasonov E. Shmidt P. Emery A. Munafo 《Arthritis \u0026amp; Rheumatology》2008,58(1):61-72
Objective
Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation‐inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes.Methods
In this multicenter, phase Ib, randomized, placebo‐controlled, dose‐escalating trial, 73 patients were enrolled into 6 escalating‐dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2‐week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose.Results
Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment‐related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti–citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose‐related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3‐month treatment. Little effect on the erythrocyte sedimentation rate or C‐reactive protein levels was seen.Conclusion
Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.13.
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Face,content, and construct validation of a low‐cost,non‐biologic,sinus surgery task trainer and knowledge‐based curriculum
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Richard A. Harbison MD Kaalan E. Johnson MD Craig Miller MD Maya G. Sardesai MD MEd Greg E. Davis MD MPH 《International forum of allergy & rhinology》2017,7(4):405-413
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Janet Pope Donna McBain Lisa Petrlich Sharon Watson Louise Vanderhoek Faye de Leon Shannon Seney Kelly Summers 《Arthritis \u0026amp; Rheumatology》2011,63(11):3547-3551
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To better understand the feasibility of using imatinib, a tyrosine kinase inhibitor, to treat active diffuse cutaneous systemic sclerosis (dcSSc).Methods
We performed a 6‐month, randomized, double‐blind, placebo‐controlled, proof‐of‐concept pilot study of imatinib in patients with active dcSSc. Data on safety, modified Rodnan skin thickness scores (MRSS), Health Assessment Questionnaire (HAQ) scores, patient's and physician's global assessments (100‐mm visual analog scale), and biomarkers in serum and skin biopsy samples were collected. We used a 4:1 randomization strategy (imatinib 200 mg administered twice a day versus placebo), stratifying according to current use of methotrexate. The plan was to enroll 20 dcSSc patients.Results
After enrolling 10 patients (9 receiving active drug and 1 receiving placebo), we found poor tolerability and high rates of adverse events with imatinib, and study enrollment was discontinued. There was no significant difference in the mean MRSS in all patients who took imatinib (31.1 at baseline versus 29.4 at 6 months) or in only those who completed 6 months of imatinib (31.0 at baseline versus 30.3 at 6 months), and there was no difference in the C‐reactive protein level, erythrocyte sedimentation rate, physician's global assessment, patient's global assessment, response to the Health Transition query, or the HAQ scores between those who did and those who did not complete 6 months of therapy. Side effects were edema, fluid retention, fatigue, nausea, cramps/myalgias, diarrhea, alopecia, and anemia. Most side effects occurred within the first week of treatment, and even when imatinib was reintroduced at a lower dosage (200 mg daily), it was poorly tolerated. Two patients were hospitalized because of side effects of the medication. In general, biomarker levels in plasma and skin did not change.Conclusion
Imatinib was poorly tolerated, and this could limit its application in SSc. The study was too small to form conclusions about the efficacy of imatinib in SSc.16.
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P. Barrington J. Y. Chien F. Tibaldi H. D. H. Showalter K. Schneck B. Ellis 《Diabetes, obesity & metabolism》2011,13(5):434-438
Aim: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics and potential immunogenicity of single, escalating subcutaneous injections of a once‐weekly glucagon‐like peptide‐1 analogue in healthy subjects. Methods: This phase 1, three‐period, crossover, double‐blind, placebo‐controlled study investigated single, escalating subcutaneous doses of LY2189265 (LY) ranging from 0.1 to 12 mg; approximately six subjects were randomized to each dose. Parameters of safety, including adverse events, were assessed. The pharmacokinetic profile was assessed over 14 days. Pharmacodynamic parameters (glucose and insulin concentrations) were measured following a step‐glucose infusion (day 3) and as part of an oral glucose tolerance test (OGTT) (day 5). Results: LY was generally well tolerated with some increase in gastrointestinal symptoms with escalating doses. There were small dose‐dependent increases in pulse rate with doses ≥1.0 mg and diastolic blood pressure with doses ≥3.0 mg. The half‐life of LY was approximately 90 h, with Cmax occurring between 24 and 48 h in most subjects. Evidence of increase in glucose‐dependent insulin secretion and suppression of serum glucose excursions were observed during an OGTT at all doses compared to placebo; no episodes of hypoglycaemia occurred. No subjects developed antibodies to LY2189265. Conclusions: LY showed an acceptable safety profile and exhibited the expected glucagon‐like peptide‐1 pharmacological effects on glucose suppression and insulin secretion with a half‐life that supports once‐weekly dosing. 相似文献