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A 300 mg controlled-release theophylline formulation was developed as a tablet prepared by wet granulation using the acrylic resins Eudragit S 100R and Eudragit RSPMR. The tablet was compared with a marketed controlled-release capsule using in vivo and in vitro tests. The in vitro dissolution of theophylline from the tablets followed an apparent zero order kinetics. The in vivo comparison was performed in a cross over fashion in four healthy volunteers who received one tablet or capsule every 12 hours during seven days. The results showed no statistically significant differences in AUC, tmax and in plasma theophylline concentrations at the different times. Nevertheless, concentrations were lower after the administration of the tablets than when the volunteers received the capsules. On the other hand, the apparent elimination half lives obtained after the tablets were longer than with the capsules. An excessive retardation in the release of theophylline from the tablet could be responsible for this fact. 相似文献
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The aim of this study was to compare the survival of 116 patients with breast cancer initially treated at the First Teaching Hospital (FTH) of Norman Bethune University of Medical Sciences located in Changchun, China, from 1986 to 1991 with the survival of 886 patients seen in the “Hipital du Saint-Sacrement” (HSS) located in Quebec City, Canada, from 1987 to 1992. The clinical data were collected from the hospital records at FTH. The vital status for Chinese patients was obtained from letters of follow-up or the records of local police offices. The list of patients treated at HSS and the data for each woman were extracted from computerized data banks. The major variables studied included age at diagnosis, tumor size at pathology (cm), number of lymph nodes involved, breast surgery and adjuvant treatments of breast cancer (chemotherapy, radiotherapy, immuno-therapy). Age at diagnosis was substantially lower among patients with breast cancer seen at FTH compared to those treated at HSS (x) 1 2 =60.95,P<0.0001). The average age at diagnosis for Chinese women was about 10 years less than that for Canadian women. Patients in the two hospitals differed with respect to tumor size at pathology (x 2 2 =6.67,P=0.036). The proportion of patients with tumor size larger than 2.0 cm was larger at FTH (48.3%) than at HSS (41.1%). The mean tumor size at pathology was 3.0 cm (standard deviation =2.1 cm) for patients treated at FTH, but 2.6 cm (standard deviation=1.8 cm) for women treated at HSS (P=0.07). The proportion of women with lymph node involvement was greater at FTH (61.1 % than that at HSS (37.3%) (x 1 2 =16.51,P<0.0001). Surgical treatment of breast cancer varied considerably. In Changchun, radical mastectomy was frequent for any stage of breast cancer patients, but partial mastectomy was never performed. The situation was reversed in Quebec. The five year observed survival was 74.2% (standard error, 0.05) among breast cancer patients seen at FTH compared to 76.0% (standard error, 0.02) among women treated at HSS. After adjustments of confounding factors, there were no significant difference in five year observed survival between the patients treated at the two hospitals (P=0.42). 相似文献
4.
Modulation of the immunological response of guinea pig mast cells by carbon monoxide. 总被引:2,自引:0,他引:2
J F Ndisang P Gai L Berni C Mirabella R Baronti P F Mannaioni E Masini 《Immunopharmacology》1999,43(1):65-73
Challenge of guinea pig mast cells with antigen under aerobic conditions induced the expected release of histamine and led to a significant increase in intracellular calcium ([Ca2+]i) and cyclic adenosine monophosphate (cAMP) levels. Prior exposure to CO decreased the immunological histamine release. This effect was accompanied by a decrease in the levels of [Ca2+]i and by an increase in the cyclic guanosine monophosphate (cGMP) levels. The exposure of mast cells to nitrogen (N2) did not modify the release of histamine. The CO-mediated inhibition of the immunological release of histamine was reversed by the soluble guanylate cyclase inhibitor (1 H-[1.2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) and by oxyhaemoglobin (HbO2). Incubation of mast cells for 4 h with hemin, a heme oxygenase (HO) inducer, resulted in an increase in HO activity, measured as bilirubin production. Hemin abated the immunological release of histamine, in similar fashion to exogenous CO, and increased the cGMP levels. These effects were reversed by ODQ and HbO2. It is proposed that CO from an exogenous or endogenous source stimulates guanylyl cyclase and causes cGMP formation which then induces calcium to be sequestrated so that the [Ca2+]i concentration falls and histamine release is inhibited. 相似文献
5.
目的;探讨血管损伤修复中Ⅲ型胶原的分泌规律及其与血管平滑肌细胞(VSMC)增生的关系,方法:26只犬冠状动脉植入过大钽丝支架建立再狭窄模型,分别于术后7天,14天和28天处死动物,用透射电镜及免疫组化染色观察新生内膜中Ⅲ型胶原分泌和VSMC特征,并用图像处理技术对Ⅲ型胶原的染色密度作定量分析,结果:支架植入后7天以VSMC移行增生为主,14天时VSMC增生达高峰并有较多胶原分泌,28天时VSMC由 相似文献
6.
新型药物开发制备过程中,需要对药物颗粒进行粒子设计,通过多层微胶囊化而得到复合包覆药物颗粒。药物包覆、微胶囊制备方法很多,可分为化学法、物理化学法、物理法。本文着重介绍了制备复合多层包覆药物颗粒的几种物理机械方法:复合杂化系统,高速椭圆转子混合法、喷流床包覆法。简要分析了该技术用于中药现代化加工的可能性。 相似文献
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Qing Zhou Guannan Kang Peiyong Jiang Rong Qiao W. K. Jacky Lam Stephanie C. Y. Yu Mary-Jane L. Ma Lu Ji Suk Hang Cheng Wanxia Gai Wenlei Peng Huimin Shang Rebecca W. Y. Chan Stephen L. Chan Grace L. H. Wong Linda T. Hiraki Stefano Volpi Vincent W. S. Wong John Wong Rossa W. K. Chiu K. C. Allen Chan Y. M. Dennis Lo 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(44)
Cell-free DNA (cfDNA) fragmentation patterns contain important molecular information linked to tissues of origin. We explored the possibility of using fragmentation patterns to predict cytosine-phosphate-guanine (CpG) methylation of cfDNA, obviating the use of bisulfite treatment and associated risks of DNA degradation. This study investigated the cfDNA cleavage profile surrounding a CpG (i.e., within an 11-nucleotide [nt] window) to analyze cfDNA methylation. The cfDNA cleavage proportion across positions within the window appeared nonrandom and exhibited correlation with methylation status. The mean cleavage proportion was ∼twofold higher at the cytosine of methylated CpGs than unmethylated ones in healthy controls. In contrast, the mean cleavage proportion rapidly decreased at the 1-nt position immediately preceding methylated CpGs. Such differential cleavages resulted in a characteristic change in relative presentations of CGN and NCG motifs at 5′ ends, where N represented any nucleotide. CGN/NCG motif ratios were correlated with methylation levels at tissue-specific methylated CpGs (e.g., placenta or liver) (Pearson’s absolute r > 0.86). cfDNA cleavage profiles were thus informative for cfDNA methylation and tissue-of-origin analyses. Using CG-containing end motifs, we achieved an area under a receiver operating characteristic curve (AUC) of 0.98 in differentiating patients with and without hepatocellular carcinoma and enhanced the positive predictive value of nasopharyngeal carcinoma screening (from 19.6 to 26.8%). Furthermore, we elucidated the feasibility of using cfDNA cleavage patterns to deduce CpG methylation at single CpG resolution using a deep learning algorithm and achieved an AUC of 0.93. FRAGmentomics-based Methylation Analysis (FRAGMA) presents many possibilities for noninvasive prenatal, cancer, and organ transplantation assessment.Fragmentation patterns of cell-free DNA (cfDNA) molecules contain a wealth of molecular information related to their tissues of origin (1). For instance, compared with the background DNA molecules that are mainly derived from the hematopoietic system (2, 3), size shortening of fetal and tumoral DNA molecules occurs in the plasma DNA of pregnant women and cancer patients, respectively (4–6). In addition, a series of 10-bp periodicities were present in fetal and tumoral DNA molecules below 146 bp, with a relative reduction in the major peak at 166 bp (1). Such characteristic size profiles suggest that the fragmentation of cfDNA may be associated with nucleosome structures (5, 7). Many important characteristics pertaining to cfDNA fragmentation have been unveiled recently, such as nucleosome footprints (8, 9), fragment end motifs (10), preferred ends (7, 11), and jagged ends (12), which are examples of fragmentomic markers (1).cfDNA fragmentomics is an emergent and actively pursued area, with wide-ranging biological and clinical implications. It has been reported that the use of fragmentation patterns of cfDNA could inform the expression status of genes (13, 14). Using mouse models, DNA nucleases (e.g., DNASE1L3) were found to play important roles in the generation of plasma DNA molecules (15, 16). Fragmentomic features, such as cfDNA end motifs and jagged ends, were further demonstrated to be useful for monitoring DNA nuclease activities, providing biomarkers for autoimmune diseases (e.g., systemic lupus erythematosus) (17, 18). In addition, the deficiencies of nuclease activities in a mouse model resulted in altered DNA methylation profiles of plasma DNA molecules (19). However, how cfDNA fragmentation patterns interplay with DNA methylation in human individuals under different pathophysiological conditions, such as pregnancy and oncogenesis, and in healthy patients without nuclease deficiency, is unknown. It is also not known whether fragmentomic features can be used to deduce cfDNA methylation status.A widely employed way to assess DNA methylation is through bisulfite sequencing (20). A key limitation of this approach is the severe degradation of DNA molecules caused by the bisulfite treatment (21), which greatly increases the sampling variation when analyzing rare target molecules (e.g., tumoral cfDNA at early stages of cancer). Many efforts have been made toward overcoming this issue. For example, Vaisvila et al. developed enzymatic methyl sequencing for which DNA molecules were treated using tet methylcytosine dioxygenase 2 and T4 phage β-glucosyltransferase, followed by the apolipoprotein B mRNA editing enzyme catalytic subunit 3A (APOBEC3A) treatment. Cytosine conversion based on enzymatic processes was reported to be much less destructive (22). Recently, researchers developed approaches making use of third-generation sequencing technologies such as single-molecule real-time sequencing (Pacific Biosciences) (23) and nanopore sequencing (24) to analyze cytosine-phosphate-guanine (CpG) methylation patterns in native DNA molecules, theoretically overcoming the above-mentioned limitation. However, compared with second-generation sequencing (also called next-generation sequencing [NGS]) technologies, the throughput of third-generation sequencing technologies is generally lower and the sequencing cost per nucleotide (nt) is much higher, thus restricting its immediate application in clinical settings. Here, we explore the feasibility of enabling the assessment of DNA methylation using fragmentomic characteristics of cfDNA molecules deduced from NGS results without the use of bisulfite or enzymatic treatment. If successful, such an approach could leverage the high throughput of NGS while obviating the use of chemical/enzymatic conversion and could potentially be readily integrated into currently used NGS-based platforms for cfDNA analysis.In this study, we utilize the fragmentation patterns proximal to a CpG site for deducing its methylation status. The fragmentation pattern is depicted by the frequency of cfDNA fragment ends at each position within a certain nt range relative to a CpG of interest, termed a cleavage profile (Fig. 1). Such a cleavage profile varies according to the methylation status of the CpG site of interest, providing the basis for methylation analysis by using fragmentomic features. We further correlated two types of end motifs (CGN and NCG; N represents any nucleotide of A, C, G, or T) resulting from differential cutting in the measurement window related to DNA methylation, attempting to construct a simplified approach for methylation analysis. Modeling CpG methylation using cfDNA fragmentation may facilitate noninvasive prenatal testing, cancer detection, and tissue-of-origin analysis (Fig. 1). Furthermore, we explore the feasibility of using deep learning to deduce the methylation status at single CpG resolution through the cleavage profile (Fig. 1). We refer to this FRAGmentomics-based Methylation Analysis as FRAGMA in this study.Open in a separate windowFig. 1.Schematic for FRAGMA of cfDNA molecules. cfDNA molecules were sequenced by massively parallel sequencing and aligned to the human reference genome. The cleavage proportion within an 11-nt window (the cleavage measurement window) was used to measure the cutting preference of cfDNA molecules. The patterns of cleavage proportion within a window (the cleavage profile) depended on the methylation status of one or more CpG sites associated with that window. For example, a methylated CpG site might confer a higher probability of cfDNA cutting at the cytosine in the CpG context, but an unmethylated site might not. Such methylation-dependent differential fragmentation within a cleavage measurement window resulted in the change in CGN/NCG motif ratio. Thus, the CGN/NCG motif ratio provided a simplified version for reflecting CpG methylation, allowing cfDNA tissue-of-origin analysis of cfDNA and cancer detection. Furthermore, the great number of cleavage profiles derived from cfDNA molecules might provide an opportunity to train a deep learning model for methylation prediction at the single CpG resolution. 相似文献
9.
Dongzheng Gai Jin-Ran Chen James P. Stewart Intawat Nookaew Hasem Habelhah Cody Ashby Fumou Sun Yan Cheng Can Li Hongwei Xu Bailu Peng Tarun K. Garg Carolina Schinke Sharmilan Thanendrarajan Maurizio Zangari Fangping Chen Bart Barlogie Frits van Rhee Guido Tricot John D. Shaughnessy Jr. Fenghuang Zhan 《The Journal of clinical investigation》2022,132(18)
Osteolytic bone disease is a hallmark of multiple myeloma (MM). A significant fraction (~20%) of MM patients do not develop osteolytic lesions (OLs). The molecular basis for the absence of bone disease in MM is not understood. We combined PET-CT and gene expression profiling (GEP) of purified BM CD138+ MM cells from 512 newly diagnosed MM patients to reveal that elevated expression of cystatin M/E (CST6) was significantly associated with the absence of OL in MM. An enzyme-linked immunosorbent assay revealed a strong correlation between CST6 levels in BM serum/plasma and CST6 mRNA expression. Both recombinant CST6 protein and BM serum from patients with high CST6 significantly inhibited the activity of the osteoclast-specific protease cathepsin K and blocked osteoclast differentiation and function. Recombinant CST6 inhibited bone destruction in ex vivo and in vivo myeloma models. Single-cell RNA-Seq showed that CST6 attenuates polarization of monocytes to osteoclast precursors. Furthermore, CST6 protein blocks osteoclast differentiation by suppressing cathepsin-mediated cleavage of NF-κB/p100 and TRAF3 following RANKL stimulation. Secretion by MM cells of CST6, an inhibitor of osteoclast differentiation and function, suppresses osteolytic bone disease in MM and probably other diseases associated with osteoclast-mediated bone loss. 相似文献
10.
目的建立UPLC法测定生、制白术配伍枳术丸中橙皮苷、柚皮苷、芸香柚皮苷、柚皮素、橙皮素、辛弗林、荷叶碱、白术内酯Ⅱ、白术内酯Ⅰ、白术内酯Ⅲ中的含有量。方法枳术丸甲醇提取物的分析采用ACQUITY UPLC HSS T3色谱柱(2. 1 mm×100 mm,1. 8μm);流动相0. 1%甲酸-0. 1%甲酸乙腈,梯度洗脱;体积流量0. 4 m L/min;柱温30℃;283 nm波长下测定橙皮苷、柚皮苷、芸香柚皮苷、柚皮素、橙皮素、辛弗林、荷叶碱、白术内酯Ⅱ;220 nm波长下测定白术内酯Ⅰ、白术内酯Ⅲ。结果 10种成分在各自范围内线性关系良好(r>0. 999 0),平均加样回收率97. 5%~100. 6%,RSD 1. 89%~3. 16%。结论该方法准确稳定,重复性好,可用于枳术丸的质量控制。 相似文献