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1.
    
To overcome pharmacokinetic and solubility problems observed in early clinical trials with the potent anticancer compound CHS828, we synthesised a series of prodrugs with improved properties. The best compound obtained was EB1627, with a tetraethyleneglycol moiety attached to the parent drug via a carbonate linkage. This compound was found soluble enough to be given i.v. and the drug was rapidly released in vivo exerting a very potent inhibitory activity alone and in combination with known cytostatics (etoposide) in animal models in vivo.  相似文献   
2.
    

Introduction

Spondyloarthritis (SpA), an interrelated group of rheumatic diseases, has been suggested to be triggered by bacterial infections prior to the development of an autoimmune response that causes inflammation of the spinal and peripheral joints. Because human heat shock protein 60 (HSP60), recently renamed HSPD1, and bacterial HSP60 are highly homologous, immunological cross-reactivity has been proposed as a mechanism of disease initiation. However, previous investigations of the humoral immune response to HSP60 in SpA patients have lacked determination of immunoglobulin G (IgG) subclasses and patient follow-up. In this study, we have focused on these parameters in a cohort of axial SpA patients with a well-established set of clinical characteristics, including MRI changes and human leukocyte antigen B27.

Methods

IgG subclass antibodies (IgG1, IgG2, IgG3 and IgG4) against recombinant HSP60 of three reactive arthritis-related bacteria; human HSP60; and the microorganisms Chlamydia trachomatis and C. pneumoniae were determined by ELISA. Serum samples collected from 2004 to 2006 and in 2010 and 2011 from 39 axial SpA patients were analyzed and compared with samples from 39 healthy controls. The Mann-Whitney U test and Wilcoxon matched pairs test were used to compare the antibody levels in different and paired groups, respectively. P < 0.01 was considered significant. The Spearman nonparametric correlation was used to determine correlation between antibody levels and between antibody levels and the disease parameters.

Results

Elevated levels of IgG1 and IgG3 to human HSP60 and IgG1 to HSP60 of Salmonella enterica Enteritidis were observed in SpA patients compared with healthy controls at both time points. The antibody levels were almost constant over time for IgG1, whereas high levels of IgG3 to human HSP60 tended to decrease over time. The antibody response to human HSP60 was predominantly of the IgG3 subclass, and patients with high levels of IgG3 to this antigen had low levels of IgG1, indicating an inverse association. Different IgG subclasses were produced against bacterial and human HSP60 in the same serum sample, IgG1 and IgG3, respectively, indicating that there was no cross-reaction.

Conclusions

A significant association was observed between axial SpA and the presence of IgG1/IgG3 antibodies to human HSP60 and of IgG1 to S. enterica Enteritidis and C. trachomatis. Generation of antibodies to human HSP60 was independent of the presence of antibodies to bacterial HSP60. No association was observed between clinical and MRI changes with antibodies over time. Altogether, such antibodies do not reflect the disease activity in these patients.This study has been approved by the Regional Research Ethics Committee of Central Jutland, Denmark. Trial registration numbers: 20050046 and 20100083  相似文献   
3.
    
The unfolded protein response (UPR) is activated in response to hypoxia-induced stress such as in the tumor microenvironment. This study examined the role of CREB3L1 (cyclic AMP [cAMP]-responsive element-binding protein 3-like protein 1), a member of the UPR, in breast cancer development and metastasis. Initial experiments identified the loss of CREB3L1 expression in metastatic breast cancer cell lines compared to low-metastasis or nonmetastatic cell lines. When metastatic cells were transfected with CREB3L1, they demonstrated reduced invasion and migration in vitro, as well as a significantly decreased ability to survive under nonadherent or hypoxic conditions. Interestingly, in an in vivo rat mammary tumor model, not only did CREB3L1-expressing cells fail to form metastases compared to CREB3L1 null cells but regression of the primary tumors was seen in 70% of the animals as a result of impaired angiogenesis. Microarray and chromatin immunoprecipitation with microarray technology (ChIP on Chip) analyses identified changes in the expression of many genes involved in cancer development and metastasis, including a decrease in those involved in angiogenesis. These data suggest that CREB3L1 plays an important role in suppressing tumorigenesis and that loss of expression is required for the development of a metastatic phenotype.  相似文献   
4.
  总被引:4,自引:9,他引:4  
Passive stretch, isometric contraction, and shortening were studied in electron micrographs of striated, non-glycerinated frog muscle fibers. The artifacts due to the different steps of preparation were evaluated by comparing sarcomere length and fiber diameter before, during, and after fixation and after sectioning. Tension and length were recorded in the resting and contracted fiber before and during fixation. The I filaments could be traced to enter the A band between the A filaments on both sides of the I band, creating a zone of overlap which decreased linearly with stretch and increased with shortening. This is consistent with a sliding filament model. The decrease in the length of the A and I filaments during isometric contraction and the finding that fibers stretched to a sarcomere length of 3.7 µ still developed 30 per cent of the maximum tetanic tension could not be explained in terms of the sliding filament model. Shortening of the sarcomeres near the myotendinous junctions which still have overlap could account for only one-sixth of this tension, indicating that even those sarcomeres stretched to such a degree that there is a gap between A and I filaments are activated during isometric contraction (increase in stiffness). Shortening, too, was associated with changes in filament length. The diameter of A filaments remained unaltered with stretch and with isometric contraction. Shortening of 50 per cent was associated with a 13 per cent increase in A filament diameter. The area occupied by the fibrils and by the interfibrillar space increased with shortening, indicating a 20 per cent reduction in the volume of the fibrils when shortening amounted to 40 per cent.  相似文献   
5.
6.
The kinetics of colchicine uptake into Chinese hamster ovary cells have been investigated and found to be consistent with an unmediated diffusion mode. A variety of compounds such as local anesthetics and non-ionic detergents as well as drugs such as vinblastine, vincristine, daunomycin and actinomycin D potentiate the rate of colchicine uptake into these cells and into colchicine resistant mutants. In all cases, higher concentrations of these compounds were required to stimulate colchicine uptake in the colchicine resistant mutants than in the cells of the parental line. This stimulation was observed also in the uptake of puromycin, a structurally and functionally different drug. These stimulatory agents did not, however, cause the cells to become nonspecifically leaky since the uptake of 2-deoxy-d-glucose was unaffected. In addition, the activation energy of colchicine uptake was unaltered in the presence of stimulating agents, implying that they were not causing colchicine to enter the cells via a different mechanism. The results are compatible with the view that these compounds are membrane-active, and are able to stimulate an increased rate of unmediated diffusion of colchicine into the cells. It appears that a mechanism for the regulation of passive permeability is modified in the resistant mutants.  相似文献   
7.
报道了内蒙古清水河黄土丘陵地区发现的紫萼藓科1新变种——缨齿藓菱形变种[Jaffueliobryum wrightii(Sull.)Thér.var.rhombicumX.L.BaiSarula],该变种与干旱山地岩面生境中的原变种缨齿藓[Jaffueliobryum wrightii(Sull.)Thér.]相似,生境的变化导致其形态发生变化,主要表现在上部细胞菱形和细胞壁背部强烈加厚,未分化的叶上部边缘细胞、中肋横切面细胞不分化,叶片长0.7~0.8mm,毛尖长0.8~1.3mm。文中对缨齿藓及其新变种的形态学特征,分布和生境进行了描述,并提供了显微照片,另外,列出了缨齿藓属5个种的检索表。  相似文献   
8.
This study examines the effects of burning and granivory on the reproductive success of the rare plant Amsinckia grandiflora (Boraginaceae). Fire is often used in California grasslands as a means of exotic species control, but the indirect effects these controls have on the reproductive ecology of native plants are rarely assessed. The interaction of fire with granivory of A. grandiflora seeds was examined in California grasslands over five years (1998–2002). In 1998 and 1999, both burned and unburned plots had bird-exclusion (netted) and no-exclusion (open) treatments. Predation rates were high (51–99%) and final predation rates did not differ among treatments. In 2000, granivory rates in the unburned, open plots were lower than in previous years (14%), and rodent trapping yielded only a single animal. Low granivory rates were observed in 2001 for unburned, open plots (47%). In 2001, burned/open plots experienced significantly more granivory (87%) than either burned/netted plots (37%) or unburned/open plots (47%). In 2002, every seed was taken from burned, open plots. Granivory was highly variable, ranging from 4 to 100% per plot over a 3-week period. Nearly all plots were discovered (>10% predation) by granivores in all trials in all years. When data from all treatments were combined, significant differences in granivory rates occurred among years, indicating stronger inter-year effects than within-year effects due to burning or bird exclusion. Fire affects granivory when overall predation rates are low, but when predation levels are high (as they were in 1998 and 1999), fire may not affect granivory occurring within the same year. Models extending seed survivorship through the dry summer indicate that most seeds are eaten, even when granivory rates are low.  相似文献   
9.
Chimpanzees are naturally and asymptomatically infected by simian immunodeficiency virus (SIV). Pathogenic properties of SIV/HIV vary and differences in susceptibility and pathogenicity of SIV/HIV depend in part on host-specific factors such as virus-receptor/co-receptor interactions. Since CD4 plays a primary role in virus binding and since SIVcpz have been found only in two African chimpanzee subspecies, we characterized the genetic diversity of CD4 receptors in all four recognized subspecies of chimpanzees. We found noticeable variation in the first variable region V1 of CD4 and in intron six among the subspecies of chimpanzees. We found the CD4 receptor to be conserved in individuals belonging to the P. t. verus subspecies and divergent from the other three subspecies, which harbored highly variable CD4 receptors. The CD4 receptor of chimpanzees differed from that of humans. We question whether the observed diversity can explain the species-specific differences in susceptibility to and pathogenicity of SIV/HIV.  相似文献   
10.
    
In High Arctic ecosystems, plant growth and reproduction are limited by low soil moisture and nutrient availability, low soil and air temperatures, and a short growing season. Mycorrhizal associations facilitate plant nutrient acquisition and water uptake and may therefore be particularly ecologically important in nutrition‐poor and dry environments, such as parts of the Arctic. Similarly, endophytic root associates are thought to play a protective role, increasing plants' stress tolerance, and likely have an important ecosystem function. Despite the importance of these root‐associated fungi, little is known about their host specificity in the Arctic. We investigated the host specificity of root‐associated fungi in the common, widely distributed arctic plant species Bistorta vivipara, Salix polaris and Dryas octopetala in the High Arctic archipelago Svalbard. High‐throughput sequencing of the internal transcribed spacer 1 (ITS1) amplified from whole root systems generated no evidence of host specificity and no spatial autocorrelation within two 3 m × 3 m sample plots. The lack of spatial structure at small spatial scales indicates that Common Mycelial Networks (CMNs) are rare in marginal arctic environments. Moreover, no significant differences in fungal OTU richness were observed across the three plant species, although their root system characteristics (size, biomass) differed considerably. Reasons for lack of host specificity could be that association with generalist fungi may allow arctic plants to more rapidly and easily colonize newly available habitats, and it may be favourable to establish symbiotic relationships with fungi possessing different physiological attributes.  相似文献   
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