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91.
Inhibition of the intrinsic factor X activating complex by protein S: evidence for a specific binding of protein S to factor VIII 总被引:4,自引:2,他引:2
Protein S is a vitamin K-dependent nonenzymatic anticoagulant protein that acts as a cofactor to activated protein C. Recently it was shown that protein S inhibits the prothrombinase reaction independent of activated protein C. In this study, we show that protein S can also inhibit the intrinsic factor X activation via a specific interaction with factor VIII. In the presence of endothelial cells, the intrinsic activation of factor X was inhibited by protein S with an IC50 value of 0.28 +/- 0.04 mumol/L corresponding to the plasma concentration of protein S. This inhibitory effect was even more pronounced when the intrinsic factor X activation was studied in the presence of activated platelets (IC50 = 0.15 +/- 0.02 mumol/L). When a nonlimiting concentration of phospholipid vesicles was used, the plasma concentration of protein S (300 nmol/L) inhibited the intrinsic factor X activation by 40%. Thrombin-cleaved protein S inhibited the endothelial cell-mediated factor X activation with an IC50 similar to that of native protein S (0.26 +/- 0.02 mumol/L). Protein S in complex with C4b-binding protein inhibited the endothelial cell-mediated factor X activation more potently than protein S alone (IC50 = 0.19 +/- 0.03 mumol/L). Using thrombin activated factor VIII, IC50 values of 0.53 +/- 0.09 mumol/L and 0.46 +/- 0.10 mumol/L were found for native protein S and thrombin-cleaved protein S, respectively. The possible interactions of protein S with factor IXa, phospholipids, and factor VIII were investigated. The enzymatic activity of factor IXa was not affected by protein S, and interaction of protein S with the phospholipid surface could not fully explain the inhibitory effect of protein S on the factor X activation. Using a solid-phase binding assay, we showed a specific, saturable, and reversible binding of protein S to factor VIII with a high affinity. The concentration of protein S where half-maximal binding was reached (B1/2max) was 0.41 +/- 0.06 mumol/L. A similar affinity was found for the interaction of thrombin-cleaved protein S with factor VIII (B1/2max = 0.40 +/- 0.04 mumol/L). The affinity of the complex protein S with C4B-binding protein appeared to be five times higher (B1/2max = 0.07 +/- 0.03 mumol/L). Because the affinities of the interaction of the different forms of protein S with factor VIII correspond to the IC50 values observed for the intrinsic factor X activating complex, the interaction of protein S with factor VIII may explain the inhibitory effect of protein S on the intrinsic factor X activating complex.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
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Raman Jay JE Heckman L Hinshaw S Best M Lubner DF Jarrard TM Downs SY Nakada FT Lee W Huang T Ziemlewicz 《Urologic oncology》2017,35(3):119
Purpose
Percutaneous biopsy obtained from a single location is prone to sampling error in large heterogeneous renal masses, leading to nondiagnostic results or failure to detect poor prognostic features. We evaluated the accuracy of percutaneous biopsy for large renal masses using a modified multi-quadrant technique vs. a standard biopsy technique.Materials and methods
Clinical and pathological data for all patients with cT2 or greater renal masses who underwent percutaneous biopsy from 2009 to 2014 were reviewed. The multi-quadrant technique was defined as multiple core biopsies from at least 4 separate solid enhancing areas in the tumor. The incidence of nondiagnostic findings, sarcomatoid features and procedural complications was recorded, and concordance between biopsy specimens and nephrectomy pathology was compared.Results
A total of 122 biopsies were performed for 117 tumors in 116 patients (46 using the standard biopsy technique and 76 using the multi-quadrant technique). Median tumor size was 10 cm (IQR: 8–12). Biopsy was nondiagnostic in 5 of 46 (10.9%) standard and 0 of 76 (0%) multi-quadrant biopsies (P = 0.007). Renal cell carcinoma was identified in 96 of 115 (82.0%) tumors and nonrenal cell carcinoma tumors were identified in 21 (18.0%). One complication occurred using the standard biopsy technique and no complications were reported using the multi-quadrant technique. Sarcomatoid features were present in 23 of 96 (23.9%) large renal cell carcinomas studied. Sensitivity for identifying sarcomatoid features was higher using the multi-quadrant technique compared to the standard biopsy technique at 13 of 15 (86.7%) vs. 2 of 8 (25.0%) (P = 0.0062).Conclusions
The multi-quadrant percutaneous biopsy technique increases the ability to identify aggressive pathological features in large renal tumors and decreases nondiagnostic biopsy rates. 相似文献95.
96.
RA Schwartz†‡ TM Bridges§ AK Butani† A Ehrlich§ 《Journal of the European Academy of Dermatology and Venereology》2008,22(5):606-615
Solar ultraviolet light electromagnetic waves are a known environmental carcinogenic agent closely associated with the development of skin cancer in light‐complexioned individuals. Outdoor workers have higher annual exposure to ultraviolet light. We will review the topic of actinic keratoses among these individuals as this common rudimentary form of superficial cutaneous squamous cell carcinoma is explored in greater detail. 相似文献
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98.
Anny JTP Peters Maja Micevska Scharf Francien TM van Driel Willy HM Jansen 《Globalization and health》2010,6(1):23
This study analyses the priorities of public donors in funding HIV prevention by either integrated condom programming or HIV
preventive microbicides and vaccines in the period between 2000 and 2008. It further compares the public funding investments
of the USA government and European governments, including the EU, as we expect the two groups to invest differently in HIV
prevention options, because their policies on sexual and reproductive health and rights are different. We use two existing
officially UN endorsed databases to compare the public donor funding streams for HIV prevention of these two distinct contributors.
In the period 2000-2008, the relative share of public funding for integrated condom programming dropped significantly, while
that for research on vaccines and microbicides increased. The European public donors gave a larger share to condom programming
than the United States, but exhibited a similar downward trend in favour of funding research on vaccines and microbicides.
Both public donor parties invested progressively more in research on vaccines and microbicides rather than addressing the
shortage of condoms and improving access to integrated condom programming in developing countries. 相似文献
99.
P-glycoprotein expression in human plasma cell myeloma: correlation with prior chemotherapy 总被引:3,自引:3,他引:3
Grogan TM; Spier CM; Salmon SE; Matzner M; Rybski J; Weinstein RS; Scheper RJ; Dalton WS 《Blood》1993,81(2):490-495
Multidrug-resistant (MDR) myeloma patients failing chemotherapy may express P-glycoprotein (PGP), which serves as an efflux pump protecting the neoplastic cells. Unknown is whether PGP expression might relate to prior cytotoxic drug exposure. To address this question, we studied 106 consecutive bone marrow samples from 104 myeloma patients with samples studied either before or after therapy and at the time of relapse. We performed an established immunocytochemical assay of PGP using an MDR-1- specific monoclonal antibody and correlated PGP status with prior chemotherapy dosage. Myeloma patients with no prior therapy had a low incidence of PGP expression (6%, 3/47), whereas those receiving chemotherapy had a significantly higher incidence (43%, 21/49) (P < .0001). A substantially higher incidence of PGP expression (50%, 83%, respectively) occurred when the total vincristine dose exceeded 20 mg and when doxorubicin exceeded 340 mg. In the 11 patients who received both high vincristine and doxorubicin dosages (> 20 mg, > 340 mg total dose) there was 100% incidence of PGP expression in the tumor cells. These data provided the basis for a predictive mathematical model from which dose-related PGP expression normograms were generated. Time with myeloma for PGP-negative patients (mean 33 months) had overlapping confidence limits with PGP-positive patients (mean 42 months), suggesting that disease duration was not a significant variable. PGP expression did not correlate with other clinical factors or immunophenotypic factors. Our findings indicate a strong correlation between PGP expression in myeloma and past chemotherapy in myeloma, in particular, related to prior exposure to the natural product agents vincristine and doxorubicin. Additionally, the proportion of PGP- positive plasma cells was significantly higher in the doxorubicin- treated patients than the nondoxorubicin-treated patients (87.7% v 65.17%; P = .013). Combined high vincristine and doxorubicin total dosage appear highly predictive of PGP expression. 相似文献
100.
Absence of human T-cell lymphotropic virus type I coinfection in human immunodeficiency virus-infected hemophilic men 总被引:2,自引:0,他引:2
Concern for transmission of human T-cell lymphotropic virus, type 1 (HTLV-1) infection to recipients of infected cellular blood products has prompted development of tests to eliminate blood units with HTLV-I antibodies. Most hemophilic men from the United States became infected with human immunodeficiency virus (HIV) before HIV donor screening and before blood products were processed to inactivate the virus. To assess whether these men might also be infected with HTLV-I, we examined the HTLV-I antibody status of 127 factor VIII (hemophilia A) recipients and 71 factor IX (hemophilia B) recipients. One HIV-seronegative and four HIV-seropositive persons were HTLV-I reactive by enzyme-linked immunosorbent assay (ELISA). Four of five ELISA-reactive serum samples were negative by HTLV-I immunoblot assay (IB); 1 reactive and 1 borderline reactive serum were indeterminate on IB (p19 reactivity), but negative by radioimmunoprecipitation assay (RIPA). Peripheral blood mononuclear cells from one patient with indeterminate HTLV-I IB were negative for HTLV-I genomic sequences by polymerase chain reaction. The other indeterminate patient's serum antibody pattern was stable over a 2-year period, suggesting this was not an instance of early HTLV-I seroconversion. These results reaffirm the safety of factor components in the United States with regard to HTLV-I but emphasize the importance and need for further testing of reactive HTLV-I ELISA results with a second more specific technique. 相似文献