Monoterpene geraniol prevents acute allograft rejection.
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Acute Disease↗
Biomedical subjects
P Ji
Publications and source records attributed to P Ji.
Identification of metastasis-associated genes in early stage non-small cell lung cancer by subtractive hybridization.
Non-small cell lung cancer (NSCLC) is a leading cause of death and a substantial fraction of patients with surgically resected disease ultimately dies due to distant metastasis. To identify gene expression differences in early stage adenocarcinoma that either did or did not metastasize within a 5-year period, we employed a subtractive hybridization strategy of pooled RNA from primary adenocarcinomas (stage I) of the lung. Individual clones (n=225) of the subtracted cDNA library were sequenced. Further analyses of mRNA expression levels in a cohort of 70 NSCLC patients (stage I to IIIA) showed that the metastasis association of the identified genes was stage and histology specific. Cox regression analyses identified two genes (EIF4A1, MALA1) to be independent prognostic parameters for patients' survival in stage I and II disease. These findings could help to identify early-stage NSCLC patients at high risk for the development of distant metastasis.
Biomarkers, Tumor↗
Photon acceleration based on plasma.
A formalism is presented to examine the interaction of laser field with plasma wave in which the interaction is described as some geometric metric (optical metric) and then a laser beam is treated as a packet of photons moving along null geodesics with respect to that metric. Photon motion equations are derived and solved analytically in both the one-dimensional and the three-dimensional cases. The expressions for the frequency shifts of laser pulses are presented and it is found that the frequency shifting results from the plasma density gradient. Three-dimensional solution shows that a laser beam diffraction occurs in the presence of a radial variation of the plasma density. It is argued that the focusing mechanism originated from the plasma wave can curb laser diffracting, so that photons can be trapped in the plasma wave and accelerated continuously.
Journal Article↗
Microdialysis studies of the middle ear distribution kinetics of amoxicillin in the awake chinchilla.
This work was performed to develop an experimental animal model for the study of antibiotic drug distribution into middle ear fluid (MEF) and to evaluate its relevance and significance to the clinical treatment of otitis media (OM). Chinchillas were assigned to normal or infected ear groups after Eustachian tube obstruction (ETO) or direct trans-bullar inoculation with type 3 Streptococcus pneumoniae. Following survival surgery to implant microdialysis (MD) probes in the jugular vein and middle ear (ME), amoxicillin was given intravenously (iv) as a bolus or infusion. Drug concentrations in blood and MEF were continuously monitored by microdialysis. The measured concentrations were corrected for probe recovery by simultaneous retrodialysis. Multiple MEF and blood sampling was also performed to validate the animal model and MD sampling technique. Bacterial infection was successfully induced 3-7 days after the inoculation, whereas the control group gave negative bacterial culture results. The beta-lactam antibiotic, amoxicillin, exhibited an elimination half-life of 0.33+/-0.23 h (n = 9) in chinchilla blood, 1.46+/-0.50 h (n = 5) and 1.75+/-0.84 h (n = 4) in MEF of normal and infected ears (p = 0.6), respectively. MEF-to-blood amoxicillin concentration ratios at steady state following iv infusion were 0.26+/-0.06 (n = 5) and 0.28+/-0.11 (n = 4) for normal and infected ears (p = 0.7), respectively. MD allows continuous monitoring of drug concentration-time profiles in blood and MEF in an awake chinchilla model. The concentrations measured by MD were validated by direct sampling. The ratio of the area under the curve (AUC) of drug concentration in MEF versus time to that in blood after iv bolus doses was less than unity, as was the steady-state concentration ratio following constant-rate iv infusion, suggesting an active transport mechanism was involved in the efflux of amoxicillin from the ME of chinchilla. The results of studies involving infected ears were not significantly different from those in normal ears in terms of amoxicillin distribution across the ME mucosal membrane after systemic administration.
Amoxicillin↗
Is intraoperative cholangiography during laparoscopic cholecystectomy cost effective?
BACKGROUND: Common bile duct injuries occur in 0.2% to 0.8% of laparoscopic cholecystectomies (LC). Intraoperative cholangiograms (IOCG) are a useful means of detecting common bile duct injuries in the operating room. METHODS: Data were retrospectively reviewed for patients referred for management of common duct injuries from 1996 to 2000. Cost data were obtained from hospital records. Legal settlements were obtained from published sources. RESULTS: Twenty-one patients (0.133%) were found to have bile duct injuries and incurred median hospital stays of 11.5 days at an average cost of $587,491. The average cost of those requiring reoperation was $669,134. The 21 cases in our sample had total charges of $10,819,767. Performing IOCG during each LC in Orange County would have cost $10,669,725. If extrapolated to state and nationwide levels, the savings is far greater. CONCLUSIONS: IOCG during LC is a cost-effective means of preventing the costs of delayed recognition of bile duct injuries.
Adult↗
Laparoscopic ultrasound with radiofrequency ablation in cirrhotic patients with hepatocellular carcinoma: technique and technical considerations.
The optimal treatment for hepatocellular carcinoma (HCC) is surgical resection. However, only a small percentage of patients are operative candidates. CT-guided percutaneous radiofrequency ablation (RFA) has been shown to be efficacious in treatment of unresectable HCC. CT-guided RFA, however, may fail to detect small intrahepatic metastases and tumor thrombi, which thus minimizes possible gains from the procedure. Recent advances in laparoscopic ultrasound have greatly improved the accuracy in detecting intrahepatic HCC metastases many of which were missed by CT. Combining intraoperative laparoscopic ultrasound with laparoscopic RFA greatly utilizes advances in both fields and is technically feasible. Our objective is to introduce a novel operative combination of laparoscopic ultrasound with laparoscopic RFA in treatment of HCC. Childs class B patients with unresectable HCC were considered for this study. Twelve patients underwent laparoscopic ultrasound and RFA of 17 lesions. Tumors ranged from 0.27 to 7 cm in diameter. Laparoscopic ultrasound identified tumor not detected preoperatively in one patient (8.3%). A single pneumothorax was the only complication. A single patient (8.3%) had recurrent disease and accounted for the only mortality in the study. We conclude that the use of both laparoscopic ultrasound and RFA is an excellent use of existing technology. The procedure combines improved tumor localization with the means to treat patients with unresectable disease. Because RFA is a relatively recent development long-term results are not yet available. Randomized prospective studies comparing RFA with other modalities will determine the ultimate utility of this procedure.
Adult↗
Natural killer cell- and macrophage mediated discordant guinea pig-->rat xenograft rejection in the absence of complement, xenoantibody and T cell immunity.
BACKGROUND: The role of natural killer (NK) cells and macrophages (Møs) in the absence of T cell immunity in discordant xenograft (xg) rejection was investigated. METHODS: Guinea pig hearts were transplanted into athymic nude rats receiving no treatment or antixenoantibody (xAb), anticomplement (C), antinatural killer (NK) cell therapy (antiasialo GM1 [anti-ASGM1]) or their combinations. For anti-xAb therapy, natural xAbs were absorbed/neutralized by pretransplant guinea pig blood transfusion (pGPBT), followed by administration of the malononitriloamide MNA715. Cobra venom factor (CVF) was administered as anti-C therapy. FACScan analysis and a standard cytotoxicity assay determined NK cell number and cytotoxicity, respectively. ELISA and the CH50 assay measured titers of xAb and C activity, respectively. Rejected Xgs were examined by light microscopy and by immunohistochemistry. RESULTS: All hyperacutely (15+/-4 min) rejected Xgs from untreated rats showed deposits of C3 and IgM without cellular infiltrates. Combined anti-xAb and anti-C (pGPBT/MNA715/CVF) treatment significantly prolonged the survival of Xgs (3.7+/-0.6 days, P<0.001 vs. control group) showing NK cell and Mø infiltration without deposition of xAbs or C3. NK cell depletion (day -12) followed by exposure of recovering NK cells to the guinea pig antigens failed to induce specific NK cell nonresponsiveness and to further prolong xg survival in combined anti-xAb/anti-C group. In contrast, adding of continuous and repetitive depletion of NK cells significantly further prolonged xg survival to 7.4+/-0.5 days (P<0,001 vs. the anti-xAb/anti-C group) with rejected Xgs densely infiltrated by activated Møs without involvement of NK cells, C or xAbs. CONCLUSIONS: When xAb and C are suppressed in the discordant guinea pig-into-nude rat model, NK cells play an important role in xg rejection. When also NK cells are suppressed, activated Møs seem to reject discordant Xgs. The induction of specific NK cell nonresponsiveness fails in the guinea pig-into-rat combination.
Animals↗
Immunomodulatory effects of pretransplant donor blood transfusion on T-cell-independent xenoreactive immunity.
BACKGROUND: Pretransplant blood transfusions have beneficial effects on both clinical and experimental allograft survival. In the present study, we examined whether pretransplant hamster blood transfusions (pHBT) alone or together with peritransfusion immunosuppressive strategies designed to target B cells and/or natural killer (NK) cells, could modulate T cell-independent (T-I) xenoreactivity in athymic nude rats. METHODS: Hamster or mouse hearts were heterotopically xenotransplanted into untreated or treated athymic nude rats receiving either pHBT, anti-B cell or anti-NK cell therapy alone or their combinations. Xenoreactive antibodies (xAbs) and the percentage of NK cells were analyzed by FACScan analysis. NK cytotoxicity was measured by a standard 4 hr 51Cr release assay. Xenografts (Xgs) were examined by hematoxylin-eosin (H&E), by light microscopic method with Masson's trichrome and orcein staining, by immunofluorescent staining for immunoglobulin M and C3 deposition, and by immunohistochemical staining for infiltration of NK cells and macrophages (Mphis). RESULTS: In 1 of 6 rats given pHBT alone 2 weeks before receiving hamster xenografts, Xg survival was prolonged to 55 days compared with 3.0+/-1.2 days in the other 5 animals and with 3.0+/-0.6 days in untreated animals. In the 55 days, surviving Xg infiltration of Mphis and NK cells was seen together with severe signs of chronic rejection, such as fibrosis and obliterative vasculopathy. The addition of the anti-B cell immunosuppressant MNA715 (malononitriloamide x920715, 20 mg/kg/day) from day -14 to day +14 or of 100 microL of rabbit anti-asialo GM1 serum ([anti-ASGM1] an NK cell depleting antibody) on day -14 resulted in a significant and species-specific prolongation of the survival of hamster Xgs, respectively 59.8+/-9.6 days and 58.2+/-14.7 days (P<0.001 vs. control group), but not of mouse heart Xgs that were rejected in a normal tempo. All prolonged hamster Xgs were infiltrated with Mphis and NK cells and developed severe lesions of chronic rejection, such as fibrosis and obliterative vasculopathy. In contrast, MNA715 or anti-ASGM1 alone had no effect on Xg survival (4.8+/-1.7 days and 2.7+/-0.6 days, respectively). Combined MNA715/anti-ASGM1 treatment only moderately promoted Xg survival (10+/-5.0 days; P<0.001). A simultaneous administration of pHBT, MNA715, and anti-ASGM1 induced indefinite and species-specific Xg survival in all recipients. In vivo and in vitro studies demonstrated that both T-I B cell and NK cell species-specific xenotolerance were achieved. CONCLUSIONS: Pretransplant blood transfusion may have a species-specific immunomodulatory effect on T-I xenoreactivity. This effect is further enhanced by a temporary co-administration of MNA715 or by a single injection of anti-ASGM1. A combination of pHBT, MNA715, and anti-ASGM1 induces species-specific T-I xenotolerance.
Animals↗
Perillyl alcohol inhibits TCR-mediated [Ca(2+)](i) signaling, alters cell shape and motility, and induces apoptosis in T lymphocytes.
Perillyl alcohol (POH) inhibits isoprenylation and has shown anticancer and chemopreventive properties in rodent models. The mechanism that underlies the anticancer activity of POH and other isoprenylation inhibitors is unknown but has been postulated to involve decreased levels of isoprenylated Ras and Ras-related proteins. Previously we demonstrated that POH effectively inhibits human T cell proliferation in vitro and can prevent acute and chronic rejection in a rat cardiac transplant model. In this report, we investigate the effects of POH on T lymphocytes at the single-cell level. POH disrupts the polarized shape and motility of antigen-specific murine 1E5 T cells. Using an optical trap to position anti-CD3-coated beads in contact with 1E5 T cells, we demonstrate that POH inhibits their TCR-mediated calcium response. Furthermore, we show that POH preferentially induces apoptosis in PHA-activated human T cells as well as in 1E5 T cells.
Adult↗
Absence of cross-reactivity between xenoantibodies directed against concordant or discordant xenoantigens in rats.
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Animals↗
Complement- and xenoantibody-independent discordant xenograft rejection in a guinea pig to rat model.
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Animals↗
Synergistic effect of pretransplant xenogeneic blood transfusion with NK cell and/or B-cell immunosuppression to modulate T-cell-independent xenoreactivity.
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Animals↗
Tolerance induction with FTY720 and donor-specific blood transfusion: discrepancy between heart transplantation and intestinal transplantation.
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Animals↗
Approaches toward T cell-independent and -dependent xenograft tolerance.
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Animals↗
Induction of xenotransplant tolerance.
Clinical xenotransplantation will depend on the induction of xeno-tolerance. Conversely, xenotransplantation may offer opportunities to induce transplantation tolerance. We have previously shown that, xenotransplant tolerance for vascularized hamster organs could be achieved in athymic rats as far as the T-cell independent xeno-reactivity is concerned. This tolerance was shown to be based on specific T-independent B lymphocyte and NK cell unresponsiveness. In the present study we have shown that this T-independent xeno-tolerance can be achieved also in a semi-discordant situation using rat recipients with high titers of pre-existing anti-hamster IgM xenoantibodies. In addition, we showed that T-independent xeno-tolerance can also be induced together with T-dependent xeno-tolerance using xeno-thymus transplantation. These experiments may be of relevance for clinical xenotransplantation. The major next question to be addressed is to see how self tolerance in xeno-thymus grafted recipients can be improved as until now the latter recipients usually develop a multi-organ autoimmune syndrome, several weeks after transplanting a xeno-thymus.
Animals↗
Tyrosine phosphorylation of alpha-actinin in activated platelets.
The integrin alpha(IIb)beta(3) mediates tyrosine phosphorylation of a 105-kDa protein (pp105) in activated platelets. We have partially purified a 105-kDa tyrosine-phosphorylated protein from platelets stimulated with phorbol 12-myristate 13-acetate and obtained the sequence of an internal 12-mer peptide derived from this protein. The sequence was identical to human alpha-actinin sequences deposited in the Swiss Protein Database. alpha-Actinin, a 105-kDa protein in platelets, was subsequently purified from activated platelets by four sequential chromatographic steps. Fractions were analyzed by Western blotting and probed with alpha-actinin and anti-phosphotyrosine antibodies. The distribution of alpha-actinin and pp105 overlapped throughout the purification. Furthermore, in the course of this purification, a 105-kDa tyrosine-phosphorylated protein was only detected in fractions that contained alpha-actinin. The purified alpha-actinin protein was immunoprecipitated with antibodies to phosphotyrosine in the absence but not in the presence of phenyl phosphate. alpha-Actinin resolved by two-dimensional gel electrophoresis of activated platelet lysates was recognized by the antibodies to phosphotyrosine, whereas pretreatment of the platelets with bisindolylmaleimide, a protein kinase C inhibitor that prevents tyrosine phosphorylation of pp105, inhibited the reactivity of the antibodies to phosphotyrosine with alpha-actinin. Taken together, these data demonstrate that a fraction of alpha-actinin is tyrosine-phosphorylated in activated platelets.
Actinin↗
Maintenance and reversibility of natural killer cell- and T cell-independent B lymphocyte xenotolerance in athymic nude rats.
BACKGROUND: We previously described that a tolerogeneic regimen (TR) including (1) the infusion of a minced hamster heart suspension (MHH), (2) a single injection of an anti-natural killer (NK) cell serum (rabbit anti-asialo GM1 serum), and (3) a 4-week course of the B cell immunosuppressant leflunomide (20 mg/kg/ day) induced T cell-independent (T-I) B lymphocyte and NK cell tolerance for hamster xenoantigens in T-deficient athymic nude rats. In addition, the TR allowed for long-term hamster cardiac xenograft (Xg) survival when Xgs were transplanted 2 weeks (Day 0) after the initiation of the TR (started on Day - 14). The present study was undertaken to investigate some of the characteristics of this T-I xenotolerance in more detail. METHODS: To investigate the duration of the effect of the TR on the T-I xenotolerance, hamster Xgs were transplanted at various times after initiation of the TR. To investigate whether the maintenance of the T-I xenotolerance depended on the presence of the graft, tolerated Xgs were removed on Day +28, and the subsequent evolution of the T-I xenotolerance as well as of second hamster Xg was followed. In addition, the reversibility of NK cell nonresponsiveness by recombinant interleukin-2 was investigated in vitro. RESULTS: Xgs transplanted on day 0 or Day +7 showed long-term survival. However, all Xgs transplanted on Day +15, +30, and +60 were rapidly rejected. The latter rejection occurred in the absence of formation of anti-hamster immunoglobulin (Ig)M xenoreactive antibodies (xAbs) but correlated with the recovery of anti-hamster NK cell reactivity from day +14 on. Rejected Xgs showed infiltration of NK cells but absence of IgM xAbs or complement factor deposition. When tolerated first Xgs (transplanted on Day 0) were removed on Day +28, second hamster Xgs survived without treatment when transplanted 1 or 2 weeks later. However, second hamster Xgs transplanted 3 weeks after removal of the first Xgs were all rapidly rejected. Again, the latter rejection was characterized by the infiltration of the Xgs with NK cells and by the absence of anti-hamster IgM xAbs formation. Xenoreactive NK cell nonresponsiveness was not only shorter than xenoreactive B cell nonresponsiveness, but was also more fragile. This was evident from the fact that after addition of recombinant interleukin-2 in vitro, specific anti-hamster NK nonresponsiveness was easily broken. CONCLUSIONS: NK cell and T-I B cell xenotolerance can be induced in T-deficient rats. Compared with B cell xenotolerance, the maintenance of NK cell xenotolerance is much shorter, more dependent on the presence of the graft, and easily reversible in vitro.
Animals↗
Induction of T-independent xenotolerance in a semi-discordant hamster-to-presensitized, nude rat model.
BACKGROUND: We have previously demonstrated that in a concordant hamster-to-nude rat cardiac transplant model, T-independent specific B-lymphocyte and natural killer (NK)-cell tolerance could be induced, leading to long-term xenograft (Xg) survival. Here, we investigated whether the same could be achieved in a clinically more relevant semi-discordant model involving hamster hearts transplanted into pre-sensitized, nude rats. METHODS: Sensitized, nude rats with high titers of anti-hamster immunoglobulin (Ig)M xenoantibodies (XAbs) were prepared by transplanting a first hamster heart without treatment. One week after rejection, a complete tolerizing regimen was given, including the following: a) an i.v. injection of hamster heart antigens; b) a 4-week administration of malononitriloamide; and c) a single injection of an anti-NK antiserum. Two weeks later, a second hamster heart was grafted. The isotype and level of XAb were examined by fluorescence-activated cell sorting. NK cytotoxicity was evaluated by a standard 4-hr 51Cr release assay. Hamster heart Xgs were examined by conventional histologic and immunohistochemical analysis. RESULTS: Untreated, presensitized, nude rats developing high titers of IgM XAb underwent hyperacute rejection within 4 hr (n=4) after transplantation of the second hamster heart. Immunohistochemical analysis showed intensive staining for IgM and C3 along the vascular endothelia in the rejected Xgs. In contrast, presensitized, nude rats receiving the complete tolerizing regimen had a rapid decrease in anti-hamster IgM XAb. The second hamster hearts were not rejected and showed long-term survival even after withdrawal of malononitriloamide (n=6). Moreover, tolerant rats showed specific B-lymphocyte tolerance and a specific continuous absence of anti-hamster NK-cell reactivity. CONCLUSION: T-independent B-lymphocyte and NK-cell xenotolerance can also be achieved in recipients with pre-existing IgM XAb.
Animals↗