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Biomedical subjects

F Xiao

Publications and source records attributed to F Xiao.

At least 73 records · Page 4Linked to original sources
PubMed1996

[The expression of Rb, p16 and cyclin D1 in 41 esophageal cancers].

D-type cyclins being considered as oncogenes promote progression of the cell through the G1 phase of the cell cycle by CDK4 mediated phosphorylation of the retinoblastoma protein. The activities of CDK4 is constrained by inhibitors such as p16, the product of the CDKN2 in tumor cells and primary tumors suggests that p16 acts as a tumor suppressor. We examined these proteins and genes by immunohistochemistry and in situ hybridization techniques in 41 primary esophageal cancers. Overexpression of cyclin D1 was revealed in 26/41 samples (63.4%) and also in the mucosa adjacent to the cancers in 10 of 26 cyclin D1 overexpression samples, which also have high levels of cyclin D1. P16 was undetectable in 13 of 41 samples. Interestingly, 17 of 24 Rb positive cancers had no or low p16, while 9 Rb-negative cancers showed high levels of p16. These results suggest that the overexpression of cyclin D1 may be a common molecular abnormality and an early molecular event in esophageal cancer, followed either by Rb loss, as occurred in Rb negative samples, or by loss of p16, as occurred in p16 negative samples. Cyclin D1 overexpression and Rb inactivation can coexist in esophageal cancer. However, there is a reciprocity between Rb inactivation and p16 expression in esophageal cancer. Thus, abnormality in the negative feedback regulatory pathway of cyclin D1/CDK4, Rb and p16 may be involved in the molecular mechanism of esophageal cancer.

Carcinoma, Squamous Cell↗
PubMed1995

Pharmacologically induced regression of chronic transplant rejection.

Chronic rejection, characterized by a progressive obliterative arteriopathy, is a major cause of graft failure in long-surviving human transplants for which there is no effective treatment. Leflunomide, an isoxazol derivative, has been shown to be a novel immunomodulatory drug that profoundly suppresses the immune response. In this study, 58 Fisher-344 rats received cardiac transplantation from Lewis rats. All the recipients were given CsA at 2.5 mg/kg for 5 days postoperatively. Without further treatments, the arterial intima was progressively injured by mononuclear cell infiltration and Ab deposition. Smooth muscle cell and fibroblast proliferation in the intima became a predominant phenomenon by day 90. CsA was ineffective in controlling the progress of arterial intimal thickening when treatment began on day 30. Leflunomide at 5 mg/kg failed to control arterial intimal thickening by day 60 when therapy began on day 30. However, the progress of arterial intimal thickening was significantly inhibited by day 90 when the dosage of leflunomide had been increased to 10 mg/kg on day 60. Combined therapy with leflunomide and CsA at 5 mg/kg for 30 days dramatically reversed the arterial thickening by day 60. After increasing the dosages of both leflunomide and CsA to 10 mg/kg on day 60, the combination therapy steadily controlled the chronic rejection. Only the combination therapy significantly down-regulated circulating antidonor IgM and IgG titers. In rat smooth muscle cell culture, this same drug combination had a synergistic inhibitory effect on proliferation. Therefore, the combination therapy of leflunomide and CsA could reverse and control the progress of chronic rejection, while leflunomide, at higher dosage as a monotherapy, could stabilize chronic rejection in this model. The mechanism of the regression of chronic rejection by leflunomide and cyclosporine may be related to their in vitro abilities to control not only lymphocyte but smooth muscle cell proliferation, as well. The synergistic effect of these two drugs on vascular smooth muscle cell proliferation in vitro may be an important part of this novel activity. This unique feature holds intriguing possibilities for treating established chronic rejection.

Animals↗
PubMed1995

Epinephrine and sodium bicarbonate during CPR following asphyxial cardiac arrest in rats.

Although high-dose epinephrine during CPR improves coronary perfusion pressure (CoPP) and rate of return of spontaneous circulation (ROSC) in some models, its impact on long term outcome (> or = 72 h) has not been evaluated. Previous studies of sodium bicarbonate (NaHCO3) therapy during CPR indicate that beneficial effects may be dependent on epinephrine (EPI) dose. We hypothesized that EPI and NaHCO3 given during CPR have a significant impact on long term outcome. One hundred male Sprague-Dawley rats were prospectively studied in a block randomized placebo controlled trial. Rats were anesthetized, paralyzed, mechanically ventilated, instrumented, and each underwent 10 min of asphyxia, resulting in 6.8 +/- 0.4 min of circulatory arrest. Resuscitation was performed by mechanical ventilation and manual external chest compressions. EPI 0.0 (placebo), 0.01, 0.1, or 1.0 mg/kg IV was given at the onset of CPR, followed by NaHCO3 0.0 (placebo) or 1.0 mEq/kg IV. Successfully resuscitated rats were monitored and ventilated for 1 h without hemodynamic support. Neurologic deficit scores (NDS), cerebral histopathologic damage scores (CHDS) and myocardial histopathologic damage scores (MHDS) were determined in rats that survived 72 h. EPI improved CoPP and ROSC in a dose-dependent manner up to 0.1 mg/kg. Rats receiving EPI 0.1 and 1.0 mg/kg during CPR exhibited prolonged post-ROSC hypertension and metabolic acidemia, increased A-a O2 gradient, and an increased incidence of post-ROSC ventricular tachycardia or fibrillation. Overall survival was lower with EPI 0.1 and 1.0 mg/kg compared to 0.01 mg/kg. Although NDS was significantly less with EPI 0.1 mg/kg compared to placebo, there was no difference in CHDS between groups. In contrast, MDS was significantly higher with EPI 0.1 mg/kg compared to placebo or EPI 0.01 mg/kg. There was an overall trend toward improved survival at 72 h in rats that received NaHCO3 which was most evident in the EPI 0.1 mg/kg group. We conclude that (1) EPI during CPR has a biphasic dose/response curve in terms of survival, when post-resuscitation effects are left untreated and (2) NaHCO3 doses greater than 1.0 mEq/kg may be necessary to treat the side-effects of high-dose EPI. Further work is needed to determine if treating the immediate post-resuscitation effects of high-dose EPI can prevent detrimental effects on long-term outcome.

Animals↗
PubMed1995

Peritoneal cooling for mild cerebral hypothermia after cardiac arrest in dogs.

After normothermic cardiac arrest in dogs, we found that mild hypothermia (34 degrees C) of 1-2 h reduced brain damage, providing that hypothermia was achieved within 15 min of reperfusion. A clinically feasible rapid brain-cooling method is needed. As head-neck surface cooling alone in dogs was found to be too slow (0.1 degrees C/min), we reviewed peritoneal cooling in the Introduction and Discussion sections. PRELIMINARY EXPERIMENTS WITHOUT CARDIAC ARREST: In 5 dogs with spontaneous circulation and IPPV, 2 L of Ringer's solution at 10 degrees C were instilled into the peritoneal cavity, left for 5 min, and drained. Brain (tympanic membrane) temperature (Tty) decreased by a mean of 0.3 degrees C/min (12 min to 34 degrees C). Core (pulmonary artery) temperature (Tpa) decreased by a mean of 0.8 degrees C/min (5 min to 34 degrees C). COOLING AFTER CARDIAC ARREST: In our reproducible dog model of normothermic ventricular fibrillation cardiac arrest of 11 min (no flow), brief low-flow normothermic cardiopulmonary bypass (CPB) was used for reperfusion and restoration of spontaneous circulation (ROSC) within 2 min. In 24 dogs, mild hypothermia was induced by head-neck surface cooling with ice bags, starting with reperfusion, plus peritoneal lavage as above, starting with ROSC. All 24 dogs were resuscitated. Initial head-neck surface cooling alone over 2 min decreased Tty by only 0.15 degrees C/min. Subsequent additional peritoneal lavage decreased Tty by a mean of 0.3 degrees C/min (11 min to 34 degrees C); and Tpa 0.6 degrees C/min (7 min to 34 degrees C). There were no significant physiologic effects. We conclude that peritoneal instillation of cold Ringer's solution is more rapidly effective than other non-intravascular cooling methods reported previously. Peritoneal cooling should be tried in patients during CPR.

Animals↗
PubMed1995

ESR study on calcineurin.

X-band electron spin resonance spectroscopy was used to investigate the binding of Mn2+ to the apo-forms of calcineurin and its A and B subunits. The results indicated the presence of 2 Mn2+ binding sites of different affinities (20 mumol/L and 60 mumol/L) in the calcineurin A subunit and 4 Mn2+ binding sites in the calcineurin subunit B, 2 high affinity and 2 low affinity binding sites with Kd's of 4 mumol/L and 90 mumol/L, respectively. Interestingly and quite surprisingly, Mn2+ binding to the holoenzyme was characterized by only 2 binding sites with Kd's of 7 mumol/L and 33 mumol/L. However, in the presence of calmodulin about 10 Mn2+ sites were detected, and the Mn2+ calmodulin-calcineurin complex exhibited enzymatic activity. These results, based on direct spectral measurements of the metal ligand, demostrate that Mn2+ binds to both free subunits of calcineurin in a manner distinct from binding to the holoenzyme. Also, the data suggest that conformational changes occur upon heterodimer formation and association of the holoenzyme with the regulatory protein calmodulin.

Animals↗
PubMed1994

Leflunomide controls rejection in hamster to rat cardiac xenografts.

Leflunomide is an isoxazole derivative that has the ability to prevent acute rejection of cardiac, renal, and skin transplants in strongly rejecting rat models. Furthermore, leflunomide is able to interact synergistically with CsA to inhibit allograft rejection and also reverse ongoing allograft rejection. In vitro studies suggest that the mechanism of action of leflunomide is via an interruption of cytokine signaling in T cells. This study defines the ability of leflunomide to prevent and reverse rejection of concordant xenografts. One hundred nine adult Lewis rats in 13 groups received abdominal heterotopic cardiac transplants from Golden Syrian hamsters. The xenograft survived 3.9 +/-0.3 days without treatment. When leflunomide was given at 2.5, 5, 10, 15, or 20 mg/kg by gavage daily, the cardiac xenograft survivals were 5.0 +/- 0.6, 8.0 +/- 3.0, 52.0 +/- 20.2, 76.5 +/- 21.14, and 58.9 +/- 28.1 days, respectively. The survival rates were 4.0 +/- 0 and 27.7 +/- 28.7 days when CsA was given at 10 and 20 mg/kg i.m., respectively. The combination of CsA at 10 mg/kg with leflunomide at 10 mg/kg or 5 mg/kg prolonged cardiac xenograft survival to 106.0 +/- 50.2 days and > 90 days, respectively. There were no observable side effects in the latter combination. Histologic studies of untreated graft hearts 4 days after transplantation revealed infarction of myocardium and severe RBC extravasation. In contrast, the rejected hamster hearts from long-term survivors showed massive mononuclear cell infiltration and myocardium fibrosis in contrast to the early rejected picture. Therapy with leflunomide begun on day 2 reversed these rejection responses by day 6. In addition, the increase in allospecific IgM titers observed on day 2 was reversed, and the allospecific IgM to IgG isotype switch that occurred in untreated animals was prevented by leflunomide. These observations demonstrate that leflunomide, at nontoxic doses, effectively controlled acute rejection of concordant xenografts and synergistic immunosuppressive effect was achieved with leflunomide and CsA.

Animals↗
PubMed1994

An evaluation of leflunomide in the canine renal transplantation model.

Leflunomide is an isoxazole with newly discovered immunosuppressive properties. Its mechanism of action operates later in the cell cycle than cyclosporine and appears to interfere with lymphocyte IL-2 responsiveness. With the encouraging results from in vitro and small-animal studies, we subjected leflunomide to the rigorous canine renal transplantation model in a dose response protocol. Thirty-eight female mongrel dogs underwent renal transplantation and bilateral nephrectomy. Immunosuppression was stratified from controls with no immunosuppression to monotherapy with leflunomide at 2, 4, 8, and 16 mg/kg/day given orally and in a combination therapy with cyclosporine. To evaluate its toxicity while maintaining a low constant blood level, eight dogs were treated by continuous intravenous infusion at doses of 2, 4, 6, and 8 mg/kg/day. The mean survival time for nonimmunosuppressed controls (n = 2) was 9 days, leflunomide 2 mg/kg/day (n = 2) was 9 days, leflunomide 4 mg/kg/day (n = 4) was 16 days, leflunomide 8 mg/kg/day (n = 5) was 28 days, leflunomide 16 mg/kg/day (n = 7) was 21 days. Cyclosporine alone at 10 mg/kg/day (n = 4) resulted in a mean survival time of 13 days. The mean survival time with the combination of cyclosporine 10 mg/kg/day with leflunomide 4 mg/kg/day (n = 6) was 68 days. The mean survival time for continuous intravenous leflunomide 2 mg/kg/day (n = 2) was 10 days; for leflunomide 4 mg/kg/day, 20 days; for leflunomide 6 mg/kg/day, 14 days; and leflunomide 8 mg/kg/day, 21 days. The mean serum trough levels of leflunomide ranged from 10 micrograms/ml at the 2 mg dose to 55 micrograms/ml for the 16 mg dose, levels that have been well tolerated in man. Leflunomide at 16 mg/kg/day reliably prevented acute allograft rejection, but the dogs died of inanition with normal renal function. Leflunomide at a nontoxic dose of 4 mg/kg/day extended survival to 16 days, but all dogs died of rejection. A combination of inadequate doses of leflunomide (4 mg/kg/day) and cyclosporine (10 mg/kg/day) resulted in all animals having normal renal function and weight for > or = 30 days. Even at a high dose of 16 mg/kg/day, no viral or bacterial infections were noted. These observations in a canine system add to the growing enthusiasm for the evaluation of leflunomide in human transplantation.

Administration, Oral↗
PubMed1994

Leflunomide in experimental transplantation. Control of rejection and alloantibody production, reversal of acute rejection, and interaction with cyclosporine.

Leflunomide is a compound recently shown to reduce T and B cell-mediated responses in a number of experimental rat, mouse, and human systems. To explore its potential as an immunosuppressant, we studied leflunomide in 128 Brown-Norway/Lewis cardiac transplants and in 48 unoperated Lewis rats. At doses ranging from 0.63 mg/kg to 10 mg/kg given for 7 days, leflunomide significantly prolonged graft survival compared with controls. When cyclosporine or leflunomide was given for 21 days at a dose of 5 mg/kg, indefinite graft survival occurred in 3/6 animals receiving leflunomide but in none of the 21-day cyclosporine-treated animals. When acute rejection was allowed to develop for four days in untreated rats, leflunomide but not cyclosporine reversed the rejection, returning histology to a normal appearance by seven days. Alloantibody responses measured in microcytoxicity assays as well as total allospecific IgG and IgM in the rejecting animals also were returned to baseline levels by leflunomide but not cyclosporine. When both drugs were used together, a synergistic effect was observed at low doses of both drugs. Pharmacokinetics studies showed that their combined use for up to 28 days did not affect the trough levels of cyclosporine or cyclosporine elimination, suggesting that the synergistic effect was not caused by reduced elimination. The toxicity of each drug was negligible in a group of 32 rats receiving the drugs alone or in combination as measured by serial observation of general appearance, testing of serum ALT, AST, bilirubin, creatinine, white blood cell counts, hemoglobin, and gross necropsy appearance. Weight gain was slightly reduced by both drugs but combined drug use did not alter the pattern. The results of these experiments show leflunomide to be a potent, well-tolerated immunosuppressant, synergistic in its activity with cyclosporine, and would seem to encourage a closer look at this drug for potential use in man.

Abdomen↗
PubMed1993

A study of endothelium-dependent proliferation of pulmonary smooth muscle cells in vitro.

The direct effect of hypoxia and the effect of hypoxic endothelial cells conditioned medium on cultured pulmonary arterial smooth muscle cells in vitro were studied with phase contrast in microscopy, 3H-thymidine labelled technique and flow cytometric measurements. The results showed that direct hypoxia inhibited proliferation of pulmonary arterial smooth muscle cells, retained pulmonary arterial smooth muscle cells in the Go/G1 phase and decreased 3H-thymidine incorporation into pulmonary arterial smooth muscle cells and that hypoxic endothelial cells conditioned medium stimulated proliferation of pulmonary arterial smooth muscle cells, promoted pulmonary arterial smooth muscle cells from G0/G1 phase to S phase and increased 3H-thymidine incorporation into pulmonary arterial smooth muscle cells. It was reasonable to believe that hypoxia might enable pulmonary arterial endothelial cells to secrete some growth factors which could stimulate proliferation of pulmonary arterial smooth muscle cells, thereby playing an important role in structural remodeling of the pulmonary arteries and in the development of hypoxic pulmonary hypertension.

Animals↗
PubMed1993

[The effect of hypoxic endothelial cells conditioned medium on the growth of pulmonary artery smooth muscle cells].

The effect of hypoxic endothelial cells conditioned medium (HECCM) on porcine pulmonary artery smooth muscle cells (PASMC) were studied with phase contrast microscopy, 3H-thymidine labelling technique and flow cytometric analysis. The results showed that HECCM could stimulate PASMC proliferation, by promoting the cells from G0/G1 phase into S phase, and increased 3H-thymidine incorporation. Direct hypoxic condition could inhibit cultured PASMC proliferation, and arrested them at the G0/G1 phase, accompanied with decrease of 3H-thymidine incorporation. Statistical significance was obtained between data of these two groups respectively (P < 0.01). It is believed that PAEC may be the target cell to hypoxic injury, and hypoxia may lead PAEC to secrete some growth factors in auto-or paracrine manner which is effective in promoting PASMC proliferation.

Animals↗