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Edwina S Baskin-Bey

Publications and source records attributed to Edwina S Baskin-Bey.

10 recordsLinked to original sources
PubMed2006

Improving utilization of deceased donor kidneys by matching recipient and graft survival.

Younger renal transplant recipients often outlive their allografts, whereas older recipients often die before their allograft fails. Thus, our aim was to assess the utility of matching recipient and graft survival to improve allocation of deceased donor kidneys. We reviewed the records of 49,206 patients (United Network for Organ Sharing, 1995-2002). Donor grafts were stratified by Deceased Donor Score (DDS). We observed a disparity between recipient survival and renal graft survival which contributed to an annual gap between supply and demand of renal transplants. Utilization of DDS and distribution of marginal kidneys to older recipients would improve allocation.

Adolescent↗
PubMed2006

Proteasome inhibition attenuates hepatic injury in the bile duct-ligated mouse.

Proteasome inhibition has recently been demonstrated to inhibit hepatic fibrogenesis in the bile duct-ligated (BDL) mouse by blocking stellate cell NF-kappaB activation. The effect of proteasome inhibition on liver injury, however, is unclear. Our aims were to assess the effect of the proteasome inhibitor bortezomib on liver injury in the BDL mouse. Liver injury was assessed in 7-day BDL mice treated with a single dose of bortezomib on day 4 after bile duct ligation. Despite NF-kappaB inhibition by bortezomib, liver injury and hepatocyte apoptosis were reduced in treated BDL mice. The antiapoptotic effect of bortezomib was likely mediated by an increase in hepatic cellular FLICE inhibitory protein (c-FLIP) levels, a potent antiapoptotic protein. Unexpectedly, numerous mitotic hepatocytes were observed in the bortezomib-treated BDL mice liver specimens. Consistent with this observation, PCNA immunoreactivity and cyclin A protein expression were also increased with bortezomib treatment. Bortezomib therapy was also associated with a decrease in numbers and activation of Kupffer cells/macrophages. In conclusion, these data suggest that the proteasome inhibitor bortezomib reduces hepatocyte injury in the BDL mouse by mechanisms associated with a reduction in hepatocyte apoptosis, a decrease in Kupffer cell/macrophage number and activation, and increased hepatocyte proliferation.

Animals↗
PubMed2006

Proteasome inhibition induces hepatic stellate cell apoptosis.

Induction of hepatic stellate cell (HSC) apoptosis attenuates hepatic fibrosis, and, therefore, mechanisms to induce HSC cell death are of therapeutic interest. Proteasome inhibitors induce apoptosis in transformed cells, especially those cells dependent upon nuclear factor kappa B (NF-kappaB) activation. Because stimulated HSCs also trigger NF-kappaB activation, the aim of this study was to determine if proteasome inhibitors induce HSC apoptosis. The immortalized human HSC line, LX-2, and primary rat HSCs were treated with the proteasome inhibitors bortezomib and MG132. Both proteasome inhibitors induced HSC apoptosis. Proteasome inhibition blocked NF-kappaB activation and, more importantly, NF-kappaB inhibition by Bay11-7082-triggered HSC apoptosis. Activated HSC survival is dependent upon the NF-kappaB target gene A1, an anti-apoptotic Bcl-2 family member, as siRNA targeted knockdown of A1-induced HSC apoptosis. In contrast, proteasome inhibition-induced alterations in TRAIL, death receptor 5, and Bim could not be implicated in the apoptotic response. The relevance of these findings was confirmed in the bile-duct-ligated mouse where bortezomib reduced hepatic markers of stellate cell activation and fibrosis. In conclusion, proteasome inhibition is a potential therapeutic strategy for inducing HSC apoptosis and inhibiting liver fibrogenesis.

Animals↗
PubMed2006

Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteins.

The constitutive androstane receptor (CAR) modulates xeno- and endobiotic hepatotoxicity by regulating detoxification pathways. Whether activation of CAR may also protect against liver injury by directly blocking apoptosis is unknown. To address this question, CAR wild-type (CAR+/+) and CAR knockout (CAR-/-) mice were treated with the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) and then with the Fas agonist Jo2 or with concanavalin A (ConA). Following the administration of Jo2, hepatocyte apoptosis, liver injury, and animal fatalities were abated in TCPOBOP-treated CAR+/+ but not in CAR-/- mice. Likewise, acute and chronic ConA-mediated liver injury and fibrosis were also reduced in wild-type versus CAR(-/-) TCPOBOP-treated mice. The proapoptotic proteins Bak (Bcl-2 antagonistic killer) and Bax (Bcl-2-associated X protein) were depleted in livers from TCPOBOP-treated CAR+/+ mice. In contrast, mRNA expression of the antiapoptotic effector myeloid cell leukemia factor-1 (Mcl-1) was increased fourfold. Mcl-1 promoter activity was increased by transfection with CAR and administration of TCPOBOP in hepatoma cells, consistent with a direct CAR effect on Mcl-1 transcription. Indeed, site-directed mutagenesis of a putative CAR consensus binding sequence on the Mcl-1 promoter decreased Mcl-1 promoter activity. Mcl-1 transgenic animals demonstrated little to no acute liver injury after administration of Jo2, signifying Mcl-1 cytoprotection. In conclusion, these observations support a prominent role for CAR cytoprotection against Fas-mediated hepatocyte injury via a mechanism involving upregulation of Mcl-1 and, likely, downregulation of Bax and Bak.

Animals↗
PubMed2006

Liver transplantation for gastroenteropancreatic neuroendocrine cancers: Defining selection criteria to improve survival.

Liver transplantation for gastroenteropancreatic neuroendocrine cancer (GEP) is controversial. The aim of this study was to assess patient outcomes after liver transplantation for hepatic metastases from GEP. Medical records of patients who underwent liver transplantation for GEP were reviewed. Immunohistochemistry for assessing the Ki67 proliferation index was performed on explanted liver tissue. Nineteen patients who underwent liver transplantation had a mean follow-up of 22 months with a range of 0 to 84 months. There was 1 intraoperative death, and 3 patients had disease recurrence after liver transplantation leading to death in 1 patient. Overall estimated 1-year survival for 17 patients included in the treatment protocol (mean follow-up, 15 months) was 87% with an estimated 1-year recurrence-free rate (conditional on survival) of 77%. Three of 11 patients with pancreatic islet cell GEP developed disease recurrence, whereas all 8 patients with carcinoid GEP remain free of disease. Analysis of the Ki67 proliferation index in 18 patients did not differentiate those with recurrence from those without disease recurrence. In conclusion, liver transplantation for patients with hepatic metastases from GEP is a viable therapeutic option in highly selected patients.

Adult↗
PubMed2005

Improving the prediction of donor kidney quality: deceased donor score and resistive indices.

BACKGROUND: The deceased donor score (DDS), expanded criteria donor (ECD) definition, and resistive index (RI) were developed for pretransplant evaluation of donors. DDS and ECD are determined by a calculation of risk from donor variables, while RI is determined from flow characteristics of kidneys during machine preservation (MP). This study was designed to compare DDS, ECD status, and RI as predictors of outcome after deceased donor transplantation. We were also interested to see if DDS or ECD could identify kidneys most likely to benefit from MP. METHODS: We retrospectively reviewed 48,952 deceased donor renal transplants reported to UNOS from 1997-2002. DDS (0-39 pts.), ECD status (+ or -), and preservation technique (MP vs. cold storage [CS]) were determined in all cases. RI during MP was studied in a single-center cohort of 425 transplants. RESULTS: DDS was superior to ECD status and RI in its correlation with early and late renal function after transplantation. DDS identified a subgroup of ECD- kidneys, those with DDS > or = 20 pts, that functioned significantly below expectation and similar to ECD+ kidneys. Benefits of MP, which include improved early graft function and a trend towards longer graft survival, were greatest in the group of kidneys with DDS > or = 20 pts. CONCLUSIONS: DDS was the best predictor of outcome after deceased donor renal transplantation and may be useful in identifying kidneys most likely to benefit from MP.

Cadaver↗
PubMed2005

United Network for Organ Sharing's expanded criteria donors: is stratification useful?

The United Network for Organ Sharing (UNOS) Expanded Criteria Donor (ECD) system utilizes pre-transplant variables to identify deceased donor kidneys with an increased risk of graft loss. The aim of this study was to compare the ECD system with a quantitative approach, the deceased donor score (DDS), in predicting outcome after kidney transplantation. We retrospectively reviewed 49 111 deceased donor renal transplants from the UNOS database between 1984 and 2002. DDS: 0-39 points; >or=20 points defined as marginal. Recipient outcome variables were analyzed by ANOVA or Kaplan-Meier method. There was a 90% agreement between the DDS and ECD systems as predictors of renal function and graft survival. However, DDS identified ECD- kidneys (10.7%) with a significantly poorer outcome than expected (DDS 20-29 points, n = 5,252). Stratification of ECD+ kidneys identified a group with the poorest outcome (DDS >or=30 points). Predictability of early post-transplant events (i.e. need for hemodialysis, decline of serum creatinine and length of hospital stay) was also improved by DDS. DDS predicted outcome of deceased donor renal transplantation better than the ECD system. Knowledge obtained by stratification of deceased donor kidneys can allow for improved utilization of marginal kidneys which is not achieved by the UNOS ECD definition alone.

Adult↗
PubMedDate not supplied

Surgical triune.

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Adult↗