Biomedical subjects

Kimberly A Brown

Publications and source records attributed to Kimberly A Brown.

10 recordsLinked to original sources

PubMed2006

Loss of p63 leads to increased cell migration and up-regulation of genes involved in invasion and metastasis.

p63, a homologue of the tumor suppressor p53, is critical for the development and maintenance of squamous epithelia. p63 is specifically expressed in the basal layers of stratified epithelial tissues and is considered a specific marker for cells of this type. The role of p63 in tumorigenesis remains poorly defined. Numerous studies have highlighted the oncogenic potential of the predominant p63 isoform DeltaNp63alpha; however, data suggest that other p63 proteins can act as tumor suppressors or alter the metastatic potential of tumors. DeltaNp63alpha can act as a transcriptional repressor, but the link between the transcriptional functions of p63 and its biological role is still unclear. In this study, we used a loss-of-function approach to investigate the transcriptional programs controlled by p63. Disruption of p63 in squamous cell lines resulted in down-regulation of transcripts specifically expressed in squamous tissues and a significant alteration of keratinocyte differentiation. Interestingly, we found that disruption of p63 led to up-regulation of markers of nonepithelial tissues (mesenchyme and neural tissue) in both primary and immortalized squamous cells. Many of these up-regulated genes are associated with increased capacity for invasion and metastasis in tumors. Furthermore, loss of p63 expression was accompanied by a shift toward mesenchymal morphology and an increase in motility in primary keratinocytes and squamous cell lines. We conclude that loss of endogenous p63 expression results in up-regulation of genes associated with invasion and metastasis, and predisposes to a loss of epithelial and acquisition of mesenchymal characteristics. These findings have implications for the role of p63 in both development and tumorigenesis.

Carcinoma, Squamous Cell↗

PubMed2005

Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks.

Stromal fibroblasts regulate epithelial cell behavior through direct and indirect cell-cell interactions. To clarify the role of TGF-beta signaling in stromal fibroblasts during mammary development and tumorigenesis, we conditionally knocked out the TGF-beta type II receptor gene in mouse mammary fibroblasts (Tgfbr2(fspKO)). Tgfbr2(fspKO) mice exhibit defective mammary ductal development, characterized in part by increased ductal epithelial cell turnover associated with an increase in stromal fibroblast abundance. Tgfbr2(fspKO) mammary fibroblasts transplanted with mammary carcinoma cells promote growth and invasion, which is associated with increased activating phosphorylation of the receptors: erbB1, erbB2, RON, and c-Met. Furthermore, the increased receptor phosphorylation correlates with increased secretion of the cognate ligands by Tgfbr2(fspKO) fibroblasts. Treatment of tumor cells with fibroblast-conditioned medium leads to increased tumor cell proliferation and motility, which are blocked by addition of pharmacologic inhibitors of TGF-alpha signaling or neutralizing antibodies to macrophage-stimulating protein (MSP), HGF, or c-Met. These studies characterize a significant role for stromal TGF-beta signaling in mammary tissue homeostasis and mammary tumor progression via regulation of TGF-alpha, MSP, and HGF signaling pathways.

Animals↗

PubMed2005

Liver transplantation.

PURPOSE OF REVIEW: Liver transplantation continues to change as we further define appropriate criteria for allocation and utilization of this scarce resource. The following review highlights new trends and ideas in this evolving field. RECENT FINDINGS: Although the model for end-stage renal disease (MELD) scoring system appears to fairly accurately predict mortality while waiting for transplant, the system may be less accurate in predicting outcomes following transplantation. MELD scores offer an additional advantage to patients with hepatocellular carcinoma (HCC), bringing them to transplant sooner with overall better survivals. However, despite its advantages, the MELD scoring system does not resolve the disparity in the allocation of organs between various organ procurement organizations. Several variables appear to affect patients with hepatitis C undergoing liver transplantation. Selection of appropriate donors appears to be important when transplanting patients with hepatitis C virus (HCV) infection as increasing donor age is associated with poorer outcomes. However, the controversy over whether a living donor liver transplant (LDLT) results in poorer outcomes in HCV infected patients remains. Post-transplant medical treatment of HCV may result in both a sustained virologic response and improved histology. With improved overall survival in patients undergoing orthotopic liver transplant (OLT), increasing attention has been focused on the medical complications following transplant. Identifying specific contributing factors in the development of renal dysfunction and devising strategies to prevent its occurrence are critical to further improvements in outcome following OLT. SUMMARY: As the gap between patients and available organs remains, continued investigation into appropriate allocation and maximization of outcomes following liver transplant will continue.

Humans↗

PubMed2004

Induction by transforming growth factor-beta1 of epithelial to mesenchymal transition is a rare event in vitro.

INTRODUCTION: Transforming growth factor (TGF)-beta1 is proposed to inhibit the growth of epithelial cells in early tumorigenesis, and to promote tumor cell motility and invasion in the later stages of carcinogenesis through the induction of an epithelial to mesenchymal transition (EMT). EMT is a multistep process that is characterized by changes in cell morphology and dissociation of cell-cell contacts. Although there is growing interest in TGF-beta1-mediated EMT, the phenotype is limited to only a few murine cell lines and mouse models. METHODS: To identify alternative cell systems in which to study TGF-beta1-induced EMT, 18 human and mouse established cell lines and cultures of two human primary epithelial cell types were screened for TGF-beta1-induced EMT by analysis of cell morphology, and localization of zonula occludens-1, E-cadherin, and F-actin. Sensitivity to TGF-beta1 was also determined by [3H]thymidine incorporation, flow cytometry, phosphorylation of Smad2, and total levels of Smad2 and Smad3 in these cell lines and in six additional cancer cell lines. RESULTS: TGF-beta1 inhibited the growth of most nontransformed cells screened, but many of the cancer cell lines were insensitive to the growth inhibitory effects of TGF-beta1. In contrast, TGF-beta1 induced Smad2 phosphorylation in the majority of cell lines, including cell lines resistant to TGF-beta1-mediated cell cycle arrest. Of the cell lines screened only two underwent TGF-beta1-induced EMT. CONCLUSION: The results presented herein show that, although many cancer cell lines have lost sensitivity to the growth inhibitory effect of TGF-beta1, most show evidence of TGF-beta1 signal transduction, but only a few cell lines undergo TGF-beta1-mediated EMT.

Actins↗

PubMed2004

Transforming growth factor-beta induces Cdk2 relocalization to the cytoplasm coincident with dephosphorylation of retinoblastoma tumor suppressor protein.

BACKGROUND: The transforming growth factor-beta (TGF-beta) signaling pathway functions to prevent tumorigenesis, and loss of sensitivity to TGF-beta-mediated cell cycle arrest is nearly ubiquitous among human cancers. Our previous studies demonstrated that rapamycin potentiates TGF-beta-induced cell cycle arrest in nontransformed epithelial cells and partially restores TGF-beta-induced growth arrest of some human cancer cell lines. Growth arrest correlated with increased binding of p21 and p27 to cyclin-dependent kinase-2 (Cdk2), and inhibition of Cdk2 kinase activity. However, it was unclear how TGF-beta caused increased binding of p21 and p27 to Cdk2. METHODS: Cell fractionation and immunofluorescence microscopy experiments were performed to examine the effect of TGF-beta on the intracellular localization of Cdk2, p21, and p27. Kinase assays were performed on cytoplasmic and nuclear extracts to determine how TGF-beta altered Cdk2 activity in both subcellular compartments. RESULTS: In breast epithelial cells treatment with TGF-beta induced a decrease in nuclear Cdk2 concentrations and relocalization of Cdk2 to the cytoplasm. Cdk2 relocalization to the cytoplasm correlated with dephosphorylation of nuclear retinoblastoma tumor suppressor protein and decreased nuclear Cdk2 activity. In these epithelial cell lines, p21 and p27 were localized primarily in the cytoplasm. Decreases in nuclear Cdk2 concentrations correlated with increased binding of Cdk2 to cytoplasmic p21 and p27. CONCLUSION: Cooperative growth arrest induced by treatment with TGF-beta + rapamycin causes inhibition of nuclear Cdk2 activity through multiple mechanisms, including Cdk2 relocalization to the cytoplasm, increased p27 and p21 binding to Cdk2, and increased phosphorylation of nuclear Cdk2 on its inhibitory site, Tyr15.

Active Transport, Cell Nucleus↗

PubMed2004

Liver transplantation.

PURPOSE OF REVIEW: The field of liver transplantation continues to evolve. This review discusses the major themes of controversy and investigation over the past 12 months. RECENT FINDINGS: Organ allocation remains a major area of investigation and controversy in liver transplantation. The MELD system, which has been implemented since 2002, appears to adequately predict both death on the waiting list and short-term survival after OLT. However, regional variations in allocation remain despite this system. In an attempt to further increase available organs, living donor adult transplantation has gained interest. However, with continued high rates of reported complications and additional reports of donor deaths, interest has been tempered and more diligent evaluation of the ethics and techniques for this procedure have been sought. As more patients continue to survive for longer periods after OLT, medical complications from medications are now seen and require skillful management in these individuals. Recurrent viral disease after transplant remains a significant challenge as will the increasing need for retransplantation in these patients. SUMMARY: The review of the literature in liver transplantation continues to raise more issues than answer questions. It is likely that going into the future the key themes reviewed here will remain as further studies of larger patient populations will be required to more specifically identify "best practice" for care of these individuals.

Journal Article↗

PubMed2003

Liver transplantation.

Over the last 20 years dramatic improvements in liver transplantation have given children and adults a greater than 80% chance of long-term survival. The year 2002 marked a dramatic change in the system for allocating livers from a model based both on medical criteria (Child-Turcotte-Pugh) and waiting time to a system based solely on medical urgency model of end-stage liver disease (MELD). Further attempts to increase organ availability were seen in the continued increase in living donor transplants. Attention was directed both at recipient outcome and on morbidity and safety for the donor. Despite continued advances in the technical outcomes of liver transplantation, recurrent viral disease and malignancy remain major challenges.

Journal Article↗

PubMed2003

Functional analysis of inappropriate mealtime behaviors.

The purpose of the current investigation was to apply the functional analysis described by Iwata, Dorsey, Slifer, Bauman, and Richman (1982/1994) to the inappropriate mealtime behaviors of 15 children who had been referred to an intensive program for the assessment and treatment of severe feeding disorders. During Study 1, we conducted descriptive assessments of children and parents during meals. The results of Study 1 showed that parents used the following consequences for inappropriate mealtime behaviors: coaxing and reprimanding, allowing the child to periodically take a break from or avoid eating, and giving the child preferred food or toys following inappropriate behavior. The effects of these consequences were tested systematically in Study 2 when we conducted analogue functional analyses with the children. During alternating meals, one of the consequences typically used by parents consistently followed inappropriate child behavior. Results indicated that these consequences actually worsened behavior for 10 of the 15 children (67%). These results suggested that the analogue functional analysis described by Iwata et al. may be useful in identifying the environmental events that play a role in feeding disorders.

Behavior Therapy↗

PubMedDate not supplied

Impact of aberrant arterial anatomy and location of anastomosis on technical outcomes after liver transplantation.

Variations in donor and recipient arterial anatomy frequently present challenges for surgeons when attempting to establish proper arterial inflow during liver transplantation. We reviewed our data on 233 adult primary liver transplants, conducted from January 1996 through December 2001, to determine the impact of these variations on the outcomes after liver transplantation. Twenty-four (10.3%) arterial complications were encountered at a mean of 2.27 months after transplant. Carrel patches for the anastomoses were not used in 33 patients (14%), which had no relation to arterial complications (P = 0.7). Sixty-one donors (26.2%) had at least one aberrant artery, which had no relation to arterial complications. However, use of donor celiac artery for anastomosis was significantly associated with higher arterial complications (16% versus other choices, P = 0.03). Furthermore, use of common hepatic recipient artery was associated with higher arterial complications (16%, P = 0.03). There were 58 total biliary complications (24.8%). Biliary complications were associated with the presence of arterial complications (P = 0.01). In conclusion, aberrant donor arterial anatomy was not associated with an increased rate of arterial complications; however, choice of location of arterial anastomosis may be a significant factor. Biliary complications were associated with arterial complications.

Adult↗

PubMedDate not supplied

Activation of the Erk pathway is required for TGF-beta1-induced EMT in vitro.

Transforming growth factor-beta1 (TGF-beta1) can be tumor-suppressive through the activation of the Smad-mediated signaling pathway. TGF-beta1 can also enhance tumor progression by stimulating epithelial-to-mesenchymal transition (EMT) through additional pathways. EMT is characterized by the acquisition of a fibroblast-like cell morphology, dissolution of tight junctions, disruption of adherence junctions, and formation of actin stress fibers. There is evidence linking the activation of mitogen-activated protein kinase pathways to the induction of TGF-beta1-mediated EMT. However, the role of Erk in the induction of TGF-beta1-mediated EMT remains unclear. TGF-beta1 treatment of normal murine mammary gland (NMuMG) epithelial cells resulted in increased gene expression of Ras, Raf, MEK1/2, and Erk1/2, as shown by microarray analysis and real-time polymerase chain reaction. Upon 24 and 48 hours of treatment with TGF-beta1, NMuMG and mouse cortical tubule (MCT) epithelial cells underwent EMT as shown by changes in cell morphology, delocalization of zonula occludens-1 and E-cadherin from cell-cell junctions, and formation of actin stress fibers. TGF-beta1 treatment also resulted in increased levels of phosphorylated Erk and Erk kinase activity. Treatment with an MEK inhibitor, U0126, inhibited increased Erk phosphorylation and kinase activity, and blocked TGF-beta1-induced EMT in both cell lines. These data show that TGF-beta1 induces the activation of the Erk signaling pathway, which is required for TGF-beta1-mediated EMT in vitro.

Animals↗