Biomedical subjects

Eugene Y Koh

Publications and source records attributed to Eugene Y Koh.

6 recordsLinked to original sources

PubMed2006

Tibial nonunion.

Nonunions of the tibia represent challenging orthopedic problems, which require the surgeon to analyze numerous factors and choose an appropriate treatment. Tibial nonunion treatment requires establishing its existence and cause. The treatment algorithm necessitates consideration of a wide variety of factors: the location of the nonunion, the presence or absence of infection, and any angular or rotational deformity. Given advances in implant design and biologic agents, a wide variety of management options exist for the treatment of tibial nonunions. This article reviews surgical treatments for tibial nonunions.

Fracture Fixation↗

PubMed2006

Tibial malunion.

Tibial malunion, a fracture healed in a position that affects the mechanical function of the limb, can be difficult to assess and to correct surgically. Precise definition of malunion has yet to be determined, and the limits of deformity which are associated with arthritic change also remain imprecise. Surgical intervention is therefore primarily indicated in symptomatic patients or those with relatively severe deformity. The several described techniques for correction of tibial malunion can achieve excellent results, although the surgery is not without substantial risk and recovery time. These issues should be discussed at length with patients before surgery.

Fracture Fixation↗

PubMed2004

A cytoskeleton-based functional genetic screen identifies Bcl-xL as an enhancer of metastasis, but not primary tumor growth.

Many mouse models of breast cancer form large primary tumors that rarely metastasize. Models with aggressive metastasis express oncoproteins that simultaneously affect growth and apoptosis pathways. To define the role of apoptotic resistance and to model a challenge faced by tumor cells during metastatic dissemination, we focused on apoptosis induced by cell shape change. Inhibiting actin polymerization with Latrunculin-A causes cell rounding and death within hours in nontumorigenic human 10A-Ras mammary epithelial cells. In contrast, MDA-MB-231 metastatic breast tumor cells resist LA-induced death, and survive for days despite cell rounding. Infecting 10A-Ras cells with a MDA-MB-231 retroviral expression library, and selecting with Latrunculin-A repeatedly identified Bcl-xL as a suppressor of cytoskeleton-dependent death. Although Bcl-xL enhances the spread of metastatic breast tumor cell lines, the distinct effects of apoptotic resistance on tumor growth in the mammary gland and during metastasis have not been compared directly. We find that Bcl-xL overexpression in mouse mammary epithelial cells does not induce primary tumor formation or enhance MEK-induced tumorigenesis within the mammary gland environment. However, it strongly enhances metastatic potential. These results with Bcl-xL provide novel evidence that isolated apoptotic resistance can increase metastatic potential, but remain overlooked by assays based on breast tumor growth.

Animals↗

PubMed2004

Genetic complementation of cytokine signaling identifies central role of kinases in hematopoietic cell proliferation.

Molecular evidence suggests a multistep process in the development of acute leukemia. Since inappropriate activation of cytokine signaling cascades is a recurring theme in human leukemia, we performed expression screens to identify genes that transform cytokine-dependent cells. Using retroviral cDNA libraries derived from peripheral blood mononuclear cells of patients with myeloproliferative disorders, we isolated numerous genes that genetically complement cytokine requirements for proliferation of BaF/3 and TF-1 cells. The majority of recovered genes represent members of the kinase family, including several previously linked to leukemogenesis. Our unbiased screen highlights the central role of kinase activation in hematopoietic cell proliferation and identifies a number of potential leukemic oncoproteins.

Animals↗

PubMed2002

Novel retroviral vectors to facilitate expression screens in mammalian cells.

As tools for functional genomics, expression profiling and proteomics provide correlative data, while expression cloning screens can link genes directly to biological function. However, technical limitations of gene transfer, expression, and recovery of candidate genes have limited wider application of genome-wide expression screens. Here we describe the pEYK retroviral vectors, which maintain high titers and robust gene expression while addressing the major bottleneck of expression cloning--efficient candidate gene recovery. By exploiting schemes for enhanced PCR rescue or strategies for direct isolation of proviral DNA as plasmids in bacterial hosts, the pEYK vectors facilitate cDNA isolation from selected cells and enable rapid iteration of screens and genetic reversion analyses to validate gene candidates. These vectors have proven useful to identify genes linked to cell proliferation, senescence and apoptosis.

Animals↗

PubMed2002

A functional screen identifies hDRIL1 as an oncogene that rescues RAS-induced senescence.

Primary fibroblasts respond to activated H-RAS(V12) by undergoing premature arrest, which resembles replicative senescence. This irreversible 'fail-safe mechanism' requires p19(ARF), p53 and the Retinoblastoma (Rb) family: upon their disruption, RAS(V12)-expressing cells fail to undergo senescence and continue to proliferate. Similarly, co-expression of oncogenes such as c-MYC or E1A rescues RAS(V12)-induced senescence. To identify novel genes that allow escape from RAS(V12)-induced senescence, we designed an unbiased, retroviral complementary DNA library screen. We report on the identification of DRIL1, the human orthologue of the mouse Bright and Drosophila dead ringer transcriptional regulators. DRIL1 renders primary murine fibroblasts unresponsive to RAS(V12)-induced anti-proliferative signalling by p19(ARF)/p53/p21(CIP1), as well as by p16(INK4a). In this way, DRIL1 not only rescues RAS(V12)-induced senescence but also causes these fibroblasts to become highly oncogenic. Furthermore, DRIL1 immortalizes mouse fibroblasts, in the presence of high levels of p16(INK4a). Immortalization by DRIL1, whose product binds the pRB-controlled transcription factor E2F1 (ref. 8), is correlated with induction of E2F1 activity. Correspondingly, DRIL1 induces the E2F1 target Cyclin E1, overexpression of which is sufficient to trigger escape from senescence. Thus, DRIL1 disrupts cellular protection against RAS(V12)-induced proliferation downstream of the p19(ARF)/p53 pathway.

Animals↗