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Biomedical subjects

J S Koh

Publications and source records attributed to J S Koh.

35 records · Page 2Linked to original sources
PubMed1998

Induction of anti-phospholipid autoantibodies by beta2-glycoprotein I bound to apoptotic thymocytes.

The target of many anti-phospholipid autoantibodies (aPL) has been shown to be a complex between anionic phospholipid and the plasma protein beta2-glycoprotein I (beta2GPI) or the protein beta2GPI alone. As aPL binding studies have been performed almost exclusively in vitrothe identity of the natural target and/or immunogen for aPL in vivo remains undetermined. The anionic phospholipids of cell membranes represent an important potential target and immunogen for aPL. Although anionic phospholipids are normally absent from the extracellular surface of cell membranes, they redistribute from the inner to the outer leaflet during apoptosis. We have previously shown that beta2GPI binds selectively to the surface of apoptotic, but not viable, cells, and that binding of beta2GPI to the surface of apoptotic cells generates an epitope recognized by aPL from patients with primary aPL syndrome and systemic lupus erythematosus. We show here that immunization of non-autoimmune mice with beta2GPI combined with, or bound to, apoptotic cells induces aPL and lupus anticoagulant activity. Generation of aPL required heterologous beta2GPI, and occurred upon immunization with apoptotic cells and beta2GPI by three different routes of administration. Importantly, for intravenous immuniz-ations, generation of aPL occurred only when apoptotic cells and beta2GPI were injected together, but not when either was injected alone, suggesting that cell-bound beta2GPI is the true immunogen for production of aPL. Unlike other models of induced aPL, adjuvant was not an absolute requirement. Induced aPL reacted with murine, as well as bovine, beta2GPI, suggesting that heterologous beta2GPI bound to apoptotic cells can break tolerance and induce auto-antibodies reactive with autologous beta2GPI. Combined with our previous data, these results show that apoptotic cells can serve as both immunogens and natural targets for aPL.

Animals↗
PubMed1998

Role of superoxide in apoptosis induced by growth factor withdrawal.

We have examined the role of reactive oxygen species (ROS) in apoptosis induced by growth factor deprivation in primary cultures of mouse proximal tubular (MPT) cells. When confluent monolayers of MPT cells are deprived of all growth factors, the cells die by apoptosis over a 10- and 14-day period. Both epidermal growth factor (EGF) and high-dose insulin directly inhibit apoptosis of MPT cells deprived of growth factors. Growth factor deprivation results in an increase in the cellular levels of superoxide anion while apoptosis of MPT cells induced by growth factor withdrawal is inhibited by a number of antioxidants and scavengers of ROS. Growth factor deprivation also results in activation of caspase activity, which is inhibited by EGF and high-dose insulin as well as by the ROS scavengers and antioxidants that inhibit apoptosis. The cell-permeant caspase inhibitor, z-Val-Ala-Asp-CH2F (zVAD-fmk), prevents the increase in caspase activity and markedly inhibits apoptosis induced by growth factor deprivation. However, zVAD-fmk had no effect on the increased levels of superoxide associated with growth factor deprivation. Thus we provide novel evidence that ROS play an important role in mediating apoptosis associated with growth factor deprivation. ROS appear to act upstream of caspases in the apoptotic pathway. We hypothesize that oxidant stress, induced by growth factor withdrawal, represents a signaling mechanism for the default pathway of apoptosis.

Amino Acid Chloromethyl Ketones↗
PubMed1998

Necrosis and apoptosis in acute renal failure.

Renal tubular cells that are lethally injured after an acute ischemic or nephrotoxic insult to the kidney can die by necrosis or apoptosis. Necrosis is usually the result of overwhelming and severe cellular ATP depletion. In contrast, there are many potential causes of apoptosis in acute renal failure (ARF). These include cytotoxic events not severe enough to induce necrosis, a relative deficiency of renal growth factors, and loss of cell-matrix or cell-cell adhesive interactions. In some situations, receptor-mediated events induced by tumor necrosis factor-alpha (TNF-alpha) or Fas (CD95) may play a role in apoptosis in ARF. Necrosis and apoptosis are distinct morphologically and biochemically. Necrosis results in an early loss of plasma membrane integrity, the release of injurious substances from the cytosol, and an inflammatory reaction in the surrounding tissue that is readily detected morphologically. In contrast, apoptosis is characterized by progressive cell shrinkage with condensation and fragmentation of nuclear chromatin. Apoptotic cells ultimately break up into plasma membrane-bound vesicles called "apoptotic bodies" that are rapidly phagocytosed by macrophages and neighboring epithelial cells. In experimental models of ARF in vivo, apoptosis of renal tubular cells has been shown to occur in two distinct phases. The first phase of apoptosis occurs early on, between 12 and 48 hours after the acute ischemic or nephrotoxic insult. The second phase of apoptosis occurs many days later, during the recovery phase of ARF. Tubular cell apoptosis occurring shortly after the acute insult probably contributes to tubular cell loss and the tubular dysfunction associated with ARF. In contrast, the apoptosis associated with the recovery phase has been postulated to contribute to the remodeling of injured tubules and to facilitate their return to a normal structural and functional state. Therapeutic interventions that inhibit or promote apoptosis of renal tubular cells have the potential for minimizing renal dysfunction and accelerating recovery after ARF.

Acute Kidney Injury↗
PubMed1998

Idiopathic retroperitoneal fibrosis with bilateral lower ureteric obstruction--a case report with literature review.

Whilst prostatic enlargement remains the commonest cause of bilateral hydronephrosis in males greater than 50 years of age, other rarer conditions such as retroperitoneal fibrosis should be borne in mind. We report a case of bilateral hydronephrosis which was eventually diagnosed as idiopathic retroperitoneal fibrosis and treated with open surgical ureterolysis with omental wrapping.

Aged↗
PubMed1997

Apoptosis and autoimmunity.

Apoptotic cell antigens have been identified increasingly as the targets of autoantibodies in autoimmune diseases such as systemic lupus erythematosus. This review examines evidence supporting the hypothesis that apoptotic cells are a primary source of immunogen in lupus, as well as potential mechanisms by which tolerance to apoptotic cells may break down.

Animals↗
PubMed1997

Lysophosphatidic acid: a novel growth and survival factor for renal proximal tubular cells.

Lysophosphatidic acid (LPA) is the smallest and structurally simplest of all glycerophospholipids. LPA is a normal constituent of serum and binds with high affinity to albumin while retaining its biological activity. The effects of LPA are pleiotropic and range from mitogenesis to stress fiber formation. In this report, we demonstrate two novel functions for LPA. LPA acts as a survival factor to inhibit apoptosis of primary cultures of mouse renal proximal tubular (MPT) cells. LPA also acts as a potent mitogen for MPT cells. The ability of LPA to act as both a survival factor and a mitogen is mediated by the lipid kinase phosphatidylinositol 3-kinase (PI3K), since these activities were completely blocked by wortmannin or LY-294002, two structurally dissimilar inhibitors of PI3K. The identification of LPA as a proliferative and anti-apoptotic factor suggests a potential role for this lipid mediator during the injury and/or recovery phases following tubular damage.

Animals↗
PubMed1996

Antineutrophil cytoplasmic autoantibodies interact with primary granule constituents on the surface of apoptotic neutrophils in the absence of neutrophil priming.

The pathogenic role of antineutrophil cytoplasmic autoantibodies (ANCA) remains controversial because of the difficulty in explaining how extracellular ANCA can interact with intracellular primary granule constituents. It has been postulated that cytokine priming of neutrophils (PMN), as may occur during a prodromal infection, is an important trigger for mobilization of granules to the cell surface, where they may interact with ANCA. We show by electron microscopy that apoptosis of unprimed PMN is also associated with the translocation of cytoplasmic granules to the cell surface and alignment just beneath an intact cell membrane. Immunofluorescent microscopy and FACS analysis demonstrate reactivity of ANCA-positive sera and antimyeloperoxidase antibodies with apoptotic PMN, but not with viable PMN. Moreover, we show that apoptotic PMN may be divided into two subsets, based on the presence or absence of granular translocation, and that surface immunogold labeling of myeloperoxidase occurs only in the subset of PMN showing translocation. These results provide a novel mechanism that is independent of priming, by which ANCA may gain access to PMN granule components during ANCA-associated vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1996

Anti-phospholipid autoantibodies bind to apoptotic, but not viable, thymocytes in a beta 2-glycoprotein I-dependent manner.

Anti-phospholipid autoantibodies (aPL) are associated with a clinical syndrome of hypercoagulability, thrombocytopenia, and fetal loss. Several groups have shown that the in vitro target of many aPL is not a pure phospholipid Ag, but is either a complex between anionic phospholipid and the plasma protein beta2-glycoprotein I (beta 2GPI) or the protein beta 2GPI alone. Anionic phospholipids are normally absent from the extracellular surface of cell membranes but redistribute from the inner to the outer leaflet during apoptosis. We show that aPL bind specifically to apoptotic, but not viable, thymocytes, and that binding is dependent upon the presence of beta 2GPI. Moreover, we show that beta 2GPI binds selectively to the surface of apoptotic thymocytes to generate an epitope for antiphospholipid autoantibodies. These findings suggest that apoptotic cells may be the natural immunogen and/or target for aPL. Moreover, we propose that the interaction of circulating beta 2GPI with redistributed anionic phospholipid may itself generate a novel ligand by which apoptotic cells are recognized directly for phagocytic clearance.

Adsorption↗
PubMed1996

Dysregulated cytokine expression in vivo in prediseased and diseased autoimmune-prone MRL mice.

Macrophages (mø) from prediseased autoimmune-prone MRL/ + and MRL/lpr mice produce markedly decreased levels of IL-1 in vitro in response to LPS. In contrast, tissues from diseased MRL/lpr mice overexpress IL-1 in vivo. To determine whether IL-1 underproduction in the MRL strains is solely an in vitro phenomenon, we compared in vivo cytokine mRNA expression from prediseased age-matched MRL/ + and MRL/lpr mice to that from normal BALB/c and C3HeB/FeJ mice. Like mø in vitro, whole organ RNA from the spleen, liver, and kidney of MRL/ + and MRL/lpr mice showed down-regulation of IL-1 RNA following intraperitoneal injection of LPS. This abnormality in inducible IL-1 expression was present in all MRL mice, irrespective of disease stage or the presence of the lpr gene. On the other hand, only diseased MRL/lpr mice displayed elevated and constitutive expression of IL-1 in their livers and kidneys. We suggest that inducible expression is most indicative of the intrinsic, or genetic, capacity of cells to produce cytokine, whereas constitutive expression reflects extracellular disease-related inflammatory stimuli present only in the diseased MRL/lpr strains. By restricting our studies to prediseased MRL mice, we have tried to eliminate the effects of disease and to focus on the predisposing genetic background. The existence both in vitro and in vivo of a defect in inducible IL-1 expression by prediseased MRL mice suggests that the molecular abnormality underlying this defect may be a part of this predisposing background to autoimmunity.

Animals↗
PubMed1993

Thymic carcinoid tumor combined with thymoma--neuroendocrine differentiation in thymoma?

A carcinoid tumor of the thymus combined with thymoma in a 62-year-old man is described. The mediastinal tumor had been present for 13 years and was associated with pure red cell aplasia. Carcinoid tumor occupied the central two-thirds of the tumor, consisting of nests and trabeculae of monotonous round cells, which ultrastructurally showed many intracytoplasmic dense-core granules. Typical spindle cell type thymoma surrounded the carcinoid area. Clinico-pathologic findings of this unique case suggested that the carcinoid tumor developed within a preexisting thymoma, illustrating a possibility of neuroendocrine differentiation of thymic epithelial cells.

Carcinoid Tumor↗
PubMedDate not supplied

Solid phase synthesis of benzamidine and butylamine-derived hydantoin libraries.

We have constructed a number of benzamidine- and butylamine-based hydantoin compounds by means of an efficient route using solid phase synthesis in which neat diisopropylamine was employed for a novel cyclization/traceless cleavage step. All library compounds were obtained in excellent yield and high purity.

Benzamidines↗
PubMedDate not supplied

Chondrosarcoma of the proximal femur with myxoid degeneration mistaken for chondromyxoid fibroma in a young adult. A case report.

BACKGROUND: Fine needle aspiration cytology (FNAC) is effective in the diagnosis of bone tumors when combined with careful radiologic and clinical evaluation. However, cases where clinical or radiologic findings are atypical or unusual may lead to an erroneous diagnosis. CASE: A 19-year-old male presented with a pain in the left hip area that had been slowly progressive over a 10-month period. Clinical and radiologic findings suggested either giant cell tumor or chondroblastoma. The smeared aspiration specimen showed loosely cohesive, oval to round cells with moderate amounts of pale pink cytoplasm admixed with pinkish-blue, chondromyxoid material. The individual cells contained a single nucleus with evenly distributed, fine chromatin. A few osteoclastic giant cells were scattered in the smears. A cytologic diagnosis of myxoid lesion with a few giant cells, suspicious for chondromyxoid fibroma, was made. The diagnosis of chondrosarcoma was made by subsequent histologic examination. CONCLUSION: Absence of the usual clinicoradiologic features of chondrosarcoma combined with an unusual cytologic presentation in this case led to a misdiagnosis. In most centers, FNAC has achieved undisputed status as a diagnostic tool, and cytologic diagnosis often forms the basis of the therapeutic protocol. However, at some sites FNAC diagnosis is more problematic. Awareness of the limitations and pitfalls of FNAC is just as important as knowledge of the scope of FNAC in bone tumors. Tumors with chondromyxoid features provide particular difficulties.

Adult↗
PubMedDate not supplied

Fine needle aspiration cytology of late-stage callus in stress fracture. A case report.

BACKGROUND: Fine needle aspiration cytology (FNAC) is effective in the diagnosis of bone lesions when combined with careful radiologic and clinical evaluation. The cytologic features of callus have not been described before in the English-language literature. CASE: An 18-year-old female presented with a pain in the right lower leg that had been present for two months. Clinical and radiologic findings suggested either stress fracture or periosteal osteosarcoma. The aspiration specimen showed individually scattered, oval cells with moderate amounts of pale pink cytoplasm. The cells contained a single eccentrically located nucleus with evenly distributed, fine chromatin. Osteoclastic giant cells were scattered in the smears. A cytologic diagnosis of benign bone-forming lesion, compatible with callus in fracture, was made. The diagnosis of late-stage callus was confirmed by subsequent histologic examination. CONCLUSION: Typical cases of stress fracture do not need histologic examination, but some cases may be confused with benign and malignant bone tumors. The typical and unique cytologic features of late-stage callus combined with clinical and radiologic findings may prevent the use of more invasive diagnostic procedures and can be a choice for management.

Adolescent↗
PubMedDate not supplied

Glassy cell carcinoma of the uterine cervix. Cytologic features and expression of estrogen and progesterone receptors.

OBJECTIVE: To identify the cytomorphologic features and investigate the expression of estrogen receptor (ER) and progesterone receptor (PR) in glassy cell carcinoma (GCC) of the uterine cervix. STUDY DESIGN: A retrospective analysis of nine GCCs encountered at Korea Cancer Center Hospital between January 1990 and April 1999 was undertaken. The cervical smears were obtained prior to histologic diagnosis of GCC. The cytomorphologic and clinical features were reviewed, and the expression of ER and PR was investigated immunohistochemically on histologic sections. RESULTS: Smears of GCC were hypercellular and remarkably cohesive. The tumor cells were large and characterized by abundant granular cytoplasm, distinct cell membranes and round to polygonal, large nuclei with prominent nucleoli. In the background tumor diathesis and numerous inflammatory cells containing eosinophils were present. The inflammatory cells (mainly eosinophils) were intimately associated with tumor cells to form "granuloepithelial complex." Immunohistochemically, ER was identified in two of the nine cases and PR in one of them. CONCLUSION: Cytology of GCC has characteristic features that differ from those of other carcinomas or atypical reparative cells. Although there are deceptive mimics of GCC, the characteristic cytologic findings should prompt a diagnosis of GCC. ER and PR positivity was found in two cases (22%) and one case (11%), respectively, of GCC, suggesting that this tumor might be hormonally responsive.

Adult↗
PubMedDate not supplied

Overexpression of p53 and rare genetic mutation in mesenchymal chondrosarcoma.

Mesenchymal chondrosarcoma is extremely rare and accounts for less than 2% of all chondrosarcomas. The pathogenesis and the molecular genetic events which contribute to the development of mesenchymal chondrosarcoma are not well elucidated, due in part to the lack of sufficient tumor tissue available. To characterize the involvement of the p53 gene abnormality in this disease, we analyzed expression and sequence alteration of p53 by immunohistochemical analysis of the protein expression and quantitative DNA/PCR and PCR-SSCP assays of the gene in 33 paraffin-embedded tissue specimens. Immunohistochemical analysis demonstrated that 19 (61.3%) of 31 had nuclear overexpression of p53 while 7 (22.6%) showed cytoplasmic expression. The remaining 5 (16.1%) were negative for p53 staining. The nuclear positivity of p53 was observed within a range of 22-64% (mean 37.3%) of tumor cells and showed a positive staining in mesenchymal components as well as chondroid components. Quantitative DNA/PCR analysis revealed that 6 (18.2%) of the 33 specimens carried significantly reduced or undetectably low levels of p53 indicating the genomic deletion of the gene in these tumors. In contrast, however, DNA/PCR-SSCP analysis failed to detect any types of mutations resulting in amino acid substitution within exons 5-9 regions of the gene. Taken together, our data suggests that genetic alteration of p53 is a relatively rare event in mesenchymal chondrosarcomas but substantial fraction of this type of tumors carries abnormal overexpression of p53, which might result from as yet unidentified epigenetic mechanism(s).

Chondrosarcoma, Mesenchymal↗