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Biomedical subjects

S C Shih

Publications and source records attributed to S C Shih.

At least 19 recordsLinked to original sources
PubMed2001

Fibroblast growth factor 2 activation of stromal cell vascular endothelial growth factor expression and angiogenesis.

Angiogenesis is a key component of human cancer progression and metastasis. In an effort to recapitulate early events in tumor-induced angiogenesis, we have employed a subcutaneous Matrigel implant model using immunodeficient mice as hosts. Matrigel-containing fibroblast growth factor 2 (FGF-2; 1.2 microg/ml) induced stromal cell infiltration into the Matrigel/skin interface within 4 days and maximal neovascularization at 7 days. Cells staining positive for the endothelial cell marker, platelet-endothelial cell adhesion molecule 1 (PECAM-1), were present in neovessels and in isolated cells within the Matrigel matrix. Immunohistochemical analysis revealed high levels of vascular endothelial growth factor (VEGF) deposited in the stromal interface present only in the FGF-2-containing but not in control Matrigel implants. VEGF expression was confirmed with in situ hybridization. High VEGF mRNA levels were observed in the infiltrating stromal cells but not in endothelial or endothelial precursors as defined by PECAM-1 staining. In vitro analysis of FGF-2-treated embryonic fibroblasts, Balb/c 3T3 cells, showed an induction of VEGF transcription, mRNA synthesis, and protein secretion as defined by transcriptional reporter, Northern blot, and ELISA assays. The FGF-2-induced VEGF expression was not dependent on select matrix adherence or signaling components because VEGF mRNA expression induced by FGF-2 was equally activated on serum, basement membrane, and fibronectin matrix substrates. Systemic application of anti-VEGF antibodies significantly repressed FGF-2-induced angiogenesis over control antibody by 88% (p < 0.001). These data support an FGF-2 angiogenic model that is dependent on endothelial cell activation, stromal cell infiltration, and VEGF expression by the infiltrating stromal cell population.

3T3 Cells↗
PubMed2001

Role of AP-1 and HIF-1 transcription factors in TGF-beta activation of VEGF expression.

Aberrant expression of vascular endothelial growth factor (VEGF) has been demonstrated to be associated with most human solid tumors. Here we report that TGF-beta potently induces VEGF expression in human HT-1080 fibrosarcomas primarily through transcriptional activation with no significant changes in mRNA turnover. The tyrosine kinase inhibitor genistein and AP-1 inhibitor curcumin significantly blocked TGF-beta induction of VEGF expression while SP-1 and MKK1 inhibitors did not. TGF-beta enhanced both AP-1 and HIF-1 DNA binding activities whereas SP-1, AP-2 and NF-1 did not show major changes. Transcriptional reporter assays provided further evidence that TGF-beta augmented both AP-1 and HIF-1 activities. Moreover, TGF-beta-treated HT-1080 cells contained higher levels of HIF-1alpha and c-jun proteins in nuclear extracts. TGF-beta and hypoxia synergistically induced VEGF mRNA expression. Given the fact that most tumors respond to hypoxic stress with increased VEGF expression via HIF-1-dependent transcription, this study identifies for the first time that TGF-beta also increases VEGF mRNA in an AP-l/HIF-1-dependent mechanism and may potentiate the hypoxic response.

Blotting, Western↗
PubMed2000

Monoubiquitin carries a novel internalization signal that is appended to activated receptors.

Ubiquitin modification of signal transducing receptors at the plasma membrane is necessary for rapid receptor internalization and downregulation. We have investigated whether ubiquitylation alters a receptor cytoplasmic tail to reveal a previously masked internalization signal, or whether ubiquitin itself carries an internalization signal. Using an alpha-factor receptor-ubiquitin chimeric protein, we demonstrate that monoubiquitin can mediate internalization of an activated receptor that lacks all cytoplasmic tail sequences. Furthermore, fusion of ubiquitin in-frame to the stable plasma membrane protein Pma1p stimulates endocytosis of this protein. Ubiquitin does not carry a functional tyrosine- or di-leucine-based internalization signal. Instead, the three-dimensional structure of the folded ubiquitin polypeptide carries an internalization signal that consists of two surface patches surrounding the critical residues Phe4 and Ile44. We conclude that ubiquitin functions as a novel regulated internalization signal that can be appended to a plasma membrane protein to trigger downregulation.

Amino Acid Sequence↗
PubMed1999

Role of protein kinase C isoforms in phorbol ester-induced vascular endothelial growth factor expression in human glioblastoma cells.

Aberrant expression of the potent angiogenic cytokine, vascular endothelial growth factor (VEGF), has been demonstrated to be associated with most human solid tumors. Both transcriptional and post-transcriptional mechanisms have been shown to modulate VEGF expression in a multitude of cell types. Here we report that when protein kinase C (PKC) pathways were activated in human glioblastoma U373 cells by phorbol 12-myristate 13-acetate (PMA), VEGF mRNA expression was up-regulated via a post-transcriptional mRNA stabilization mechanism. PMA treatment exhibited no increase in VEGF-specific transcriptional activation as determined by run-off transcription assays and VEGF promoter-luciferase reporter assays. However, PMA increased VEGF mRNA half-life from 0.8 to 3.6 h which was blocked by PKC inhibitors but not by protein kinase A or cyclic nucleotide-dependent protein kinase inhibitors. When U373 cells were transfected with antisense oligonucleotide sequences to the translation start sites of PKC-alpha, -beta, -gamma, -delta, -epsilon, or -zeta isoforms, both PKC-alpha and -zeta antisense oligonucleotides showed substantial inhibition of PMA-induced VEGF mRNA. In addition, overexpression of PKC-zeta resulted in a strong constitutive up-regulation of VEGF mRNA expression. This study demonstrates for the first time that specific PKC isoforms regulate VEGF mRNA expression through post-transcriptional mechanisms.

Endothelial Growth Factors↗
PubMed1999

Regulation of human vascular endothelial growth factor mRNA stability in hypoxia by heterogeneous nuclear ribonucleoprotein L.

A 126-base region of human vascular endothelial growth factor (VEGF) 3'-untranslated region, which we identified as the hypoxia stability region, forms seven hypoxia-inducible RNA-protein complexes with apparent molecular masses ranging from 40 to 90 kDa in RNA-UV-cross-linking assays. In this study, we show that proteins that form the 60-kDa RNA-protein complex with the hypoxia stability region were present in both cytoplasmic and nuclear compartments. We purified the protein associated in the 60-kDa complex and identified it as heterogeneous nuclear ribonucleoprotein L (hnRNP L) by protein sequencing. Removal of hnRNP L by immunoprecipitation specifically abolished formation of the 60-kDa complex. Synthetic deoxyribonucleotide competition studies defined the RNA-binding site of hnRNP L as a 21-base-long sequence, 5'-CACCCACCCACAUACAUACAU-3'. Immunoprecipitation of hnRNP L followed by reverse transcription-polymerase chain reaction showed that hnRNP L specifically interacts with VEGF mRNA in hypoxic cells in vivo. Furthermore, when M21 cells transfected with antisense oligodeoxyribonucleotide to the hnRNP L RNA-binding site, the VEGF mRNA half-life was significantly reduced under hypoxic conditions. Thus, we propose that specific association of hnRNP L with VEGF mRNA under hypoxia may play an important role in hypoxia-induced post-transcriptional regulation of VEGF mRNA expression.

Base Sequence↗
PubMed1999

Immunohistochemical studies of transforming growth factor-beta and its receptors in the gastric mucosa of patients with refractory gastric ulcer.

Transforming growth factor (TGF)-beta regulates cell growth and differentiation, and is known to play regulatory roles in the process of tissue repair and remodeling. However, the functional role of TGF-beta in gastric ulcer healing has not been addressed. In this study, we assayed the expression of TGF-beta and its receptors in the gastric mucosa of patients with healed or refractory gastric ulcers. Antibodies against TGF-beta and its receptors (both type I and type II) were employed to examine expression levels. Sixteen gastric ulcer patients, including four with completely healed ulcers and 12 with ulcers refractory to treatment were included in this study. All four patients with healed ulcers showed remarkable expression levels of both TGF-beta and its receptors. On the other hand, two of the 12 patients with refractory ulcers had weak or deficient TGF-beta expression in the gastric mucosa, and seven lacked expression of at least one of the TGF-beta receptors. The remaining three patients had normal (moderate to weak) expression levels of TGF-beta and its two receptors. These results suggest that both TGF-beta and its receptors are essential for gastric ulcer healing.

Adult↗
PubMed1998

Hypoxia-mediated regulation of gene expression in mammalian cells.

The molecular mechanism underlying oxygen sensing in mammalian cells has been extensively investigated in the areas of glucose transport, glycolysis, erythropoiesis, angiogenesis and catecholamine metabolism. Expression of functionally operative representative proteins in these specific areas, such as the glucose transporter 1, glycolytic enzymes, erythropoietin, vascular endothelial growth factor and tyrosine hydroxylase are all induced by hypoxia. Recent studies demonstrated that both transcriptional activation and post-transcriptional mechanisms are important to the hypoxia-mediated regulation of gene expression. In this article, the cis-acting elements and trans-acting factors involved in the transcriptional activation of gene expression will be reviewed. In addition, the mechanisms of post-transcriptional mRNA stabilization will also be addressed. We will discuss whether these two processes of regulation of hypoxia-responsive genes are mechanistically linked and co-operative in nature.

Animals↗
PubMed1998

Identification of a human VPF/VEGF 3' untranslated region mediating hypoxia-induced mRNA stability.

Hypoxia is a prominent feature of malignant tumors that are characterized by angiogenesis and vascular hyperpermeability. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) has been shown to be up-regulated in the vicinity of necrotic tumor areas, and hypoxia potently induces VPF/VEGF expression in several tumor cell lines in vitro. Here we report that hypoxia-induced VPF/VEGF expression is mediated by increased transcription and mRNA stability in human M21 melanoma cells. RNA-binding/electrophoretic mobility shift assays identified a single 125-bp AU-rich element in the 3' untranslated region that formed hypoxia-inducible RNA-protein complexes. Hypoxia-induced expression of chimeric luciferase reporter constructs containing this 125-bp AU-rich hypoxia stability region were significantly higher than constructs containing an adjacent 3' untranslated region element without RNA-binding activity. Using UV-cross-linking studies, we have identified a series of hypoxia-induced proteins of 90/88 kDa, 72 kDa, 60 kDa, 56 kDa, and 46 kDa that bound to the hypoxia stability region element. The 90/88-kDa and 60-kDa species were specifically competed by excess hypoxia stability region RNA. Thus, increased VPF/VEGF mRNA stability induced by hypoxia is mediated, at least in part, by specific interactions between a defined mRNA stability sequence in the 3' untranslated region and distinct mRNA-binding proteins in human tumor cells.

Base Sequence↗
PubMed1996

Cell cycle-dependent tumor necrosis factor apoptosis.

To determine if tumor necrosis factor (TNF)-mediated apoptosis affects cells at defined stages of the cell cycle, WEHI-164/2F (WEHI) cells were synchronized at G0-G1 after 3-day cultures in medium containing RPMI 1640 and 0.5% FCS (RPMI-0.5% FCS). The arrested WEHI cells (60-75% in G0-G1) showed increased sensitivity to TNF killing, measured as 48-h 3-(5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assays, and 15-h apoptosis by propidium iodide staining and flow cytometry analysis. The TNF killing kinetics of G0-G1-arrested cells was similar to controls, and TNF did not accelerate or retard cell cycle progression of the arrested cells after feeding with fresh RPMI-0.5% FCS. However, TNF inhibited WEHI DNA synthesis as early as 1 h after treatment, and inhibition was proportionate to sensitivity to TNF-induced apoptosis. WEHI cells treated with TNF showed a higher percentage of cells in S phase with concomitant decrease in G0-G1 and G2-M. When cultured for 3-18 h in fresh RPMI-0.5% FCS to allow progression of the G0-G1-arrested cells toward the G1-S boundary, WEHI cells became more sensitive to TNF killing, especially at the 3-9 h time points. Moreover, TNF did not degrade [125I]5-iodo-2'-deoxyuridine-labeled WEHI DNA if the labeled cells were precultured for 9 h in fresh RPMI-0.5% FCS to allow them to pass S phase before the addition of TNF. These results show that TNF-induced apoptosis of WEHI cells is connected to cell cycle events; WEHI targets receive the TNF cytotoxic signal mainly at the G1-S boundary and begin to die by apoptosis as they exit from S phase.

Apoptosis↗
PubMed1996

Correlation of toxic signs, ultrasonographic findings and pathological changes in cholecystitis.

BACKGROUND: Cholecystitis is a frequently encountered clinical problem. What parameters are reliable in helping predict its severity? METHODS: One hundred and forty-nine cholecystectomized cases of cholecystitis were analysed of which 99 (95 calculous) cases were pathologically diagnosed as chronic cholecystitis and 50 acute (43 calculous) cholecystitis. Medical records were reviewed to determine the frequency of toxic signs. Sonographic findings (performed within three days prior to operation), and final pathological changes with respect to the thickness and echotexture of the gallbladder wall were compared. RESULTS: Of 99 chronic cholecystitis patients, 13 cases showed toxic signs. Sonography detected an abnormal wall in 64, but made a correct diagnosis in only 34 cases. A great discrepancy was found in wall thickness as measured by sonography and pathology. A discrepancy > or = 2mm was noted in 19 cases. Of 50 patients with acute cholecystitis (20 cases had complications, defined as severe acute cholecystitis), 31 cases (14 of the 20 severe acute cases) showed toxic signs. Sonographic findings demonstrated an abnormal wall in 46 cases (19 of the severe acute cases) and an accurate diagnosis in 28 cases (13 of the severe acute cases). A difference in the measurement of gallbladder wall thickness > or = 2mm was noted in 26 patients. CONCLUSIONS: Clinical toxic signs and sonographic findings could not offer sufficient information to quickly identify lifethreatening gallbladder diseases.

Acute Disease↗
PubMed1995

Pulmonary metastasis of hepatocellular carcinoma associated with transarterial chemoembolization.

UNLABELLED: Recent advances in both diagnosis and treatment of hepatocellular carcinoma have improved the prognosis and changed the clinical significance of the subsequently increasing distant metastases. Pulmonary metastasis of hepatocellular carcinoma associated with transcatheter arterial chemoembolization has rarely been reported. METHODS: To evaluate whether transcatheter arterial chemoembolization increases the risk of pulmonary metastasis of hepatocellular carcinoma, 230 patients were studied. Among them, 156 received transcatheter arterial chemoembolization with an interval of 12-16 weeks, the remaining 74 cases refused transcatheter arterial chemoembolization and received only conservative treatment. All patients were followed up with chest x-ray films taken before transcatheter arterial chemoembolization, during admission or in the out-patient department. The mean follow-up interval was 3.37 +/- 1.51 months. RESULTS: Pulmonary metastasis was found in 25.6% (40/156) and 8.1% (6/74) of the patients with and without transcatheter arterial chemoembolization (p = 0.002). The median interval between initial diagnosis and pulmonary metastasis was 3.39 +/- 0.08 and 11.72 +/- 2.91 months among patients with and without transcatheter arterial chemoembolization (p = 0.001). The mean age, sex, existence of cirrhosis, severity of cirrhosis, presence of collateral arterial circulation, amount of lipiodol and agent of anti-cancer drugs were not associated with the development of lung metastasis. However, factors predisposing to lung metastasis included: solitary tumor with tumor size > 10 cm, multiple tumors with main tumor > 5 cm or diffuse hepatocellular carcinoma, intrahepatic portal vein thrombosis, arterioportal or arteriovenous shunt, and the presence of incomplete tumor necrosis after transcatheter arterial chemoembolization (especially combined with necrotic area > 50% main tumor size). CONCLUSIONS: Pulmonary metastasis associated with transcatheter arterial chemoembolization has a strong adverse impact on patient survival.

Analysis of Variance↗
PubMed1995

Hepatic actinomycosis: a case report.

A 64-year-old man with hepatic actinomycosis presented with several months of weight loss and poor appetite. However, no fever was noted before admission. Findings on abdominal sonography and computed tomography scan were suggestive of hepatocellular carcinoma. A sono-guided percutaneous liver biopsy specimen demonstrated only chronic fibrosing inflammation. Therefore, laparotomy was performed and the diagnosis of hepatic actinomycosis was established after surgical resection. The patient was then successfully treated. The fact that hepatic actinomycosis may be very similar to hepatocellular carcinoma should be highly suspected. The hospital course of this patient concerning this condition and a brief review of the literature are presented to illustrate the diagnostic difficulties which may be encountered in such cases.

Actinomycosis↗
PubMed1995

Prevalence of antibodies to hepatitis C virus in patients with nonalcoholic fatty liver.

BACKGROUND: Nonalcoholic fatty liver can be caused by obesity, diabetes mellitus, hyperlipidemia or nonalcoholic steatohepatitis. Hepatitis C viral infection can also cause macrovesicular steatosis and such inflammation of the liver as nonalcoholic steatohepatitis. To determine whether the prevalence of anti-HCV is higher in patients with nonalcoholic fatty liver, this clinical study was undertaken; we also tried to detect which factors predict the presence of anti-HCV in these patients. METHODS: The study included 205 nonalcoholic fatty liver patients (122 males and 83 females) with a mean age of 46.5 years, diagnosed by ultrasonic examination, on whom anti-HCV antibody tests were then done. RESULTS: Eleven cases (5.4%) were anti-HCV positive with a higher mean age of 56.4 +/- 11.1 years (p < 0.05). Anti-HCV positive patients had higher serum AST and ALT levels than negative patients (95 +/- 59 U/L, 166 +/- 116 U/L vs. 34 +/- 26 U/L, 51 +/- 43 U/L; p < 0.05), while anti-HCV negative patients had higher mean body weight (124 +/- 15% vs. 114 +/- 11% of IBW) and serum cholesterol levels (202 +/- 41 mg/dl vs. 159 +/- 45 mg/dl). There was no statistical difference between anti-HCV positive and negative groups in clinical parameters including gender, presence of HBsAg, history of DM, operation, blood transfusion, oral contraceptive usage, and cancer with or without chemotherapy. The prevalence of anti-HCV increased with age from 1.8% in the fourth and fifth decades to 25% in the eighth decade. The prevalence of anti-HCV was 1.4% (1 case) in 72 fatty liver with normal biochemical tests and 7.5% (10 cases) in 133 cases with abnormal biochemical tests, a difference which was statistically marginally significant (p = 0.055). Those with ALT levels greater than three-fold the normal limit had a significantly higher anti-HCV prevalence rate (25.9%) than those with normal (1.4%) or mildly (2.8%) elevated ALT levels (p < 0.001). Logistic regression analysis revealed that only age and serum ALT levels were independent predictive factors for the presence of HCV infection. CONCLUSIONS: Results revealed that the prevalence of anti-HCV in patients with nonalcoholic fatty liver was 5.4%, slightly higher than in the general population. Age and serum ALT level were the predictive factors for the presence of HCV infection.

Adult↗
PubMed1994

Coexisting sharp ductal angulation with intrahepatic biliary strictures in right hepatolithiasis.

OBJECTIVE: To investigate the clinical characteristics of a coexisting sharp ductal angulation (< 90 degrees) with biliary stricture and to evaluate the difficulties it imposes in the management of retained or recurrent hepatolithiasis. DESIGN: Case-controlled study. SETTING: A referral center. PATIENTS: Eighteen consecutive patients having right-sided hepatolithiasis and a coexisting sharp ductal angulation associated with biliary stricture (group 1) were compared with 84 patients matched with sex, age, and conditions of hepatolithiasis and intrahepatic biliary stricture(s) but no sharp angulated duct (group 2). INTERVENTION: Postoperative cholangioscopic management (electrohydraulic lithotripsy or other lithotripsy, lithotomy, balloon dilation, biopsy, etc, via T-tube tract or percutaneous transhepatic route). MAIN OUTCOME MEASURES: Sessions of manipulations, incidence of complications associated with interventions or disease, and mortality were compared. RESULTS: Patients of group 1 needed more sessions of postoperative manipulation of stones and strictures (13.7 +/- 4.2 vs 8.0 +/- 2.3; P < .001). During management, there was a significantly increased vulnerability of severe and/or recurrent cholangitis (66.7% vs 9.5%; P < .001), septic shock (77.8% vs 11.9%; P < .001), liver abscess (55.6% vs 7.1%; P < .001), or massive hemobilia (33.3% vs 7.4%) in group 1 than in group 2. Their risks of coexisting secondary biliary cirrhosis (55.6% vs 9.5%; P < .001) and/or cholangiocarcinoma (16.6% vs 2.4%; P < .04) and mortality (27.8% vs 4.8%; P < .01) were also significantly higher in group 1. CONCLUSION: Our results suggest that the coexisting sharp ductal angulation with biliary strictures in right-sided hepatolithiasis is a distinct difficult clinical entity in the field of biliary tract calculi.

Adult↗
PubMed1994

Spontaneous rupture of the liver associated with pregnancy: a report of two cases.

Spontaneous rupture of the liver associated with pregnancy is a rare and grave complication, usually occurring in preeclampsia or eclampsia. Two cases of ruptured subcapsular hematoma of the right liver during pregnancy are reported. The first case was a 19-year-old woman who had suffered from epigastralgia and absent fetal heart beat in the 32nd week of gestation. The second case was a 31-year-old female who complained of nausea and right upper quadrant pain in the 35th week of pregnancy. Both had preeclampsia, and developed shock with disseminated intravascular coagulation soon after admission. Both received surgery and were found to have ruptured hematoma over the right liver. Finally, the first patient died of renal failure, but the second survived because preoperative diagnosis had been exact. Greater suspicion, then awareness of diagnosis can lead to better timing of surgery and an improved prognosis for mother and child.

Adult↗
PubMed1994

Cytomegalovirus-associated gastric ulcers in a normal host: a case report.

Cytomegalovirus (CMV) is an ubiquitous organism, recognized as an important pathogen in patients from the neonatal period through adulthood. Although CMV infections in the gastrointestinal tract of immunocompromised individuals have been reported in increasing frequency in recent years, there have been only a few reports of CMV infections in the gastrointestinal tract of normal hosts. Here a 43-year-old female is described; she had had a four-month history of epigastric pain, and an upper gastrointestinal endoscopy revealed multiple gastric ulcers. Histologic examination of biopsies from the ulcers showed cytomegalovirus inclusion bodies. She had no detectable immunological abnormalities, blood transfusion or organ transplant history. Conventional antiulcer treatments achieved no response.

Adult↗
PubMed1994

Inflammatory fibroid polyp of the jejunum causing intussusception: a case report.

Inflammatory fibroid polyp is a rare benign lesion of the gastrointestinal tract. This report concerns a 56-year-old female who presented with intermittent abdominal pain, vomiting and diarrhea; she had had partial intestinal obstruction over a period of two months. Plain abdomen showed dilatation of the small bowels. Abdominal echo revealed intussusception of the small intestine. During exploratory laparotomy a polypoid dumb-bell shaped polyp was noted as the leading point of the jejunojejunal intussusception, segmental resection of the jejunum was performed. Histological features of the polyp met the diagnosis of inflammatory fibroid polyp.

Female↗