bluuebunny/crossref_metadata_2025 huggingface dataset:
Trinuclear Cobalt(III) Complex Having Partial Cubane Co3O4 Core: Synthesis and Structural Analysis of the Complex Containing Bis(2-pyridylmethyl)amine
Authors: Ama Tomoharu , Okamoto Ken-ichi , Yonemura Toshiaki , Kawaguchi Hiroshi , Ogasawara Yoshiko , Yasui Takaji
Published: March 2004

The trinuclear cobalt(III) complex with the partial cubane Co3O4 core, [Co3(dpa)3(μ-OH)3(μ3-O)]4+ (dpa: bis(2-pyridylmethyl)amine), was prepared and the structure was determined by the X-ray diffraction method. Though the partial cubane structure was slightly distorted by the N–H↔H–N repulsive interaction, this complex is stable at least 5 days in its neutral aqueous solution.
Synthesis of SBA-1 Mesoporous Silica Crystals with Tunable Pore Size Using Sodium Silicate and Alkyltrimethylammonium Surfactants
Authors: Chao Man-Chien , Lin Hong-Ping , Wang Da-Shin , Mou Chung-Yuan
Published: March 2004

The spherical micelle-templated SBA-1 mesoporous silicas with different pore size were conveniently synthesized from commercially available alkyltrimethylammonium surfactants and sodium silicate components in dilute solution.
GaAs Nanocrystals via Hydrothermal Redox Reaction
Authors: Wei Shuo , Lu Jun , Yu Weichao , Zhang Houbo , Qian Yitai
Published: March 2004

GaAs nanocrystals of 35 nm were synthesized via hydrothermal redox reaction of metal gallium with As2O3 and following annealing, which were characterized by X-ray diffraction, transmission electron microscopy, X-ray photoelectron spectra. The formation mechanism was discussed.
Preparation of Controllable Crystalline Nano-TiO2 by Homogeneous Hydrolysis
Authors: Liu Wei , Chen Ai-Ping , Lin Jia-Ping , Dai Zi-Ming , Qiu Wei , Liu Wei , Zhu Meng-Qin , Usuda Shouji
Published: March 2004

The crystal-form-controllable nanosize TiO2 was obtained using homogeneous hydrolysis method by the addition of toluene-p-sulfonic acid (TSA). Two processes of the rutile phase formation were proposed. The sample with 0.2 mole ratio of toluene-p-sulfonic acid was a mixed crystal of anatase and rutile, and characterised that the size of nano-crystalline was 19.5 nm for rutile, and 13.5 nm for anatase, the specific surface area was 72.7 m2/g, and the energy of band gap was 2.83 eV. The mechanism of development of rutile nanosize TiO2 was presented in homogeneous hydrolysis system with TSA.
Main Structural and Stereochemical Aspects of the Antiherpetic Activity of Nonahydroxyterphenoyl‐Containing C‐Glycosidic Ellagitannins
Authors: Quideau Stéphane , Varadinova Tatiana , Karagiozova Diana , Jourdes Michael , Pardon Patrick , Baudry Christian , Genova Petia , Diakov Theodore , Petrova Rozalina
Published: March 2004

Antiherpetic evaluation of five nonahydroxyterphenoyl‐containing C‐glycosidic ellagitannins, castalagin (1), vescalagin (2), grandinin (3), roburin B (5), and roburin D (7), was performed in cultured cells against four HSV‐1 and HSV‐2 strains, two of which were resistant to Acyclovir. All five ellagitannins displayed significant anti‐HSV activities against the Acyclovir‐resistant mutants, but the monomeric structures 1–3 were more active than the dimers 5 and 7. Vescalagin (2) stands out among the five congeners tested as the most potent and selective inhibitor, with an IC50 value in the subfemtomolar range and a selectivity index 5×105 times higher than that of Acyclovir. Molecular modeling was used to provide a rationale for the surprisingly lower activity profile of its epimer castalagin (1). These ellagitannins have promising potential as novel inhibitors in the search for non‐nucleoside drugs active against Acyclovir‐resistant herpes viruses.
Two Pyrrolo[1,2‐a]azepine Type Alkaloids from Stemona collinsaeCraib: Structure Elucidations, Relationship to Asparagamine A, and a New Biogenetic Concept of Their Formation
Authors: Seger Christoph , Mereiter Kurt , Kaltenegger Elisabeth , Pacher Thomas , Greger Harald , Hofer Otmar
Published: March 2004

The alkaloids 1′,2′‐didehydrostemofoline (2) and 2′‐hydroxystemofoline (3) from Stemona collinsae Craib (Stemonaceae) were studied by X‐ray crystallography and NMR spectroscopy, and they are compared with the parent compound stemofoline (1). The X‐ray analysis of the CH2Cl2 solvate of 2′‐hydroxystemofoline (3) allowed the determination of the absolute configuration of this compound unequivocally, whereas optical rotation was used to infer the absolute configuration of 1′,2′‐didehydrostemofoline (2). Based on these results, it is shown that asparagamine A isolated from Asparagus racemosus Willd. (Asparagaceae) is identical to 1′,2′‐didehydrostemofoline obtained from S. collinsae Craib, and that the reported plant source of asparagamine A was most likely a Stemona species. In the context of the current investigations, a novel concept on the biosynthesis of Stemona alkaloids has been worked out and is presented here.
Complexity Analysis of Yeast Proteome Network
Authors: Bonchev Danail
Published: March 2004

Topological and compositional complexity of proteinprotein networks is assessed in a variety of ways making use of graph theory and information theory. The methodology used is borrowed from mathematical chemistry and includes complexity descriptors such as substructure count, overall connectivity, walk count, and information on various vertex distributions. The approach is applied to the (incomplete) proteome of Saccharomyces cerevisiae containing 232 protein complexes of a total of 1,440 proteins. The proteome network and each of its nine functional subsets of protein complexes are disconnected graphs, containing a number of noninteracting species and a major component. A weighted edge between two vertices in these graphs stands for the number of shared proteins between the respective complexes. The major component is a highly connected, ‘small‐world’ network, in which the average vertex distance between protein complexes does not exceed 2.2 (2.4 for the entire proteome), whereas the maximum distance does not exceed 4 (or 5 for the proteome). The vertex degree distribution in the major proteome component with 199 complexes follows the power law P(k)∼k−γ, with γ≈1.7. The analysis of the functional organization of the yeast proteome has shown that, for any pair of biological functions, there always exist many proteins that can perform both functions. The potential application of the quantitative proteome descriptors discussed includes quantitative relationships between the structure and biological action of dynamic protein complexes in changing environment, identification of targets for markers/drugs, as well as system analysis and comparative studies of proteomes.
Synthesis and Biological Evaluation of PaclitaxelThiocolchicine Hybrids
Authors: Danieli Bruno , Giardini Alessandra , Lesma Giordano , Passarella Daniele , Silvani Alessandra , Appendino Giovanni , Noncovich Alain , Fontana Gabriele , Bombardelli Ezio , Sterner Olov
Published: March 2004

The bifunctional taxoidcolchicinoid hybrids 6–8 were synthesized and evaluated in assays of cytotoxicity and tubulin assembly/disassembly. All compounds showed a high degree of cytotoxicity, but, while 6 and 7 behaved as bifunctional tubulin binders not unlike an equimolecular mixture of taxol and thiocolchicine, 8 was surprisingly devoid of tubulin activity, acting on a distinct and yet to identify molecular target.
Neoadjuvant radiochemotherapy of oral cavity and oropharyngeal cancer: evaluation of tumor response by ct differs from histopathologic response assessment in a significant fraction of patients
Authors: Klug Clemens , Keszthelyi David , Ploder Oliver , Sulzbacher Irene , Voracek Martin , Wagner Arne , Millesi Werner , Kornek Gabriele , Kainberger Franz , Kermer Christian , Selzer Edgar
Published: March 2004

Background.

Our aim was to compare and assess the predictive value of CT and histopathologic grading of tumor regression at primary tumor sites in patients with squamous cell carcinoma of the oral cavity and oropharynx after neoadjuvant (preoperative) radiochemotherapy (RCT).

Methods.

We investigated 55 patients with carcinomas of the oral cavity and oropharynx who underwent RCT before curative surgery. Two blinded observers measured RCT‐induced reduction of tumor volume in pretherapeutic and posttherapeutic CT scans. Volume changes were compared with histopathologic findings obtained at surgery.

Results.

Histopathologic response evaluation revealed 31 complete remissions, 12 cases of partial response, and 12 nonresponders. We performed a logistic regression analysis to evaluate whether measured volume reduction could predict the likelihood of belonging to a certain response group. Taken together, we found 35 correct, 12 false‐negative, and seven false‐positive predictions.

Conclusions.

The extent of remission as assessed by CT scans 4 to 5 weeks after completion of neoadjuvant RCT leads to false predictions in a significant percentage of patients. © 2004 Wiley Periodicals, Inc. Head Neck 26: 224–231, 2004
Impact of magnetic resonance imaging versus CT on nasopharyngeal carcinoma: primary tumor target delineation for radiotherapy
Authors: Chung Na‐Na , Ting Lai‐Lei , Hsu Wei‐Chung , Lui Louis Tak , Wang Po‐Ming
Published: March 2004

Background.

Our aim was to assess the capacity of CT versus MRI for delineating to the primary tumor extent of nasopharyngeal carcinoma (NPC) in treated patients.

Methods.

From December 1997 to April 2000, 258 patients with NPC were enrolled. We focused on the primary tumor extension and the discrepancy between CT and MRI. The delineation of tumor invasion was crucial for determination of the gross tumor volume (GTV) before radiation therapy.

Results.

A total of 104 patients (40.3%) had intracranial infiltration detected by MRI, whereas CT showed negative findings (p = 6.879 × 10−11). Once the pterygopalatine fossa was involved, the chance of intracranial invasion was increased (96.1%). The detectable percentage of pterygopalatine fossa involvement accompanying intracranial invasion was higher with MRI than with CT (96.1% vs 56.9%).

Conclusions.

More detailed information about T and N classification of NPC was provided by MRI than by CT, which led to better target delineation for radiotherapy. © 2004 Wiley Periodicals, Inc. Head Neck 26: 241–246, 2004
Unnecessary laryngeal irradiation in the IMRT era
Authors: Amdur Robert J. , Li Jonathan G. , Liu Chihray , Hinerman Russell W. , Mendenhall William M.
Published: March 2004

Purpose.

The purpose of this review is to address the issue of unnecessary irradiation of the normal larynx.

Methods.

We performed a literature review and dosimetry evaluation of intensity modulated radiotheraphy (IMRT) techniques.

Results.

Data suggest that matching conventional parallel opposed photon fields through adenopathy is a reasonable alternative to the common practice of unnecessarily irradiating the normal larynx to high doses. The dosimetry evaluation demonstrates that the laryngeal dose is much higher when the entire neck is included in the IMRT field as opposed to using a standard anterior low‐neck field below the level of the thyroid notch.

Conclusions.

Lateral opposed fields should not be extended to include the larynx to avoid matching fields through adenopathy. IMRT fields should not include the normal larynx when the laryngeal dose would be substantially lower with a technique that shields the larynx in an anterior low‐neck field. © 2004 Wiley Periodicals, Inc. Head Neck 26: 257–264, 2004
Frequent compartmentalization of hepatitis C virus variants in circulating B cells and monocytes
Authors: Ducoulombier Delphine , Roque-Afonso Anne-Marie , Di Liberto Gaëtana , Penin François , Kara Rachid , Richard Yolande , Dussaix Elisabeth , Féray Cyrille
Published: March 2004

Differences in the composition of the hepatitis C virus (HCV) quasispecies between plasma and blood mononuclear cells (BMC) strongly suggest that BMCs support viral replication. We examined the frequency of such compartmentalization, the cell types involved, the constraints exerted on the different variants, and the role of immunoglobulin-complexed variants. We screened the hypervariable region (HVR1) of HCV isolates from 14 HBsAg- and HIV-seronegative patients with chronic HCV infection. HCV RNA was amplified and cloned from plasma, the immunoglobulin G (IgG)-bound fraction, and total and sorted BMCs (CD19+, CD8+, CD4+, and CD14+ cells). Compartmentalization was estimated using a matrix correlation test. The ratio of nonsynonymous/synonymous substitutions (dN/dS ratio) was calculated for each compartment. HCV RNA was detected in 3/3 BMC, 11/11 CD19+, 10/11 CD14+, 4/11 CD8+ and 0/11 CD4+ cell samples. HVR1 sequences were significantly different between plasma and at least one cellular compartment in all nine cases analyzed, and between B cells (CD19+) and monocytes (CD14+) in all five available cases. IgG-bound variants were distinct from cellular variants. DN/dS ratios were similar (n = 3) or lower (n = 6) in cellular compartments compared with plasma and the IgG-bound fraction. In conclusion, HCV compartmentalization is a common phenomenon. B cells and monocytes harbor HCV variants showing a low rate of nonsynonymous mutations, a feature that might contribute to the persistence of HCV infection. (Hepatology 2004;39:817-825.)
Ischemic preconditioning affects interleukin release in fatty livers of rats undergoing ischemia/reperfusion
Authors: Serafín Anna , Roselló-Catafau Joan , Prats Neus , Gelpí Emilio , Rodés Joan , Peralta Carmen
Published: March 2004

The present study evaluates the effect of ischemic preconditioning on interleukin-1 (IL-1) and interleukin-10 (IL-10) generation following hepatic ischemia/reperfusion (I/R) in normal and steatotic livers as well as the role of nitric oxide (NO) in this process. Increased IL-1β and IL-10 levels were observed in normal livers after I/R. Steatotic livers showed higher IL-1β levels than normal livers, and IL-10 at control levels. The injurious role of IL-1β and the benefits of IL-10 on hepatic I/R injury was shown with the use of IL-1 receptor antagonist (IL-1ra), anti-IL-10 polyclonal antibody against IL-10 (anti-IL-10) and exogenous IL-10. The effective dose of these treatments was different in both types of livers. Preconditioning prevented IL-1β release and increased IL-10 generation after I/R in normal and steatotic livers. IL-1β or anti-IL-10 pretreatments reversed the benefits of preconditioning. IL-1β action inhibition in a preconditioned group that was pretreated with anti-IL-10 did not modify the benefits of preconditioning. In addition, anti-IL-10 pretreatment in the preconditioned group resulted in IL-1β levels comparable to those observed after I/R. NO inhibition eliminated the benefits of preconditioning on IL-10 release, IL-1β levels, and hepatic injury. In conclusion, preconditioning, through IL-10 overproduction, inhibits IL-1β release and the ensuing hepatic I/R injury in normal and steatotic livers. IL-10 generation induced by preconditioning could be mediated by NO. (Hepatology 2004;39:688-698.)
Impact of cytomorphological detection of circulating tumor cells in patients with liver cancer
Authors: Vona Giovanna , Estepa Laurence , Béroud Christophe , Damotte Diane , Capron Frédérique , Nalpas Bertrand , Mineur Alexandra , Franco Dominique , Lacour Bernard , Pol Stanislas , Bréchot Christian , Paterlini-Bréchot Patrizia
Published: March 2004

The clinical impact of circulating tumor cell (CTC) detection is controversial, mainly due to drawbacks of molecular approaches applied to this field. We sought to determine if the specific identification and counting of circulating tumor cells by cytomorphologic analysis has clinical usefulness. Peripheral blood (6 mL), treated using isolation by size of epithelial tumor cells, was obtained from 44 patients with primary liver cancer (PLC) and without metastases, 30 patients with chronic active hepatitis, 39 with liver cirrhosis, and 38 healthy individuals, and followed up for a mean period of 1 year. We searched for β-catenin mutations in 60 single microdissected CTCs. One patient with liver cancer developed extrahepatic metastases during follow-up. CTCs and microemboli were found in 23 of the 44 patients with liver cancer and in none of the patients with chronic active hepatitis, patients with cirrhosis, or healthy subjects. Their presence was significantly associated with tumor diffusion (P = .0001) and portal tumor thrombosis (P = .006). Both the presence (P = .01) and number (P = .02) of CTCs and microemboli were significantly associated with a shorter survival. β-Catenin mutations were found in 3 of 60 CTCs, arguing against their impact on the initial step of tumor cell invasion. In conclusion, the highly sensitive and specific detection of CTCs and microemboli may have clinical implications for cancer staging and outcome prediction. We also show the feasibility of molecular studies of individual circulating tumor cells, aimed at identifying gene mutations involved in tumor invasion. (Hepatology 2004;39:792-797.)
Dietary n-3 polyunsaturated fatty acids decrease hepatic triglycerides in Fischer 344 rats
Authors: Levy James R. , Clore John N. , Stevens Wayne
Published: March 2004

Dietary fatty acid composition modifies hepatic lipid metabolism. To determine the effects of fatty acids on hepatic triglyceride storage, rats were fed diets enriched in carbohydrates (control), fish oil, or lard. After 4 weeks, the animals were fasted overnight. In the morning, the animals were either sacrificed or fed 8 g of their respective diets before sacrifice. Animals ingested more food calories with diets containing fish oil than with other diets. However, fish oil-fed animals weighed less and had less body fat. In fish oil-fed animals, liver triglyceride was lower by 27% (P < .05) and 73% (P < .01) than in control- and lard-fed animals, respectively. Fish oil altered the postprandial gene expression of hepatic regulators of fatty acid degradation and synthesis. Fish oil feeding blunted the normal postprandial decline in fatty acid degradation genes (PPARα, CPT1, and ACO) and blunted the normal postprandial rise in triglyceride synthesis genes (SREBP1-c, FAS, SCD-1). Therefore, the direct postprandial effect of fish oil ingestion decreases the propensity for hepatic triglyceride storage. In conclusion, n-3 polyunsaturated fatty acids decrease total body weight, total body fat, and hepatic steatosis. (Hepatology 2004;39:608-616.)
Subliminal Fas stimulation increases the hepatotoxicity of acetaminophen and bromobenzene in mice
Authors: Tinel Marina , Berson Alain , Vadrot Nathalie , Descatoire Véronique , Grodet Alain , Feldmann Gérard , Thénot Jean Paul , Pessayre Dominique
Published: March 2004

The hepatotoxicity of several drugs is increased by mild viral infections. During such infections, death receptor ligands are expressed at low levels, and most parenchymal cells survive. We tested the hypothesis that subliminal death receptor stimulation may aggravate the hepatotoxicity of drugs, which are transformed by cytochrome P-450 cytochrome P-450 into glutathione-depleting reactive metabolites. Twenty-four-hour-fasted mice were pretreated with a subtoxic dose of the agonistic Jo2 anti-Fas antibody (1 μg per mouse) 3 hours before acetaminophen (500 mg/kg) or 1 hour before bromobenzene (400 mg/kg) administration. Administration of Jo2 alone increased hepatic inducible nitric oxide synthase nitric oxide synthase but did not modify serum alanine aminotransferase (ALT), hepatic adenosine triphosphate (ATP), glutathione (GSH), cytochrome P-450, cytosolic cytochrome c, caspase-3 activity or hepatic morphology. However, pretreating mice with Jo2 further decreased both hepatic GSH and ATP by 40% 4 hours after acetaminophen administration, and further increased serum ALT and the area of centrilobular necrosis at 24 hours. In mice pretreated with the Jo2 antibody before bromobenzene administration, hepatic GSH 4 hours after bromobenzene administration was 51% lower than in mice treated with bromobenzene alone, and serum ALT activity at 24 hours was 47-fold higher. In conclusion, administration of a subtoxic dose of an agonistic anti-Fas antibody before acetaminophen or bromobenzene increases metabolite-mediated GSH depletion and hepatotoxicity. Subliminal death receptor stimulation may be one mechanism whereby mild viral infections can increase drug-induced toxicity. (Hepatology 2004;39:655-666.)
Minimal hepatic encephalopathy impairs fitness to drive
Authors: Wein Christian , Koch Horst , Popp Birthe , Oehler Gerd , Schauder Peter
Published: March 2004

It has been suggested that the ability to drive a car is impaired in patients with cirrhosis of the liver and minimal hepatic encephalopathy (MHE). However, the only study using an on-road driving test did not reveal such an impairment. In a prospective controlled study, we evaluated patients with cirrhosis of the liver for MHE and the ability to drive a car. MHE was diagnosed using three psychometric tests: Number Connection Test Part A, Digit Symbol Test, and a Complex Choice Reaction Test. In a standardized on-road driving test (22 miles, 90 minutes), designed for patients with brain impairment, a professional driving instructor blind to the subjects' diagnosis and test results assessed the driving performance. Four global driving categories (car handling, adaptation to traffic situation, cautiousness, maneuvering), 17 specific driving actions (e.g., changing lanes, overtaking, etc.), and a total score of driving performance were rated using a 6-point scale. Of 274 consecutive patients with liver cirrhosis, 48 fulfilled the medical and driving inclusion criteria, 14 of them with and 34 without MHE. Forty-nine subjects in a stable phase of chronic gastroenterological diseases and with normal liver findings served as controls. The total driving score of patients with MHE was significantly reduced in comparison to either cirrhotic patients without MHE or to controls (P < .05). Significant differences in ratings were found in the following driving categories: car handling, adaptation, and cautiousness. Significant differences were also found in specific driving actions. The instructor had to intervene in the driving of 5 of the 14 MHE patients to avoid an accident, significantly more than in cirrhotic patients without MHE and in controls. There was no significant difference in any driving category or specific driving action in cirrhotic patients without MHE compared to controls. In conclusion, fitness to drive a car can be impaired in patients with MHE. Therefore, patients with liver cirrhosis should be tested for MHE and informed in the case of abnormal test results. Therapy known to improve psychometric test results should be initiated. (Hepatology 2004;39:739 -745.)
Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in mice
Authors: Takeuchi Dan , Yoshidome Hiroyuki , Kato Atsushi , Ito Hiroshi , Kimura Fumio , Shimizu Hiroaki , Ohtsuka Masayuki , Morita Yasuhiro , Miyazaki Masaru
Published: March 2004

Hepatic ischemia/reperfusion injury is a clinically important problem. While the mechanisms of the initial event and subsequent neutrophil-dependent injury are somewhat understood, little is known about the regulation of endogenous hepatoprotective effects on this injury. Interleukin 12 (IL-12) plays a role in the induction of this injury, but involvement of interleukin 18 (IL-18) has not been clarified. Using a murine model of partial hepatic ischemia and subsequent reperfusion, the aim of the current study was to determine whether IL-18 is up-regulated during hepatic ischemia/reperfusion and to determine the role of endogenous IL-18 in the development and regulation of inflammatory hepatic ischemia/reperfusion injury. Hepatic IL-18 expression was up-regulated from 1 to 8 hours after reperfusion. Hepatic ischemia/reperfusion induced nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) activation, as defined by electrophoretic mobility shift assay, and caused significant increases in liver neutrophil recruitment, apoptosis, hepatocellular injury, and liver edema as defined by liver myeloperoxidase content, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining, serum aminotransferase levels, and liver wet-to-dry weight ratios. In mice treated with neutralizing antibody to IL-18, ischemia/reperfusion-induced increases in CXC chemokine expression, activation of NF-κB and AP-1, and apoptosis were greatly reduced. Furthermore, under blockade of IL-18, anti-inflammatory cytokines such as IL-4 and IL-10 were greatly up-regulated. Signal transducer and activator of transcription 6 (STAT6) was significantly activated under blockade of IL-18. These conditions also caused significant reduction in liver neutrophil sequestration and liver injury. In conclusion, the data suggest that IL-18 is required for facilitating neutrophil-dependent hepatic ischemia/reperfusion injury through suppressing anti-inflammatory cytokine expression. (Hepatology 2004;39:699-710.)
Oxysterols induce cyclooxygenase-2 expression in cholangiocytes: Implications for biliary tract carcinogenesis
Authors: Yoon Jung-Hwan , Canbay Ali E. , Werneburg Nathan W. , Lee Sum P. , Gores Gregory J.
Published: March 2004

Cyclooxygenase-2 (COX-2), which is expressed by cholangiocytes in biliary tract disorders, has recently been implicated in biliary tract carcinogenesis. The mechanisms responsible for this COX-2 expression remain unclear. In human diseases, bile contains oxygenated derivatives of cholesterol (oxysterols) which possess diverse biological properties. Therefore, we determined if oxysterols modulate COX-2 expression. The effect of an oxysterol (22(R)-hydroxycholesterol, 22-HC) on COX-2 expression in KMBC cells, a human cholangiocarcinoma cell line, was examined. 22-HC enhanced COX-2 protein expression. This oxysterol activated p42/44 and p38 MAPK, but not JNK 1/2. A p42/44 MAPK inhibitor did not block COX-2 induction, while p38 MAPK inhibitor effectively attenuated COX-2 induction. Although COX-2 mRNA levels were increased by 22-HC, this increase was not transcriptionally regulated, as 22-OH did not increase activity in a COX-2 promoter gene assay. In contrast, COX-2 mRNA stability was augmented by 22-HC treatment, and this effect was reversed by a p38 MAPK inhibitor. In conclusion, the results demonstrate that the oxysterol 22-HC stabilizes COX-2 mRNA via a p38 MAPK-dependent mechanism. This enhanced COX-2 protein expression by oxysterols may participate in the genesis and progression of cholangiocarcinoma. (Hepatology 2004;39:732-738.)
Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: A randomized trial
Authors: Hou Ming-Chih , Lin Han-Chieh , Liu Tsu-Te , Kuo Benjamin Ing-Tieu , Lee Fa-Yauh , Chang Full-Young , Lee Shou-Dong
Published: March 2004

Bacterial infection may adversely affect the hemostasis of patients with gastroesophageal variceal bleeding (GEVB). Antibiotic prophylaxis can prevent bacterial infection in such patients, but its role in preventing rebleeding is unclear. Over a 25-month period, patients with acute GEVB but without evidence of bacterial infection were randomized to receive prophylactic antibiotics (ofloxacin 200 mg i.v. q12h for 2 days followed by oral ofloxacin 200 mg q12h for 5 days) or receive antibiotics only when infection became evident (on-demand group). Endoscopic therapy for the GEVB was performed immediately after infection work-up and randomization. Fifty-nine patients in the prophylactic group and 61 patients in the on-demand group were analyzed. Clinical and endoscopic characteristics of the gastroesophageal varices, time to endoscopic treatment, and period of follow-up were not different between the two groups. Antibiotic prophylaxis decreased infections (2/59 vs. 16/61; P < .002). The actuarial probability of rebleeding was higher in patients without prophylactic antibiotics (P = .0029). The difference of rebleeding was mostly due to early rebleeding within 7 days (4/12 vs. 21/27, P = .0221). The relative hazard of rebleeding within 7 days was 5.078 (95% CI: 1.854-13.908, P < .0001). The multivariate Cox regression indicated bacterial infection (relative hazard: 3.85, 95% CI: 1.85-13.90) and association with hepatocellular carcinoma (relative hazard: 2.46, 95% CI: 1.30-4.63) as independent factors predictive of rebleeding. Blood transfusion for rebleeding was also reduced in the prophylactic group (1.40 ± 0.89 vs. 2.81 ± 2.29 units, P < .05). There was no difference in survival between the two groups. In conclusion, antibiotic prophylaxis can prevent infection and rebleeding as well as decrease the amount of blood transfused for patients with acute GEVB following endoscopic treatment. (Hepatology 2004;39:746-753.)
Risks of a range of alcohol intake on hepatitis C-related fibrosis
Authors: Monto Alexander , Patel Keyur , Bostrom Alan , Pianko Stephen , Pockros Paul , McHutchison John G. , Wright Teresa L.
Published: March 2004

Heavy alcohol use contributes to liver disease in the setting of chronic hepatitis C virus (HCV) infection. Whether this is true for light or moderate alcohol use has not been demonstrated. Light alcohol use has survival benefits at a population level and is practiced by most patients with chronic HCV infection. In this study, 800 patients with HCV undergoing liver biopsy at three sites had detailed alcohol histories recorded and the relationship between alcohol and hepatic fibrosis was assessed. On univariate analysis, heavy alcohol use (>50 g/day) was associated with an increase in mean fibrosis (P = .01). Such an association could not be demonstrated for light and moderate alcohol use. For each category of alcohol intake (none, light, moderate, and heavy), a spectrum of fibrosis was observed. On multivariate analysis, age, serum alanine aminotransferase (ALT), and histological inflammation were the independent predictors of fibrosis (P = <.0001, .0003, <.0001, respectively). In conclusion, heavy alcohol use exerts a greater effect on fibrosis than light or moderate use. There is a range of fibrosis at each level of alcohol use. Age, serum ALT, and inflammation are independently associated with fibrosis in multivariate analysis, highlighting the fact that variables other than alcohol intake predominate in the production of hepatic fibrosis. (Hepatology 2004;39:826-834.)
Hepatocyte growth factor induces Mcl-1 in primary human hepatocytes and inhibits CD95-mediated apoptosis via Akt
Authors: Schulze-Bergkamen Henning , Brenner Dirk , Krueger Andreas , Suess Dorothee , Fas Stefanie C. , Frey Christian R. , Dax Andreas , Zink Dorothea , Büchler Peter , Müller Martina , Krammer Peter H.
Published: March 2004

CD95 (APO-1/Fas)-mediated apoptosis of hepatocytes plays a central role in the pathophysiology of various human liver diseases. Hepatocyte growth factor (HGF) was shown to exert antiapoptotic functions in rodent hepatocytes. We previously showed that primary human hepatocytes (PHH) are a valuable tool for the investigation of apoptotic processes in liver cells. In this study, we analyzed the influence of HGF on CD95-mediated apoptosis of PHH and its molecular determinants. HGF significantly inhibited CD95-mediated apoptosis of PHH as well as cleavage of caspase-8 and poly (ADP-ribose)polymerase. HGF transcriptionally induced the expression of the anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1). In contrary, HGF did not alter the expression levels of Bcl-2 or Bcl-xL. HGF activated survival pathways such as the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK and the signal transducer and activator of transcription 3 (STAT3) pathway. Notably, HGF triggered serine727—but not tyrosine705—phosphorylation of STAT3. Pretreatment of PHH with the PI3K inhibitor LY294002 as well as adenoviral transduction of dominant negative Akt1 prevented HGF-mediated Mcl-1 induction and reversed the antiapoptotic effects of HGF. In conclusion, HGF confers survival of PHH by activation of the PI3K/Akt pathway. PI3K/Akt activation by HGF results in the induction of antiapoptotic proteins such as Mcl-1. Thus, application of HGF may be a therapeutic approach to prevent CD95-mediated hepatocellular damage in human liver diseases. (Hepatology 2004;39:645-654.)
Body fat distribution, relative weight, and liver enzyme levels: A population-based study
Authors: Stranges Saverio , Dorn Joan M. , Muti Paola , Freudenheim Jo L. , Farinaro Eduardo , Russell Marcia , Nochajski Thomas H. , Trevisan Maurizio
Published: March 2004

Regional body fat distribution may represent an independent risk factor for several conditions, especially metabolic and cardiovascular diseases; recent findings have shown that abdominal fat accumulation can be an independent predictor of hepatic steatosis. Very few studies, mostly using selected clinical samples, have focused on the relationship between indices of abdominal visceral fat accumulation and the most commonly used biochemical liver tests, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT). The aim of the present study was to evaluate the relation between central fat accumulation, as assessed by abdominal height, relative weight, as determined by body mass index (BMI), and liver function tests (ALT, AST, and GGT) in a random sample of 2,704 residents of Erie and Niagara Counties in New York State, 35-80 years of age and free from known hepatic disease. Multiple linear regression models were used, with liver enzymes as dependent variables with abdominal height and BMI as independent variables, and the inclusion of several covariates (age, race, education, smoking status, pack-years of smoking, drinking status, and total ounces of ethanol in the past 30 days). Abdominal height was consistently a better correlate of ALT and GGT levels than BMI in both sexes. In addition, abdominal height was the most powerful independent predictor of ALT in both sexes as well as of GGT among women. In conclusion, these findings support a role for central adiposity independent from BMI in predicting increased levels of hepatic enzymes, likely as a result of unrecognized fatty liver. (Hepatology 2004;39:754-763.)
BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis
Authors: Pauli-Magnus Christiane , Kerb Reinhold , Fattinger Karin , Lang Thomas , Anwald Birgit , Kullak-Ublick Gerd A. , Beuers Ulrich , Meier Peter J.
Published: March 2004

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are characterized by a cholestatic pattern of liver damage, also observed in hereditary or acquired dysfunction of the canalicular membrane transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein type 3 (MDR3, ABCB4). Controversy exists whether a genetically determined dysfunction of BSEP and MDR3 plays a pathogenic role in PBC and PSC. Therefore, 149 healthy Caucasian control individuals (control group) were compared to 76 PBC and 46 PSC patients with respect to genetic variations in BSEP and MDR3. Sequencing spanned ˜10,000 bp including promoter and coding regions as well as 50-350 bp of flanking intronic regions. In all, 46 and 45 variants were identified in BSEP and MDR3, respectively. No differences between the groups were detected either in the total number of variants (BSEP: control group: 37, PBC: 37, PSC: 31; and MDR3: control group: 35; PBC: 32, PSC: 30), or in the allele frequency of the common variable sites. Furthermore, there were no significant differences in haplotype distribution and linkage disequilibrium. In conclusion, this study provides an analysis of BSEP and MDR3 variant segregation and haplotype structure in a Caucasian population. Although an impact of rare variants on BSEP and MDR3 function cannot be ruled out, our data do not support a strong role of BSEP and MDR3 genetic variations in the pathogenesis of PBC and PSC. (Hepatology 2004;39:779-791.)
Mutation analysis of the apoptotic “death‐receptors” and the adaptors TRADD and FADD/MORT‐1 in osteosarcoma tumor samples and osteosarcoma cell lines
Authors: Dechant Markus J. , Fellenberg Jörg , Scheuerpflug Christian G. , Ewerbeck Volker , Debatin Klaus‐Michael
Published: March 2004

Apoptosis is a key mechanism of the organism that regulates embryogenesis and development, maintains homeostasis of the immune system and removes potentially hazardous cells. A dysregulation of apoptosis signaling may thus disturb the balance of cell survival and cell death, leading to the development of several diseases including cancer. In order to determine whether osteosarcomas display an increased frequency of genetic alterations that affect apoptosis signaling, we analyzed the death domains of the death receptor genes CD95/Fas/Apo1, TNFR1, DR3/Apo3/WSL‐1/LARD/TRAMP, DR5/TRAIL‐R2/TRICK2/KILLER, DR6 and the complete coding sequences of the death receptor gene DR4/TRAIL‐R1 and the genes of the adaptors TRADD and FADD/MORT‐1. The investigation included 15 osteosarcoma tumor samples, 3 osteosarcoma cell lines (SAOS‐2, HOS and MG63) and peripheral blood from 20 donors as controls. We were able to identify 4 different sequence variations within the DR4 gene located on exons 3, 4, 5 and 10 (death‐domain). No alterations have been detected in the other genes or exons investigated. Except the sequence variant affecting exon 4, the alterations were homozygous in 15% of the tumor samples and cell lines, whereas the same alterations found in the control group were heterozygous or even not detectable. Three out of 4 alterations are located in the receptor's extracellular cysteine rich domain, which contains the ligand binding area and 1 on exon 10 coding for the death‐domain. They may thus exert influence on ligand‐receptor interactions and subsequent apoptosis induction. Our findings suggest that homozygous genetic alterations within the DR4 gene may be implicated in the formation of osteosarcoma. © 2004 Wiley‐Liss, Inc.
Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types
Authors: Shivapurkar Narayan , Toyooka Shinichi , Toyooka Kiyomi O. , Reddy Jyotsna , Miyajima Kuniharu , Suzuki Makoto , Shigematsu Hisayuki , Takahashi Takao , Parikh Gunjan , Pass Harvey I. , Chaudhary Preet M. , Gazdar Adi F.
Published: March 2004

TNF‐related apoptosis‐inducing ligand (TRAIL) selectively induces programmed cell death (apoptosis) in various cancer cells but not in normal cells. TRAIL is known to bind to 4 different receptors, 2 proapoptotic (DR4 and DR5), and 2 potentially antiapoptotic receptors lacking death domains (DcR1 and DcR2). Aberrant promoter methylation and resultant silencing of tumor suppressor genes play an important role in the pathogenesis of many tumor types. Recently aberrant methylation of TRAIL decoy receptors was reported in pediatric tumor cell lines and neuroblastomas. We examined the methylation and expression status of TRAIL receptor genes in cancers of breast, lung, mesothelioma, prostate, bladder, cervix, ovary, brain and in hematopoietic malignancies. Aberrant methylation of DcR1 or DcR2 was present in 70% of primary breast cancers, 31% of primary lung cancers, in 63% of primary malignant mesothelioma (MM), in 60% of prostate cancer, in 42% of bladder cancer, in 100% of cervical cancer, in 43% of ovarian cancer, in 41% of lymphoma, in 26% of leukemia and in 56% of multiple myeloma. Methylation of DR4 and DR5 was rare in all the tumor types examined. Methylation of all the 4 receptors was rare in non malignant tissues. In cell lines, aberrant methylation of DcR1 was present in 11 of 23 (48%) breast, 10 of 27 (37%) lung and 3 of 7 (43%) MM, whereas aberrant methylation of DcR2 was present in 17 of 23 (74%) breast, 13 of 27 (48%) lung and 5 of 7 (71%) MM. The concordance between loss of gene expression and aberrant methylation ranged from 70–100%. Treatment with 5‐aza‐2′‐deoxycytidine restored DcR1 and DcR2 expression in 9 methylated cell lines confirming that aberrant methylation was the cause for silencing of DcR1 and DcR2 expression. Our results demonstrate that DcR1 and DcR2 genes are frequently methylated in various tumor types, and that the role of decoy receptors in tumor pathogenesis needs to be re‐evaluated. © 2004 Wiley‐Liss, Inc.
Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas
Authors: Gismondi Viviana , Meta Maurizio , Bonelli Luigina , Radice Paolo , Sala Paola , Bertario Lucio , Viel Alessandra , Fornasarig Mara , Arrigoni Arrigo , Gentile Mattia , Ponz de Leon Maurizio , Anselmi Luca , Mareni Cristina , Bruzzi Paolo , Varesco Liliana
Published: March 2004

Biallelic germline mutations in the base excision repair gene MYH have been reported in patients with multiple colorectal adenomas and cancer and in sporadic FAP patients not showing a detectable APC germline mutation. In this study, the prevalence of the common Y165C and G382D germline variants of the MYH gene was examined in 70 FAP/AAPC patients with no detectable APC mutation and a family history compatible with recessive inheritance. In addition, 141 normal‐population adenoma patients (mean number of adenomas, 2.8; range, 1–9) and 52 clean colon controls were studied. The entire coding region of the MYH gene was analyzed in Y165C or G382D heterozygous patients. Since the same second mutational event (a 3 bp deletion in exon 14, 1395delGGA) was detected in 3 patients, the prevalence of this variant was also examined in all groups. In all, 14 of 70 patients in the FAP/AAPC group (20%; 95% CI = 11.7–31.6%) had biallelic germline MYH variants and 3 were heterozygotes (4.3%). None of the 141 normal‐population adenoma patients carried biallelic germline MYH variants (95% CI = 0.06–4.1%) and 3 were heterozygotes (2.1%). In the control group, no MYH variants were detected. These results indicated that MYH‐associated polyposis (MAP) is present in about 20% of Italian FAP/AAPC patients, in whom no germline APC mutation is detectable and showing a family history compatible with recessive inheritance, and in a small fraction of patients with colorectal adenomas in the general population. In addition, our data suggest that mutation 1395delGGA is a subpolymorphic MYH mutational event in some Caucasian populations. © 2004 Wiley‐Liss, Inc.
Breast cancer cells induce osteoclast formation by stimulating host IL‐11 production and downregulating granulocyte/macrophage colony‐stimulating factor
Authors: Morgan Hayley , Tumber Anthony , Hill Peter A.
Published: March 2004

Breast cancer cells frequently metastasize to the skeleton, where they induce OCL formation and activity, resulting in extensive bone destruction. However, the mechanisms by which breast cancer cells mediate increased osteolysis remain unclear. To elucidate this point, we investigated how 3 human breast cancer cell lines, MDA‐MB‐231, MDA‐MB‐435 and MCF‐7, induce OCL formation using a murine osteoblast–spleen cell coculture system and compared their effects with a human colorectal cancer cell line, HCT‐15; a human lung cancer cell line, HT‐1080; and a normal human breast cell line, HME. The breast cancer cell lines supported OCL formation only when osteoblasts were present in spleen cell cocultures, whilst the non‐breast cancer cell lines and the normal breast cell line, HME, had no effect. Fractionation of BCCM by ultrafiltration established that osteoclastogenic activity was associated with factors having m.w. >3 kDa. Breast cancer cell lines produced primarily PTHrP, with lesser amounts of IL‐6, IL‐11 and TNF‐α. The effect of BCCM on OCL formation in osteoblast–spleen cell cocultures was partially prevented by a neutralising antibody to human PTHrP and completely prevented by a neutralising antibody to either murine IL‐11 or the murine IL‐11 receptor; neutralising antibodies to human IL‐6, IL‐11 or TNF‐α were without effect. BCCM or human PTHrP induced an increase in murine osteoblast IL‐11 mRNA and protein production, effects that were prevented in the presence of a neutralising antibody to human PTHrP. The osteoclastogenic activity of IL‐11 was mediated by enhancing osteoblast production of PGE2 effects, which were abrogated by an inhibitor of cyclooxygenase. PGE2 apparently enhanced OCL formation by downregulating GM‐CSF production by spleen cells since recombinant murine GM‐CSF inhibited OCL formation and a neutralising antibody to murine GM‐CSF blocked these inhibitory effects. We conclude that breast cancer cells induce OCL formation by stimulating osteoblastic production of IL‐11. The subsequent release of PGE2 followed by inhibition of GM‐CSF production by cells within the bone microenvironment plays an important part in mediating the effects of breast cancer cells on OCL formation and their resorptive activity. © 2004 Wiley‐Liss, Inc.
Functional evaluation of collagen fiber scaffolds for ACL reconstruction: Cyclic loading in proteolytic enzyme solutions
Authors: Caruso Andrea B. , Dunn Michael G.
Published: March 2004

The mechanical properties of anterior cruciate ligament (ACL) reconstruction scaffolds were evaluated after exposure to functional challenges in vitro: cyclic loading combined with various proteolytic enzymes. Scaffolds were prepared from collagen fibers that were uncrosslinked (UNXL), crosslinked with ultraviolet irradiation (UV), or 1‐ethyl‐3‐(3‐dimethylaminopropyl) carbodiimide (EDC; 10 or 25 mM). Structural properties of scaffolds were determined following 1‐h exposure to saline, trypsin, or bacterial collagenase, with and without simultaneous cyclic tensile loading (0 to 50 g; 0.5 Hz) in vitro. The breaking load and stiffness of UNXL and UV crosslinked scaffolds were significantly reduced by exposure to either trypsin or collagenase. Cyclic loads interacted synergistically with enzymes, rendering UNXL scaffolds untestable and further decreasing the breaking load of UV crosslinked scaffolds by approximately 35%. In contrast, the breaking load and stiffness of EDC crosslinked scaffolds, which were greater than those of UNXL or UV crosslinked scaffolds, were virtually unaffected by the same load and enzyme treatments. These results suggest that EDC is more effective than UV for crosslinking and stabilizing load‐bearing collagen fiber ACL reconstruction scaffolds. Application of cyclic loads and enzymes may lead to development of physiologically relevant in vitro test methods for load‐bearing scaffolds. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 69A: 164–171, 2004