bluuebunny/crossref_metadata_2025 huggingface dataset:
Estrogen Receptor β Expression Is Associated with Tamoxifen Response in ERα-Negative Breast Carcinoma
Authors: Gruvberger-Saal Sofia K. , Bendahl Pär-Ola , Saal Lao H. , Laakso Mervi , Hegardt Cecilia , Edén Patrik , Peterson Carsten , Malmström Per , Isola Jorma , Borg Åke , Fernö Mårten
Published: April 2007

Purpose: Endocrine therapies, such as tamoxifen, are commonly given to most patients with estrogen receptor (ERα)–positive breast carcinoma but are not indicated for persons with ERα-negative cancer. The factors responsible for response to tamoxifen in 5% to 10% of patients with ERα-negative tumors are not clear. The aim of the present study was to elucidate the biology and prognostic role of the second ER, ERβ, in patients treated with adjuvant tamoxifen.

Experimental Design: We investigated ERβ by immunohistochemistry in 353 stage II primary breast tumors from patients treated with 2 years adjuvant tamoxifen, and generated gene expression profiles for a representative subset of 88 tumors.

Results: ERβ was associated with increased survival (distant disease-free survival, P = 0.01; overall survival, P = 0.22), and in particular within ERα-negative patients (P = 0.003; P = 0.04), but not in the ERα-positive subgroup (P = 0.49; P = 0.88). Lack of ERβ conferred early relapse (hazard ratio, 14; 95% confidence interval, 1.8-106; P = 0.01) within the ERα-negative subgroup even after adjustment for other markers. ERα was an independent marker only within the ERβ-negative tumors (hazard ratio, 0.44; 95% confidence interval, 0.21-0.89; P = 0.02). An ERβ gene expression profile was identified and was markedly different from the ERα signature.

Conclusion: Expression of ERβ is an independent marker for favorable prognosis after adjuvant tamoxifen treatment in ERα-negative breast cancer patients and involves a gene expression program distinct from ERα. These results may be highly clinically significant, because in the United States alone, ∼10,000 women are diagnosed annually with ERα-negative/ERβ-positive breast carcinoma and may benefit from adjuvant tamoxifen.
Utility of Circulating B-RAF DNA Mutation in Serum for Monitoring Melanoma Patients Receiving Biochemotherapy
Authors: Shinozaki Masaru , O'Day Steven J. , Kitago Minoru , Amersi Farin , Kuo Christine , Kim Joseph , Wang He-Jing , Hoon Dave S.B.
Published: April 2007

Purpose: Somatic B-RAF gene mutation has been identified in many malignancies and detected at a high frequency in cutaneous malignant melanoma. However, the significance of the B-RAF mutation (B-RAFmt) in terms of its prognostic and predictive capabilities for treatment response or disease outcome is not known. We hypothesized that circulating serum B-RAFmt (B-RAFsmt) at V600E, detected in serum, predicts response in melanoma patients receiving concurrent biochemotherapy.

Experimental Design: A real-time clamp quantitative reverse transcription-PCR assay was designed to assess B-RAFsmt by peptide nucleic acid clamping and a locked nucleic acid hybrid probe. Normal (n = 18) and American Joint Committee on Cancer stage I to IV melanoma patients (n = 103) were evaluated. These included stage IV patients (n = 48) with blood drawn before and after biochemotherapy. Patients were classified as biochemotherapy responders or nonresponders. Responders (n = 24) had a complete or partial response following biochemotherapy; nonresponders (n = 24) developed progressive disease.

Results: Of the 103 melanoma patients, 38 (37%) had B-RAFsmt DNA, of which 11 of 34 (32%) were stage I or II, and 27 of 69 (39%) were stage III or IV. Of the 48 biochemotherapy patients, 10 of 24 (42%) patients were positive for the B-RAFsmt in the respective responder and nonresponder groups before treatment. After biochemotherapy, B-RAFsmt was detected in only 1 of 10 patients (10%) in the responder group and 7 of 10 patients (70%) in the nonresponder group. B-RAFsmt is associated with significantly worse (P = 0.039) overall survival in patients receiving biochemotherapy.

Conclusion: These studies show the presence and utility of circulating B-RAFsmt DNA in melanoma patients.
Potent siRNA Inhibitors of Ribonucleotide Reductase Subunit RRM2 Reduce Cell Proliferation In vitro and In vivo
Authors: Heidel Jeremy D. , Liu Joanna Yi-Ching , Yen Yun , Zhou Bingsen , Heale Bret S.E. , Rossi John J. , Bartlett Derek W. , Davis Mark E.
Published: April 2007

Purpose: Ribonucleotide reductase (RR) is a therapeutic target for DNA replication–dependent diseases such as cancer. Here, a potent small interfering RNA (siRNA) duplex against the M2 subunit of RR (RRM2) is developed and shown to reduce the growth potential of cancer cells both in vitro and in vivo.

Experimental Design: Three anti-RRM2 siRNAs were identified via computational methods, and the potency of these and additional “tiling” duplexes was analyzed in cultured cells via cotransfections using a RRM2-luciferase fusion construct. Knockdown of RRM2 by the best duplex candidates was confirmed directly by Western blotting. The effect of potent duplexes on cell growth was investigated by a real-time cell electronic sensing assay. Finally, duplex performance was tested in vivo in luciferase-expressing cells via whole animal bioluminescence imaging.

Results: Moderate anti-RRM2 effects are observed from the three duplexes identified by computational methods. However, the tiling experiments yielded an extremely potent duplex (siR2B+5). This duplex achieves significant knockdown of RRM2 protein in cultured cells and has pronounced antiproliferative activity. S.c. tumors of cells that had been transfected with siR2B+5 preinjection grew slower than those of control cells.

Conclusions: An anti-RRM2 siRNA duplex is identified that exhibits significant antiproliferative activity in cancer cells of varying human type and species (mouse, rat, monkey); these findings suggest that this duplex is a promising candidate for therapeutic development.
A Phase I Pharmacokinetic and Pharmacodynamic Study of PX-12, a Novel Inhibitor of Thioredoxin-1, in Patients with Advanced Solid Tumors
Authors: Ramanathan Ramesh K. , Kirkpatrick D. Lynn , Belani Chandra P. , Friedland David , Green Sylvan B. , Chow H-H. Sherry , Cordova Catherine A. , Stratton Steven P. , Sharlow Elizabeth R. , Baker Amanda , Dragovich Tomislav
Published: April 2007

Purpose: Thioredoxin-1 (Trx-1) is a cellular redox protein that promotes tumor growth, inhibits apoptosis, and up-regulates hypoxia-inducible factor-1α and vascular endothelial growth factor. Objectives of this study were to determine safety, tolerability, pharmacodynamics, and pharmacokinetics of PX-12, a small-molecule inhibitor of Trx-1.

Experimental Design: Thirty-eight patients with advanced solid tumors received PX-12 at doses of 9 to 300 mg/m2, as a 1- or 3-h i.v. infusion on days 1 to 5, repeated every 3 weeks.

Results: At the 300 mg/m2 dose level, one patient experienced a reversible episode of pneumonitis during the first cycle, and a second patient developed pneumonitis after the second cycle. Doses up to 226 mg/m2 were well tolerated, and grade 3/4 events were uncommon (<3% of patients). The limiting factor on this dosing schedule was pungent odor caused by expired drug metabolite, 2-butanethiol. The best response was stable disease in seven patients (126-332 days). Whereas PX-12 was not detectable following the infusion, the Cmax of its inactive metabolite, 2-mercaptoimidazole, increased linearly with dose. PX-12 treatment lowered plasma Trx-1 concentrations in a dose-dependent manner.

Conclusions: PX-12, the first Trx-1 inhibitor to enter clinical trials, was tolerated up to a dose of 226 mg/m2 by a 3-h infusion. Based on pharmacodynamic and pharmacokinetic data, a trial of prolonged infusion schedule of PX-12 has been initiated.
Plasma Matrix Metalloproteinase-9 Level Is Better than Serum Matrix Metalloproteinase-9 Level to Predict Gastric Cancer Evolution
Authors: Wu Chun-Ying , Wu Ming-Shiang , Chiang En-Pei , Chen Yi-Ju , Chen Chien-Jen , Chi Nai-Hui , Shih Ying-Ting , Chen Gran-Hum , Lin Jaw-Town
Published: April 2007

Purpose: Matrix metalloproteinase-9 (MMP-9) in blood is a promising new tumor marker. The aims of the present study are to compare the usefulness of plasma and serum MMP-9 levels for predicting gastric cancer development, invasion, and survival.

Experimental Design: In this nested case-control study, 114 gastric cancer patients and 87 healthy controls were enrolled. MMP-9 levels and activities were quantitatively measured by ELISA assay and zymography. The results were compared with the occurrence, clinicopathologic features, and outcomes of gastric cancer patients. The follow-up time for all patients was at least 5 years.

Results: Serum MMP-9 levels were significantly higher than plasma MMP-9 levels. Both plasma and serum MMP-9 levels correlated significantly with active MMP-9 identified by zymography (P = 0.002 and P = 0.048, respectively). Plasma MMP-9 level was significantly elevated in gastric cancer patients when compared with control subjects (P < 0.001). Serum MMP-9 levels did not differ between the groups. Receiver-operator characteristics analysis showed the values of sensitivity (82.5%) and specificity (65.5%) at the maximum accuracy for plasma MMP-9 at ≥60 ng/mL (P < 0.001). Elevated plasma MMP-9 correlated significantly with lymph node metastasis [odds ratio (OR), 3.43; P = 0.019], lymphatic invasion (OR, 7.58; P = 0.009), and venous invasion (OR, 4.14; P = 0.033). Patients with elevated plasma MMP-9 levels had poorer survival rates than those with normal plasma MMP-9 levels (P = 0.038). Serum MMP-9 level did not correlate well with gastric cancer–invasive phenotypes or survival.

Conclusion: Our results suggest plasma MMP-9 level is a better marker than serum MMP-9 level for predicting gastric cancer development and progression.
Selective Tumor Targeting by the Hypoxia-Activated Prodrug AQ4N Blocks Tumor Growth and Metastasis in Preclinical Models of Pancreatic Cancer
Authors: Lalani Alshad S. , Alters Susan E. , Wong Alvin , Albertella Mark R. , Cleland Jeffrey L. , Henner William David
Published: April 2007

Purpose: The antitumor activities and pharmacokinetics of the hypoxia-activated cytotoxin AQ4N and its metabolites were assessed in several preclinical models of pancreatic cancers.

Experimental Design: The cytotoxic effects of AQ4N prodrug and its bioreduced form, AQ4, were tested against multiple human tumor cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Nude mice bearing s.c. or orthotopically implanted human BxPC-3 or Panc-1 tumor cells were treated with AQ4N. Tumor growth inhibition, time to progression/end point, and liver metastasis were evaluated in treatment versus control groups. Plasma and tumor levels of AQ4N and its metabolites were quantitated by liquid chromatography-tandem mass spectrometry.

Results: In contrast to AQ4N, the bioreduced AQ4 metabolite displayed potent cytotoxicity in many human tumor lines, including those derived from human pancreatic adenocarcinomas. Single-agent administration of AQ4N significantly delayed tumor growth, progression, and survival in a manner comparable with gemcitabine in multiple pancreatic tumor models in vivo. Survival increases were accompanied by a reduction in incidence and spread of liver metastasis. Quantitation of AQ4N and its metabolites in tumor-bearing mice showed that the prodrug is rapidly cleared from the circulation by 24 h and neither of the bioreduced metabolites was detected in plasma. In contrast, AQ4N readily penetrated BxPC-3 tumors and the cytotoxic AQ4 metabolite rapidly accumulated in tumor tissues at high levels in a dose-dependent fashion.

Conclusion: AQ4N undergoes rapid and selective conversion into the potent antineoplastic metabolite AQ4 in tumors in vivo and provides proof of principle for the use of hypoxia-activated prodrugs in the treatment against pancreatic cancers.
Identification of a Highly Effective Rapamycin Schedule that Markedly Reduces the Size, Multiplicity, and Phenotypic Progression of Tobacco Carcinogen–Induced Murine Lung Tumors
Authors: Granville Courtney A. , Warfel Noel , Tsurutani Junji , Hollander M. Christine , Robertson Matthew , Fox Stephen D. , Veenstra Timothy D. , Issaq Haleem J. , Linnoila R. Ilona , Dennis Phillip A.
Published: April 2007

Purpose: Human and murine preneoplastic lung lesions induced by tobacco exposure are characterized by increased activation of the Akt/mammalian target of rapamycin (mTOR) pathway, suggesting a role for this pathway in lung cancer development. To test this, we did studies with rapamycin, an inhibitor of mTOR, in A/J mice that had been exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

Experimental Design: Tumorigenesis was induced by i.p. injection of NNK, and rapamycin was administered 1 or 26 weeks after NNK administration. Biomarkers associated with mTOR inhibition were assessed in lung and/or surrogate tissues using immunohistochemistry and immunoblotting. Rapamycin levels were measured using mass spectroscopy.

Results: Rapamycin was administered on a daily (5 of 7 days) regimen beginning 26 weeks after NNK decreased tumor size, proliferative rate, and mTOR activity. Multiplicity was not affected. Comparing this regimen with an every-other-day (qod) regimen revealed that rapamycin levels were better maintained with qod administration, reaching a nadir of 16.4 ng/mL, a level relevant in humans. When begun 1 week after NNK, this regimen was well tolerated and decreased tumor multiplicity by 90%. Tumors that did develop showed decreased phenotypic progression and a 74% decrease in size that correlated with decreased proliferation and inhibition of mTOR.

Conclusions: Tobacco carcinogen–induced lung tumors in A/J mice are dependent upon mTOR activity because rapamycin markedly reduced the development and growth of tumors. Combined with the Food and Drug Administration approval of rapamycin and broad clinical experience, these studies provide a rationale to assess rapamycin in trials with smokers at high risk to develop lung cancer.
Molecular Characterization of Waldenstrom's Macroglobulinemia Reveals Frequent Occurrence of Two B-Cell Clones Having Distinct IgH VDJ Sequences
Authors: Kriangkum Jitra , Taylor Brian J. , Treon Steven P. , Mant Michael J. , Reiman Tony , Belch Andrew R. , Pilarski Linda M.
Published: April 2007

Purpose: Malignant B lineage cells in Waldenstrom's macroglobulinemia (WM) express a unique clonotypic IgM VDJ. The occurrence of biclonal B cells and their clonal relationships were characterized.

Experimental Design: Bone marrow and blood from 20 WM patients were analyzed for clonotypic VDJ sequences, clonal B-cell frequencies, and the complementary determining region 3 profile.

Results: Two different clonotypic VDJ sequences were identified in 4 of 20 WM. In two cases, partner clones had different VDJ rearrangements, with one clonotypic signature in bone marrow and a second in blood. For both cases, the bone marrow clone was hypermutated, whereas the blood clone was germ line or minimally mutated. In two other cases, partner clones shared a common VDJ rearrangement but had different patterns of somatic mutations. They lacked intraclonal diversity and were more abundant in bone marrow than in blood. VDJ mutation profiles suggested they arose from a common IgM progenitor. Single-cell analysis in one case indicated the partner clones were reciprocally expressed, following rules of allelic exclusion.

Conclusions: The existence of two B-cell clones having distinct VDJ sequences is common in WM, suggesting that frequent transformation events may occur. In two cases, the partner clones had distinct tissue distributions in either blood or bone marrow, were of different immunoglobulin isotypes, and in one case exhibited differential response to therapy. The contributions of each clone are unknown. Their presence suggests that WM may involve a background of molecular and cellular events leading to emergence of one or more malignant clones.
Differential Gene Expression during Development in Two Oligodendroglial Cell Lines Overexpressing Transferrin: A cDNA Array Analysis
Authors: García Corina I. , Paez Pablo M. , Soto Eduardo F. , Pasquini Juana M.
Published: April 2007

In the central nervous system, transferrin (Tf) is produced by oligodendroglial cells (OLGcs) and is essential for their development. Recently, using the complete cDNA of the human Tf gene, we obtained clones overexpressing Tf in two OLGc lines, N19 and N20.1, which represent different stages of differentiation. We showed that the overexpression of this glycoprotein promotes the maturation and myelinogenic capacity of both cell lines. In this work, using cDNA array technology, we examined changes induced by Tf in 1,176 genes. We found 41 genes differentially expressed in both cell lines, all of them involved in OLGc development. In the less mature cells (N19) overexpressing Tf, there was a significant increase in key enzymes of neurosteroid metabolism, such as cholesterol side chain cleavage cytochrome P450, 3β-hydroxysteroid dehydrogenase and 5α-reductase type 1. In the more mature cell line (N20.1), Tf overexpression produced an induction of several mRNAs of the GABAA receptor subunits, of thyroid hormone receptors and of proteins involved in axon-glia interactions such as F3/contactin. In addition, in both cell lines, Tf overexpression induced an increase in the expression of different isoforms of transforming growth factor β receptors and in several genes related to mitochondrial function and to complex lipid metabolism, crucial steps in myelin synthesis. Differentiation produced by Tf in both cell lines seems to occur by modulation of different genes depending on the maturational stage of the cells. Our findings provide new insights into the molecular basis of OLGc differentiation and on the role played by Tf in this process.
Effects of Hyperbaric Exposure with High Oxygen Concentration on the Physical Activity of Developing Rats
Authors: Matsumoto A. , Okiura T. , Morimatsu F. , Ohira Y. , Ishihara A.
Published: April 2007

The effects of hyperbaric exposure with high oxygen concentration on the physical activity of developing male rats were investigated. Five-week-old male rats were exposed to an atmospheric pressure of 1.25 with an oxygen concentration of 36.0% for 12 h (7.00–19.00 h) and exercised voluntarily for 12 h (19.00–7.00 h) daily for 8 weeks. The voluntary running activities were compared with those in age-matched rats without hyperbaric exposure. In addition, the properties of the soleus and plantaris muscle fibers and their spinal motoneurons were examined. The voluntary running activities of rats with or without hyperbaric exposure increased during development. However, the mean voluntary running activities were higher in rats with hyperbaric exposure (7,104 m/day) than in those without hyperbaric exposure (4,932 m/day). The oxidative capacities of the soleus and plantaris muscle fibers and their spinal motoneurons increased following hyperbaric exposure. It is suggested that adaptations of neuromuscular units to hyperbaric exposure with high oxygen concentration enhance the metabolism, and thus, the function of neuromuscular units is promoted.
Physiopathologie de la mucoviscidose
Authors: Donaldson Scott H. , Boucher Richard C.
Published: April 2007

La compréhension des modalités de survenue de l’atteinte respiratoire due à la mucoviscidose est un sujet de recherche depuis plusieurs décennies. Le clonage du gène régulateur de la conductance transmembranaire (CFTR) et d’autres progrès dans le domaine de la biologie de l’épithélium bronchique ont permis de beaucoup mieux connaître la physiopathologie de la maladie. Les meilleures données disponibles indiquent que l’anomalie sous-jacente est une dysrégulation du transport ionique qui induit une déplétion en liquide de la surface bronchique, donc une déshydratation, et une altération associée de l’élimination du mucus. La stase du mucus prédispose alors le poumon mucoviscidosique à une infection bactérienne qui devient rapidement chronique en raison de la nature des sécrétions. La réponse inflammatoire neutrophile persistante à cette infection chronique provoque alors des lésions bronchiques progressives et permanentes et, de ce fait, des bronchectasies et une insuffisance respiratoire sont habituelles quand l’atteinte respiratoire mucoviscidosique atteint le stade terminal. Le développement de nouveaux traitements ciblant l’anomalie sous-jacente de la déshydratation de la surface des voies aériennes permet d’espérer qu’il sera possible de prévenir cette cascade d’événements.
Role of Exercise in the Central Regulation of Energy Homeostasis and in the Prevention of Obesity
Authors: Patterson Christa M. , Levin Barry E.
Published: April 2007

Many of the small percentage of previously obese humans who successfully maintain weight loss report high levels of physical activity, suggesting a role for exercise in the maintenance of their lower body weights. The rat model of diet-induced obesity (DIO) has been particularly useful, since it shares several common characteristics with human obesity and, unlike the human condition, allows a thorough investigation of the effects of exercise on the central pathways which regulate energy homeostasis. In rats with DIO, voluntary wheel running selectively reduces adiposity without causing a compensatory increase in energy intake. These effects are likely mediated by signals generated by the exercising body such as interleukin-6, fatty acids, and heat which feed back on the brain to regulate central neuropeptide systems involved in the regulation of energy homeostasis. While exercise provides temporary reductions in obesity in adult rats, early postweaning exercise reduces adiposity in high-fat-fed DIO rats long after exercise is terminated. This suggests that early-onset exercise may permanently alter the development of the central pathways which regulate energy homeostasis. Therefore, identification of exercise-induced central and peripheral factors and elucidation of their interactions with central modulatory pathways may aid in the identification of new targets for the pharmacological treatment of human obesity.
Why Japan Will Not Go Nuclear (Yet): International and Domestic Constraints on the Nuclearization of Japan
Authors: Hughes Llewelyn
Published: April 2007

Japan's status as a nonnuclear weapons state remains of ongoing interest to policy analysts and scholars of international relations. For some, Japanese nuclearization is a question not of whether but of when. This article reassesses the state of the evidence on the nuclearization of Japan. It finds that support in Japan for the development of an independent nuclear deterrent remains negligible. Evidence demonstrates that ministries and agencies with responsibility for foreign and security policy have sought to consolidate Japan's existing insurance policies against nuclear threats—multilateral regimes and the extension of the U.S. nuclear deterrent to Japan—rather than seeking an indigenous nuclear deterrent. The article also finds, however, that the door to independent nuclearization remains ajar. Policymakers have ensured that constitutional and other domestic legal hurdles do not significantly constrain Japan from developing an independent nuclear deterrent. Further, recent centralization of authority in the prime minister and Cabinet Office has increased the freedom of action of leaders, enabling them to overcome political opposition to changes in security policy to a degree not possible in the past. This suggests that Japan's future position toward nuclear weapons could be more easily altered than before, should leader preferences change.
Getting Religion? The Puzzling Case of Islam and Civil War
Authors: Toft Monica Duffy
Published: April 2007

From 1940 to 2000, Islam was involved in a disproportionately high number of civil wars compared with other religions, such as Christianity or Hinduism. To help explain the overrepresentation of Islam in these wars, this article introduces a theory of “religious outbidding.” The theory holds that embattled political elites will tender religious bids when they calculate that increasing their religious legitimacy will strengthen their chances of survival. In combination with three overlapping factors—the historical absence of an internecine religious civil war similar to the Thirty Years’ War in Europe, proximity of Islam's holiest sites to Israel and large petroleum reserves, and jihad (i.e., defense of Islam as a religious obligation), religious outbidding accounts for Islam's higher representation in religious civil wars. The article includes a statistical analysis of the role of religion in civil wars and tests the logic of the argument of religious outbidding in the case of Sudan's two civil wars.
Editorial Introduction
Authors: van der Linden Marcel , Stutje Jan Willem
Published: April 2007

Ernest Mandel theorised the capitalist world economy as an articulated system of capitalist, semi-capitalist and precapitalist relations of production, linked to each other by capitalist relations of exchange and domination by the capitalist world market. This seems to be an interesting starting point for an historically well-founded theory, building on and going beyond Marx's work, of the worldwide expansion of the capitalist mode of production from its origins to the present. In his attempt to formulate his theory, Mandel did not succeed in resolving all difficulties, however. His main works – Marxist Economic Theory and Late Capitalism – show a number of dangling loose ends. The central question is whether these loose ends are merely technical difficulties or whether they reveal fatal flaws in the theory as a whole. In order to come a step closer to answering this question, a conference was organised in Amsterdam, November 2003. This introduction formulates the five, closely interrelated issues that were highlighted at this conference.
From Formal Subsumption to General Intellect: Elements for a Marxist Reading of the Thesis of Cognitive Capitalism
Authors: Vercellone Carlo
Published: April 2007

Since the crisis of Fordism, capitalism has been characterised by the ever more central role of knowledge and the rise of the cognitive dimensions of labour. This is not to say that the centrality of knowledge to capitalism is new per se. Rather, the question we must ask is to what extent we can speak of a new role for knowledge and, more importantly, its relationship with transformations in the capital/labour relation. From this perspective, the paper highlights the continuing validity of Marx's analysis of the knowledge/power relation in the development of the division of labour. More precisely, we are concerned with the theoretical and heuristic value of the concepts of formal subsumption, real subsumption and general intellect for any interpretation of the present change of the capital/labour relation in cognitive capitalism. In this way, we show the originality of the general intellect hypothesis as a sublation of real subsumption. Finally, the article summarises key contradictions and new forms of antagonism in cognitive capitalism.
DMNQ S‐64 Induces Apoptosis via Caspase Activation and Cyclooxygenase‐2 Inhibition in Human Nonsmall Lung Cancer Cells
Authors: LIM EU‐SOO , RHEE YUN‐HEE , PARK MIN‐KYU , SHIM BEOM‐SANG , AHN KYOO‐SEOK , KANG HEE , YOO HWA‐SEUNG , KIM SUNG‐HOON
Published: April 2007

Abstract:  Shikonin has been reported to induce apoptosis and inhibit angiogenesis in vivo and in vitro. 6‐(1‐propoxyiminoalkyl)‐5,8‐dimethoxyoxy 1,4‐naphtoquinone S‐64 (DMNQ S‐64) was synthesized as a shikonin derivative. In this article, the underlying apoptotic mechanism of DMNQ S‐64 was examined. DMNQ S‐64 exerted cytotoxicity against A549 lung carcinoma cells with IC50 of 27.3 μM. Apoptotic bodies were observed in DMNQ S‐64‐treated A549 cells by 4′‐6‐diamidino‐2‐phenylindole (DAPI) staining assay. DMNQ S‐64 also increased sub‐G1 DNA portion in a concentration‐dependent manner by flow cytometric analysis. Western blotting has revealed that DMNQ S‐64 effectively activates the expression of caspase 8, 9, and 3, cleaves poly (ADP‐ribose) polymerase, and increases the ratio of Bax/Bcl‐2. Furthermore, cytochrome c was released in a concentration‐dependent manner by DMNQ S‐64. Similarly, DMNQ S‐64 significantly increased caspase 3 activity by enzyme‐linked immunosorbent assay (ELISA). It also significantly inhibited the level of prostaglandin E2 (PGE2) by ELISA and downregulated the expression of cyclooxygenase‐2 (COX‐2) in a concentration‐dependent manner. Taken together, DMNQ S‐64 may exhibit cytotoxicity against A549 cells via caspase activation and COX‐2 inhibition.
ER Stress Induces the Expression of Jpk, which Inhibits Cell Cycle Progression in F9 Teratocarcinoma Cell
Authors: KIM HYE SUN , KONG KYOUNG‐AH , CHUNG HYUNJOO , PARK SUNGDO , KIM MYOUNG HEE
Published: April 2007

Abstract:  Jopock (Jpk), a transacting factor associated with the position‐specific regulatory element of murine Hoxa‐7, has shown to induce cell death in both prokaryotic and eukaryotic cells when introduced and overexpressed. Since Jpk protein harbors a transmembrane domain (TM) and a putative endoplasmic reticulum (ER) ‐retention signal at the N terminus, a subcellular localization of the protein was analyzed after fusing it into the green fluorescent protein (GFP). Both N–term‐ (Jpk‐EGFP) and C–term‐fused Jpk (EGFP‐Jpk) showed to be localized in the ER when analyzed under the fluorescence microscope after staining the cells with ER‐ and Mito‐Tracker. Through deletion analysis TM turned out to be important for ER localization of Jpk. When flow cytometric analysis was performed, both cells expressing Jpk‐EGFP and EGFP‐Jpk led cell cycle arrest and subsequent apoptotic cell death. In order to see whether Jpk is expressed during ER stress‐mediated apoptosis, F9 cells were treated with DTT, an ER stress inducer. In the presence of 4 mM of DTT, about 50% of cells died strongly expressing Jpk (sevenfold) as well as Grp78, a molecular chaperone, and CHOP‐10, a well‐known apoptotic protein. When cells were transfected with both pEGFP‐Jpk and pJpk‐EGFP, cell cycle progression was interrupted compared to those of control cells. In summary, excess ER stress upregulated the expression of Jpk, which seemed to inhibit the cell cycle progression. These results altogether suggest that Jpk could be a useful cell death‐triggering molecule applicable for cancer therapy as well as a useful target molecule for the treatment of certain neurodegenerative diseases caused by ER stress.
Expression of Leptin, Leptin Receptor, and Hypoxia‐Inducible Factor 1α in Human Endometrial Cancer
Authors: KODA MARIUSZ , SULKOWSKA MARIOLA , WINCEWICZ ANDRZEJ , KANCZUGA‐KODA LUIZA , MUSIATOWICZ BOGUSLAW , SZYMANSKA MAGDALENA , SULKOWSKI STANISLAW
Published: April 2007

Abstract:  Recent studies suggested that Ob (Ob) and its receptor (ObR) could be involved in the pathogenesis of various human malignancies, among others in endometrial cancer. Moreover, hypoxia, which is associated with solid tumors, might stimulate, through hypoxia‐inducible factor 1α (HIF‐1α), expression of Ob and ObR. In this article, we analyzed by immunohistochemistry the expression of Ob, ObR, and HIF‐1α in 60 cases of human endometrial cancer tissues as well as in 25 cases of normal endometria. Additionally, we assessed correlations among studied proteins as well as relationships with selected clinicopathological features of endometrial cancer. Immunoreactivity for Ob, ObR, and HIF‐1α protein was observed in 56.7%, 30.0%, and 78.3% of endometrial cancers, respectively. The expression of HIF‐1α showed a significant positive correlation with Ob (P < 0.0001, r= 0.573) and ObR (P= 0.020, r= 0.299). Moreover, we noted positive correlation between Ob and ObR (P= 0.001, r= 0.429). No statistically significant relationship was revealed between Ob, ObR, and HIF‐1α protein in regard to patient's age, histological grade, and extent of tumor growth (pT). In conclusion, HIF‐1α, which is related to tissue hypoxia in endometrial cancer, seems to be associated with overexpression of Ob and ObR. Ob could exert autocrine effect to stimulate endometrial cancer progression. Thus the autocrine Ob loop should be taken into consideration as a novel potential target in endometrial cancer prevention and treatment.
Role of Vascular Endothelial Growth Factor‐D (VEGF‐D) on IL‐6 Expression in Cerulein‐Stimulated Pancreatic Acinar Cells
Authors: LEE JANGWON , HWAN KIM KYUNG , KIM HYEYOUNG
Published: April 2007

Abstract:  Cerulein pancreatitis is similar to human edematous pancreatitis with dysregulation of the digestive enzyme production and cytoplasmic vacuolization, the death of acinar cells, edema formation, and an infiltration of inflammatory cells into the pancreas. Our preliminary proteomic analysis showed increased expression of vascular endothelial growth factor‐D (VEGF‐D) in cerulein (10−8M)‐treated pancreatic acinar cells. We hypothesized that VEGF‐D may have a role in cerulein‐induced cytokine expression in pancreatic acinar cells. This article was designed to elucidate whether cerulein induces VEGF‐D expression in pancreatic AR42J cells, and whether VEGF‐D expression is related to interleukin‐6 (IL‐6) expression by transfecting antisense oligonucleotide (AS ODN) for VEGF‐D into pancreatic acinar AR42J cells. Cerulein‐induced AP‐1 activation was monitored in the cells transfected with AS ODN or sense ODN (S ODN) for VEGF‐D. mRNA expression of IL‐6 was determined by RT‐PCR analysis. AP‐1 activation was assessed by electrophoretic mobility shift assay (EMSA). VEGF‐D expression was assessed by Western blotting. Cerulein induced IL‐6 expression and VEGF‐D expression in AR42J cells. Cerulein‐induced AP‐1 activation and IL‐6 expression was inhibited in the cells transfected with AS ODN for VEGF‐D as compared to S ODN. Cerulein‐induced VEGF‐D expression may have a role in AP‐1 activation and IL‐6 expression in pancreatic acinar cells.
Inhibition of Serine–Threonine Protein Phosphatases in Monocyte Chemoattractant Protein‐1 Expression in Helicobacter pylori‐Stimulated Gastric Epithelial Cells
Authors: CHUNG HAE‐YUN , CHA BORAM , KIM HYEYOUNG
Published: April 2007

Abstract:  The reversible phosphorylation of proteins controlled by protein kinases and protein phosphatases is a major mechanism that regulates a wide variety of cellular processes, such as inflammation. It has been reported that the activity of at least 30% of all proteins can be regulated by phosphorylation in eukaryotic cells. Among these proteins, mitogen‐activated protein kinases (MAPK) and several transcription factors play pivotal roles in inflammation. We previously demonstrated that Helicobacter pylori in a Korean isolate (HP99) induced proinflammatory chemokine expression by activating MAPK and transcription factors, nuclear factor‐κB (NF‐κB), and activator protein‐1 (AP‐1) in gastric epithelial AGS cells. In an attempt to determine the role of phosphorylation–dephosphorylation in HP99‐induced inflammation, we analyzed the expression of protein phosphatases, the activation of MAPK and transcription factors, and the production of chemokine MCP‐1 in AGS cells stimulated with HP99 (at a bacteria–cell ratio of 300:1) and cultured in the presence or absence of a nonspecific serine–threonine protein phosphatase inhibitor, okadaic acid (OA). Our results showed that HP99 induced the expression of protein phosphatases, PP1 and PP2A in AGS cells as early as 30 min. HP99 induced the activation of MAPK and AP‐1, and the production of monocyte chemoattractant protein‐1 (MCP‐1), which were augmented by pretreatment with 100 nM of OA. Gastric epithelial cells induced the expression of PP1 and PP2A in response to HP99 presumably as a defense mechanism against inflammatory chemokine expression by inhibiting the activation of MAPK and AP‐1.
Novel Involvement of the Immunomodulator AS101 in IL‐10 Signaling, via the Tyrosine Kinase Fer
Authors: HAYUN RAMI , SHPUNGIN SALI , MALOVANI HANA , ALBECK MICHAEL , OKUN EITAN , NIR URI , SREDNI BENJAMIN
Published: April 2007

Abstract:  Interleukin‐10 (IL‐10) plays a major proliferative role in many tumors, and activates the transcription factor Stat3 by tyrosine phosphorylation. The immunomodulator ammonium trichloro (dioxoethylene‐o,o') tellurate (AS101) has a direct antitumor activity, and is able to sensitize several tumors to chemotherapy, by inhibiting the tumor IL‐10 autocrine loop. The tyrosine kinase Fer is essential for the proliferation of numerous malignant cell lines and in some cases was related to Stat3 activation. This article examined the role of AS101 in IL‐10 signaling, and the correlation between Fer and Stat3, in human peripheral blood mononuclear cells (PBMC). We show that Fer was associated with Stat3 in PBMC and RAW 264.7, a macrophage cell line. Recombinant IL‐10 (rIL‐10) increased the tyrosine phosphorylation of Stat3, upregulated the levels of Fer, and increased the association of Fer with phosphorylated Stat3 (pYStat3). All the activities of IL‐10 mentioned above were reversed by AS101. The effects conferred by AS101 were totally abolished by exogenous addition of rIL‐10. These results indicate that AS101 downregulates the Stat3 IL‐10 loop, and inhibits Fer association with pYStat3. We conclude that anti‐IL‐10 treatment using AS101, may be beneficial in certain malignancies and other pathologies in which IL‐10 secretion is elevated and Stat3 is continuously phosphorylated.
Effect of Endothelin on Sodium/Hydrogen Exchanger Activity of Human Monocytes and Atherosclerosis‐Related Functions
Authors: KOLIAKOS GEORGE , BEFANI CHRISTINA , PALETAS KONSTANTINOS , KALOYIANNI MARTHA
Published: April 2007

Abstract:  The objective of this article is to investigate the influence of endothelin‐1 (ET‐1) on human monocyte Na+/H+ exchanger (NHE) activity and on the atherosclerosis‐related monocyte functions. ET‐1 caused an increase in pHi and in 22Na influx of monocytes. A reversal of ET‐1 effect on pHi was observed in the presence of the NHE1 inhibitor, cariporide. In addition, the activation of NHE1 by ET‐1 was mediated via protein kinase C (PKC), mitogen‐activated protein kinase (MAPK), phosphatidylinositol 3‐kinase (PI3K), and NADPH oxidase. Also, a link between ET‐1 and nitric oxide (NO) was observed. Furthermore, after ET‐1 treatment, an increase of the adhesive capacity, the migration ability on laminin and CD36 expression of monocytes, was observed; using cariporide this increase was abolished. Our results showed that ET‐1 induces a signaling pathway with the involvement of PKC, MAPK, PI3K, and NADPH oxidase where NHE1 plays a key role. ET‐1 also plays a significant role in atherosclerosis‐related functions of human monocytes, via NHE1 activation.
Protein Expression in the Tissues of the Cardiovascular System of the Rat under Selenium Deficiency and Adequate Conditions
Authors: KYRIAKOPOULOS A. , RICHTER A. , POHL T. , WOLF C. , GRBAVAC I. , PLOTNIKOV A. , KÜHBACHER M. , BERTELSMANN H. , BEHNE D.
Published: April 2007

Abstract:  We investigate the effects of selenium in tissues of the cardiovascular system. In order to examine the expression of the heart and aorta proteins (part of them) in the homogenate of selenium‐deficient (Se–) and selenium control rats (Se+), two‐dimensional electrophoresis was used by means of giga gels (30 × 35 cm). After electrophoresis, the protein expression pattern of the (Se–) gel and (Se+) gel was compared. The evaluation of the protein difference was implemented by means of a computer program suitable for the analysis of protein separated by the two‐dimensional electrophoresis. In this way more than 2000 proteins a gel (heart) were detected and more than 1900 protein spots were detected in the aorta fraction. Ten significant differences were found between the gel of (Se+) and (Se–) heart homogenate of the rat and more than 15 significant differences between the gel of (Se+) and (Se–) of the aorta. By means of MALDI‐MS–ESI‐MS some of these proteins with different expression levels were not determined until now. Of those, three proteins were detected as the alpha myosin heavy chain (α‐MHC), myosin light chain 1 and 2 (MLC 1 and 2), and the mitochondrial enzyme creatinine kinase. First results suggest that selenium deficiency affects myocardial energy metabolism and contractile proteins.
Exploitation of Host Signaling Pathways by B Cell Superantigens—Potential Strategies for Developing Targeted Therapies in Systemic Autoimmunity
Authors: ZOUALI MONCEF
Published: April 2007

Abstract:  Some infectious agents produce molecules capable of interacting specifically with the immunoglobulin heavy‐ or light‐chain variable regions, independently of the conventional‐binding site. They are referred to as B cell superantigens (SAgs) and include protein A of Staphylococcus aureus (S. aureus), gp120 of HIV‐1, and protein L of Peptostreptococcus magnus (P. magnus). In contrast to conventional antigens, B cell superantigens interact with conserved framework regions of immunoglobulins and can target a large proportion of B cells. In experimental models, they have been demonstrated to deplete B cell subsets responsible for innate functions, namely B‐1a and marginal zone (MZ) B cells. As a result, the interactions of these superantigens with host cells impair the humoral immune response. In addition to providing clues toward understanding host–pathogen interactions and microbial pathogenesis, B cell superantigens represent potential therapeutic agents that could be used to specifically modulate expansion of B cell subsets in diseased subjects. In systemic autoimmune diseases, for example, there is activation and expansion of B cells that secrete pathogenic autoantibodies. Their depletion results in clinical improvement in both experimental animals and patients. Currently, attempts are being made to specifically deplete pathogenic autoantibody‐producing B cells. Since B‐1a and MZ B cells have been found to be expanded in autoimmune disorders, B cell superantigens, used alone or in combination with other biological agents, may have beneficial effects in autoimmune disease management.
Antineoplastic and Anticlastogenic Properties of Curcumin
Authors: ALAIKOV TZVETAN , KONSTANTINOV SPIRO M. , TZANOVA TZVETOMIRA , DINEV KYRIL , TOPASHKA‐ANCHEVA MARGARITA , BERGER MARTIN R.
Published: April 2007

Abstract:  Curcumin is the pigment of turmeric and has been reported as a signal transduction modulator and inhibitor of transcription factors, for example, NF‐κB. In our article we found a concentration‐dependent cytotoxic activity of curcumin in a panel of eight leukemic cell lines (SKW‐3, CEM, U‐937, HL‐60, HL‐60/Dox, K‐562, LAMA‐84, and AR‐230). Additive to synergistic interactions was recorded for combinations with bendamustine and idarubicine in SKW‐3 and LAMA‐84 cells. Noteworthy, in multiple myeloma cells (RPMI‐8226 and U‐266) a potentiation of the efficacy of bendamustine by curcumin application was found. Moreover, curcumin increased the bendamustine cytotoxicity in cultures of cells isolated from the bone marrow of a patient with non‐Hodgkin's lymphoma (NHL). The increased bendamustine efficacy could be explained by NF‐κB inhibition, because this factor is activated in many cancers, especially leukemia and multiple myeloma. Curcumin is characterized by low toxicity and was described to have a chemoprotective activity. Therefore, the level of reduced glutathione (GSH) was measured and a concentration‐dependent increase of GSH levels was recorded in AR‐230 and SKW‐3 cells (concentration range 5–25 μM). Experiments with mice showed significant protection against cisplatin‐induced chromosomal aberrations (clastogenic effect) and inhibition of mitoses in bone marrow cells. Curcumin alone caused reduction of the mitotic index. In combination with cisplatin, however, this parameter was increased when compared to cisplatin alone. Our data indicate that curcumin has pleiotropic effects on signal transduction by inhibiting transcription thus exerting antitumor activity. In addition, curcumin has protective and anticlastogenic activity by enhancing the scavenging of free radicals.
Sanguinarine Inhibits VEGF‐Induced Akt Phosphorylation
Authors: BASINI GIUSEPPINA , SANTINI SUJEN ELEONORA , BUSSOLATI SIMONA , GRASSELLI FRANCESCA
Published: April 2007

Abstract:  Angiogenesis is the process of vascular growth by sprouting of preexisting vessels. This process impacts significantly on many important disease states including cancer, diabetic retinopathy, and arthritis. Endothelial cells receive multiple information from their environment, which leads them to progress along all stages of new vessel formation. Vascular endothelial growth factor (VEGF), in particular appears to be a master regulator of this process. This molecule interacts with cellular receptors and communicates with cell nucleus through a network of intracellular signaling, most of all by activating Akt pathway. This activation accounts for many of VEGF effects, including cell survival, migration, tube formation, and promotion of NO release. Sanguinarine (SA), an alkaloid isolated from Sanguinaria canadensis, is known for its antiangiogenetic effects by suppressing basal and VEGF‐induced new vessel growth. This article was aimed to evaluate the possible effect of SA (300 nM) on Akt phosphorylation in a porcine aortic endothelial cell line. The alkaloid significantly (P < 0.001) inhibited the VEGF‐induced Akt increase, thus suggesting that this mode of action could be responsible, at least partially, for the antiangiogenetic effect of SA.
Epigallocatechin Gallate Dose‐Dependently Induces Apoptosis or Necrosis in Human MCF‐7 Cells
Authors: HSUUW YAN‐DER , CHAN WEN‐HSIUNG
Published: April 2007

Abstract:  The catechins, a family of polyphenols found in tea, can evoke various responses, including cell death. However, the precise molecular mechanisms of these effects are unknown. Here, we demonstrate that treatment of human MCF‐7 cells with 50 μM (‐)‐Epigallocatechin‐3‐gallate (EGCG), a catechin that is highly abundant in green tea, can induce apoptotic changes, including mitochondrial membrane potential changes and activation of c‐Jun N‐terminal kinase (JNK), caspase‐9, and caspase‐3. In contrast, higher concentrations of EGCG (100–400 μM) do not induce apoptosis, but rather trigger necrotic cell death in MCF‐7 cells. Investigations of the possible mechanisms underlying these differences revealed that treatment with lower concentrations of EGCG (10–50 μM) directly increased intracellular oxidative stress, while higher concentrations (100–400 μM) did not. Immunoblotting revealed that treatment of MCF‐7 cells with 10–50 μM EGCG caused increases in Bax protein levels and decreases in Bcl‐2 protein levels, shifting the Bax–Bcl‐2 ratio to favor apoptosis, while treatment with 100–400 μM EGCG had no such effect. Moreover, we observed a dose‐dependent decrease in intracellular ATP levels in cells treated with high‐dose EGCG. Blockade of reactive oxygen species (ROS) generation and ATP synthesis using antioxidants and ATP synthesis inhibitors revealed that ROS and ATP play important roles to switch cell death types with apoptosis or necrosis. Collectively, these results indicate for the first time that EGCG treatment has a dose‐dependent effect on ROS generation and intracellular ATP levels in MCF‐7 cells, leading to either apoptosis or necrosis, and that the apoptotic cascade involves JNK activation, Bax expression, mitochondrial membrane potential changes, and activation of caspase‐9 and caspase‐3.