bluuebunny/crossref_metadata_2025 huggingface dataset:
Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT
Authors: Chao Jui-I , Su Wen-Chi , Liu Huei-Fang
Published: November 2007

The bioactive flavonoid baicalein has been shown to have in vitro growth-inhibitory activity in human cancer cells, although the mechanism of action is poorly understood. Baicalein (40–80 μmol/L for 24 h) more effectively induced cytotoxicity compared with other flavonoids (baicalin, catechin, genistein, quercetin, and rutin) in bladder cancer cells. Baicalein induced cell proliferation inhibition and apoptosis. The levels of cyclin B1 and phospho-CDC2 (Thr161) were reduced, whereas the G2-M phases were elevated by baicalein. Treatment of CDC2 kinase or CDC25 phosphatase inhibitors augments the baicalein-induced cytotoxicity. A variety of human bladder cancer cell lines expressed survivin proteins, which were located on the mitotic phases and regulated mitotic progression. Baicalein markedly reduced survivin protein expression. Transfection of a survivin small interfering RNA diminished the level of survivin proteins and increased the baicalein-mediated cell death. Overexpression of survivin enhanced cell proliferation and resisted the baicalein-induced cytotoxicity. Interestingly, baicalein induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and AKT. SB203580, a specific p38 MAPK inhibitor, attenuated proliferation inhibition and restored the protein levels of phospho-CDC2 (Thr161) and survivin in the baicalein-exposed cells; conversely, blockade of AKT activation enhanced cytotoxicity and the reduction of phospho-CDC2 (Thr161) and survivin proteins. As a whole, these findings provide that the opposite role of p38 MAPK and AKT regulates CDC2 kinase and survivin and the inhibition of CDC2-survivin pathway by baicalein contributes to apoptosis and proliferation retardation in cancer cells. [Mol Cancer Ther 2007;6(11):3039–48]
Under normoxia, 2-deoxy-d-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation
Authors: Kurtoglu Metin , Gao Ningguo , Shang Jie , Maher Johnathan C. , Lehrman Mark A. , Wangpaichitr Medhi , Savaraj Niramol , Lane Andrew N. , Lampidis Theodore J.
Published: November 2007

In tumor cells growing under hypoxia, inhibiting glycolysis with 2-deoxy-d-glucose (2-DG) leads to cell death, whereas under normoxic conditions cells similarly treated survive. Surprisingly, here we find that 2-DG is toxic in select tumor cell lines growing under normal oxygen tension. In contrast, a more potent glycolytic inhibitor, 2-fluorodeoxy-d-glucose, shows little or no toxicity in these cell types, indicating that a mechanism other than inhibition of glycolysis is responsible for their sensitivity to 2-DG under normoxia. A clue to this other mechanism comes from previous studies in which it was shown that 2-DG interferes with viral N-linked glycosylation and is reversible by exogenous addition of mannose. Similarly, we find that 2-DG interferes with N-linked glycosylation more potently in the tumor cell types that are sensitive to 2-DG under normoxia, which can be reversed by exogenous mannose. Additionally, 2-DG induces an unfolded protein response, including up-regulation of GADD153 (C/EBP-homologous protein), an unfolded protein response–specific mediator of apoptosis, more effectively in 2-DG–sensitive cells. We conclude that 2-DG seems to be toxic in select tumor cell types growing under normoxia by inhibition of N-linked glycosylation and not by glycolysis. Because in a phase I study 2-DG is used in combination with an anticancer agent to target hypoxic cells, our results raise the possibility that in certain cases, 2-DG could be used as a single agent to selectively kill both the aerobic (via interference with glycosylation) and hypoxic (via inhibition of glycolysis) cells of a solid tumor. [Mol Cancer Ther 2007;6(11):3049–58]
Conjugation of an anti–transferrin receptor IgG3-avidin fusion protein with biotinylated saporin results in significant enhancement of its cytotoxicity against malignant hematopoietic cells
Authors: Daniels Tracy R. , Ng Patrick P. , Delgado Tracie , Lynch Maureen R. , Schiller Gary , Helguera Gustavo , Penichet Manuel L.
Published: November 2007

We have previously developed an antibody fusion protein composed of a mouse/human chimeric IgG3 specific for the human transferrin receptor genetically fused to avidin (anti-hTfR IgG3-Av) as a universal delivery system for cancer therapy. This fusion protein efficiently delivers biotinylated FITC into cancer cells via TfR-mediated endocytosis. In addition, anti-hTfR IgG3-Av alone exhibits intrinsic cytotoxic activity and interferes with hTfR recycling, leading to the rapid degradation of the TfR and lethal iron deprivation in certain malignant B-cell lines. We now report on the cytotoxic effects of a conjugate composed of anti-hTfR IgG3-Av and biotinylated saporin 6 (b-SO6), a toxin derived from the plant Saponaria officinalis that inhibits protein synthesis. Conjugation of anti-hTfR IgG3-Av with b-SO6 enhances the cytotoxic effect of the fusion protein in sensitive cells and also overcomes the resistance of malignant cells that show low sensitivity to the fusion protein alone. Our results show for the first time that loading anti-hTfR IgG3-Av with a biotinylated toxin enhances the cytotoxicity of the fusion protein alone. These results suggest that anti-hTfR IgG3-Av has great potential as a therapeutic agent for a wide range of applications due to its intrinsic cytotoxic activity plus its ability to deliver biotinylated molecules into cancer cells. [Mol Cancer Ther 2007;6(11):2995–3008]
Clusterin mediates TRAIL resistance in prostate tumor cells
Authors: Sallman David A. , Chen Xianghong , Zhong Bin , Gilvary Danielle L. , Zhou Junmin , Wei Sheng , Djeu Julie Y.
Published: November 2007

One of the major obstacles in curing prostate cancer is the development of drug resistance to docetaxel, which is the gold standard for the treatment of this disease. It is not only imperative to discover the molecular basis of resistance but also to find therapeutic agents that can disrupt the resistant pathways. Based on initial findings that docetaxel-resistant PC3-DR and DU145-DR prostate tumor cell lines express tumor necrosis factor–related apoptosis inducing ligand (TRAIL) receptors, we examined whether TRAIL could be used as an alternative method to kill PC3-DR and DU145-DR cells. However, these tumor cells were found to be TRAIL resistant. Because PC3-DR and DU-145-DR cells were previously shown by us to be clusterin positive, we examined if clusterin could play a role in TRAIL resistance. We found that resveratrol could sensitize docetaxel-resistant tumor cells to TRAIL, and it worked by blocking clusterin expression. In particular, small interfering RNA clusterin expression in the cell lines was sufficient to produce apoptosis by TRAIL. Further analysis indicated that resveratrol functions as an effective tyrosine kinase inhibitor, similar to its analogue, piceatannol, and could inhibit Src and Jak kinases, thus resulting in loss of Stat1 activation. We have shown earlier that Stat1 is essential for gene transcription of clusterin. These results, taken together, show that resveratrol could be a useful new therapeutic agent to combat docetaxel resistance. [Mol Cancer Ther 2007;6(11):2938–47]
Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells
Authors: McAllister Sean D. , Christian Rigel T. , Horowitz Maxx P. , Garcia Amaia , Desprez Pierre-Yves
Published: November 2007

Invasion and metastasis of aggressive breast cancer cells is the final and fatal step during cancer progression, and is the least understood genetically. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Clearly, effective and nontoxic therapies are urgently required. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. Using a mouse model, we previously determined that metastatic breast cancer cells became significantly less invasive in vitro and less metastatic in vivo when Id-1 was down-regulated by stable transduction with antisense Id-1. It is not possible at this point, however, to use antisense technology to reduce Id-1 expression in patients with metastatic breast cancer. Here, we report that cannabidiol (CBD), a cannabinoid with a low-toxicity profile, could down-regulate Id-1 expression in aggressive human breast cancer cells. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion. These effects seemed to occur as the result of an inhibition of the Id-1 gene at the promoter level. Importantly, CBD did not inhibit invasiveness in cells that ectopically expressed Id-1. In conclusion, CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness. [Mol Cancer Ther 2007;6(11):2921–7]
A prostate-specific antigen–activated N-(2-hydroxypropyl) methacrylamide copolymer prodrug as dual-targeted therapy for prostate cancer
Authors: Chandran Sachin S. , Nan Anjan , Rosen D. Marc , Ghandehari Hamidreza , Denmeade Samuel R.
Published: November 2007

Prostate cancer targeted peptide prodrugs that are activated by the serine protease activity of prostate-specific antigen (PSA) are under development in our laboratory. To enhance delivery and solubility of these prodrugs, macromolecular carriers consisting of N-(2-hydroxypropyl) methacrylamide (HPMA)–based copolymers were covalently coupled to a PSA-activated peptide prodrug. HPMA copolymers are water-soluble, nonimmunogenic synthetic carriers that exhibit promise for drug delivery applications. These macromolecular copolymers enter the interstitium of solid tumors by the enhanced permeability and retention effect. The PSA-activated peptide substrate imparts selectivity because it is specifically hydrolyzed to release a cytotoxin at the site of prostate tumor. Enzymatically active PSA is present in high amounts in the extracellular fluid of a tumor, but PSA is inactivated in blood by binding to serum protease inhibitors. As an initial proof of concept, the HPMA copolymer was synthesized with a peptide substrate (HSSKLQ) bound to a fluorophore, 7-amino-4-methylcoumarin (AMC). PSA cleavage of the HPMA-HSSKLQ-AMC copolymer was observed, which led to the synthesis of an HPMA-based copolymer with the prodrug SSKYQ-L12ADT [HPMA–morpholinocarbonyl-Ser-Ser-Lys-Tyr-Gln-Leu-12-aminododecanoyl thapsigargin (JHPD)]. L12ADT is a potent analogue of the highly cytotoxic natural product thapsigargin. HPMA-JHPD was hydrolyzed by PSA in vitro and was toxic to prostate cancer cells in the presence of active PSA. The HPMA-JHPD produced no systemic toxicity when given at a 500 μmol/L L12ADT equivalent dose. Analysis of tumor tissue from mice treated with a single or multiple dose of the HPMA-JHPD copolymer showed release and accumulation of the L12ADT toxin within the tumor tissue. [Mol Cancer Ther 2007;6(11):2928–37]
Melanoma differentiation associated gene-7/interleukin-24 reverses multidrug resistance in human colorectal cancer cells
Authors: Emdad Luni , Lebedeva Irina V. , Su Zao-Zhong , Sarkar Devanand , Dent Paul , Curiel David T. , Fisher Paul B.
Published: November 2007

Overexpression of the multidrug resistance 1 (MDR1) gene, encoding P-glycoprotein (P-gp), facilitates resistance to diverse chemotherapeutic drugs and current P-gp inhibitors display high toxicity. We studied the effects of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), which exhibits cancer-specific apoptosis-inducing properties, in drug-sensitive (SW620) and drug-resistant (SW620/Dox) colorectal carcinoma cells. Adenovirus administered mda-7/IL-24, Ad.mda-7, effectively reversed resistance to doxorubicin-induced apoptosis in SW620/Dox cells by increased intracellular accumulation and decreased efflux of doxorubicin. Unexpectedly, P-gp–overexpressing cells (SW620/Dox) displayed increased apoptosis following Ad.mda-7 infection compared with parental SW620 cells, which correlated with more MDA-7/IL-24 protein in SW620/Dox than SW620 cell and potentially explains the increased sensitivity of P-gp–overexpressing cells to mda-7/IL-24. Transient overexpression of MDR1 in SW620 cells significantly increased apoptosis, decreased anchorage-independent growth, and increased MDA-7/IL-24 protein following Ad.mda-7 infection, whereas down-modulation of MDR1 in SW620/Dox cells by small interfering RNA decreased apoptosis following Ad.mda-7 infection. The increased mda-7/IL-24 sensitivity observed in SW620/Dox cells was partly due to increased reactive oxygen species generation and lower mitochondrial membrane potential. These findings confirm that mda-7/IL-24 is a potent MDR reversal agent, preferentially causing apoptosis in P-gp–overexpressing MDR cells, suggesting significant expanded clinical implications for the use of mda-7/IL-24 in treating neoplasms that have failed chemotherapy mediated by the P-gp MDR mechanism. [Mol Cancer Ther 2007;6(11):2985–94]
Blocking heat shock protein-90 inhibits the invasive properties and hepatic growth of human colon cancer cells and improves the efficacy of oxaliplatin in p53-deficient colon cancer tumors in vivo
Authors: Moser Christian , Lang Sven A. , Kainz Silvia , Gaumann Andreas , Fichtner-Feigl Stefan , Koehl Gudrun E. , Schlitt Hans J. , Geissler Edward K. , Stoeltzing Oliver
Published: November 2007

We recently showed that inhibition of heat shock protein 90 (Hsp90) decreases tumor growth and angiogenesis in gastric cancer through interference with oncogenic signaling pathways. However, controversy still exists about the antimetastatic potential of Hsp90 inhibitors. Moreover, in vitro studies suggested that blocking Hsp90 could overcome p53-mediated resistance of cancer cells to oxaliplatin. We therefore hypothesized that blocking oncogenic signaling with a Hsp90 inhibitor would impair metastatic behavior of colon cancer cells and also improve the efficacy of oxaliplatin in vivo. Human colon cancer cells (HCT116, HT29, and SW620) and the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) were used for experiments. In vitro, 17-DMAG substantially inhibited phosphorylation of epidermal growth factor receptor, c-Met, and focal adhesion kinase, overall resulting in a significant decrease in cancer cell invasiveness. Importantly, 17-DMAG led to an up-regulation of the transcription factor activating transcription factor-3, a tumor suppressor and antimetastatic factor, on mRNA and protein levels. In a cell death ELISA, 17-DMAG markedly induced apoptosis in both p53-wt and p53-deficient cells. In vivo, 17-DMAG significantly reduced tumor growth and vascularization. Furthermore, blocking Hsp90 reduced hepatic tumor burden and metastatic nodules in an experimental model of hepatic colon cancer growth. Importantly, combining oxaliplatin with 17-DMAG in vivo significantly improved growth inhibitory and proapoptotic effects on p53-deficient cells, compared with either substance alone. In conclusion, inhibition of Hsp90 abrogates the invasive properties of colon cancer cells and modulates the expression of the antimetastatic factor activating transcription factor-3. Hence, targeting Hsp90 could prove valuable for treatment of advanced colorectal cancer by effectively inhibiting colon cancer growth and hepatic metastasis and improving the efficacy of oxaliplatin. [Mol Cancer Ther 2007;6(11):2868–78]
Inhibition of hepatocellular carcinoma invasion by suppression of claudin-10 in HLE cells
Authors: Ip Ying Chi , Cheung Siu Tim , Lee Yuk Ting , Ho Jenny C. , Fan Sheung Tat
Published: November 2007

Previously, we showed that down-regulation of claudin-10 (CLDN-10) in hepatocellular carcinoma is associated with prolonged disease-free survival after curative surgery. Claudins are important tight junction components. Increasing evidence shows that claudins are involved in cancer progression but each member of claudins is specifically expressed in a variety of malignancies. The biological role of CLDN-10 in hepatocellular carcinoma is unexplored. In the current study, we investigated the CLDN-10 function in two different hepatocellular carcinoma cell lines by in vitro assays with the CLDN-10 overexpression and small interfering RNA–mediated knockdown transfectants. We observed that overexpression of CLDN-10 conferred malignant phenotypes to hepatocellular carcinoma cells, Hep3B, which lack CLDN-10 expression, by promoting cancer cell survival, motility, and invasiveness. More importantly, matrix metalloproteinase 2 (MMP2) was up-regulated. Increase in mRNA transcription and protein expression of membrane type 1-MMP (MT1-MMP) was also observed in the CLDN-10 transfectants, where MT1-MMP was a protease shown to promote intrahepatic metastasis in hepatocellular carcinoma in our earlier study. In addition, CLDN-1, CLDN-2, and CLDN-4 was up-regulated in CLDN-10 overexpression transfectants, indicating that the expression of CLDN-10 in cancer cells might affect the expression levels of its family members. On the contrary, small interfering RNA–based knockdown of CLDN-10 in HLE, an invasive cell line with high level of CLDN-10 expression, abolished invasion and strongly decreased activation of MMPs and claudin members expression. These findings showed that CLDN-10 is functionally involved in hepatocellular carcinoma invasion and is a potential target for hepatocellular carcinoma therapy. [Mol Cancer Ther 2007;6(11):2858–67]
Antibody targeting of B-cell maturation antigen on malignant plasma cells
Authors: Ryan Maureen C. , Hering Michelle , Peckham David , McDonagh Charlotte F. , Brown Lindsay , Kim Kristine M. , Meyer Damon L. , Zabinski Roger F. , Grewal Iqbal S. , Carter Paul J.
Published: November 2007

B-cell maturation antigen (BCMA) is expressed on normal and malignant plasma cells and represents a potential target for therapeutic intervention. BCMA binds to two ligands that promote tumor cell survival, a proliferation inducing ligand (APRIL) and B-cell activating factor. To selectively target BCMA for plasma cell malignancies, we developed antibodies with ligand blocking activity that could promote cytotoxicity of multiple myeloma (MM) cell lines as naked antibodies or as antibody-drug conjugates. We show that SG1, an inhibitory BCMA antibody, blocks APRIL–dependent activation of nuclear factor-κB in a dose-dependent manner in vitro. Cytotoxicity of SG1 was assessed as a naked antibody after chimerization with and without Fc mutations that enhance FcγRIIIA binding. The Fc mutations increased the antibody-dependent cell-mediated cytotoxicity potency of BCMA antibodies against MM lines by ∼100-fold with a ≥2-fold increase in maximal lysis. As an alternative therapeutic strategy, anti-BCMA antibodies were endowed with direct cytotoxic activity by conjugation to the cytotoxic drug, monomethyl auristatin F. The most potent BCMA antibody-drug conjugate displayed IC50 values of ≤130 pmol/L for three different MM lines. Hence, BCMA antibodies show cytotoxic activity both as naked IgG and as drug conjugates and warrant further evaluation as therapeutic candidates for plasma cell malignancies. [Mol Cancer Ther 2007;6(11):3009–18]
Interaction between Transcription Factor, Basal Transcription Factor 3, and the NH2-Terminal Domain of Human Estrogen Receptor α
Authors: Green Chris D. , Thompson Paul D. , Johnston Patrick G. , El-Tanani Mohamed K.
Published: November 2007

The estrogen receptor (ER), like other members of the nuclear receptor superfamily, possesses two separate transcriptional activation functions, AF-1 and AF-2. Although a variety of coactivators and corepressors of AF-2 have been identified, less is known of the mechanism of action of AF-1. We have used the yeast two-hybrid system to isolate a cDNA coding for a protein that binds specifically to the AF-1 region of human ERα. This cDNA codes for the transcription factor basal transcription factor 3 (BTF3). The specificity of the interaction between BTF3 and ERα has been confirmed in vivo and in vitro. Transient transfection experiments reveal that overexpression of BTF3 modulates the transcriptional response of reporter genes to ERα. BTF3 interacts with ERα that has been activated either by 17β-estradiol (ligand-dependent activation) or by epidermal growth factor (ligand-independent activation). The effects of BTF3 on the reporter genes requires the presence of ERα containing an active AF-1 function. BTF3 may be a component of the mechanism by which the AF-1 function of ERα stimulates gene transcription. (Mol Cancer Res 2007;5(11):1191–200)
Inhibition of Estradiol Receptor/Src Association and Cell Growth by an Estradiol Receptor α Tyrosine-Phosphorylated Peptide
Authors: Varricchio Lilian , Migliaccio Antimo , Castoria Gabriella , Yamaguchi Hiroshi , de Falco Antonietta , Di Domenico Marina , Giovannelli Pia , Farrar William , Appella Ettore , Auricchio Ferdinando
Published: November 2007

This report offers direct evidence that association of the estradiol receptor (ER) with Src triggered by steroid agonists or growth factors controls breast and prostate cancer cell growth. This association is abolished in whole cells and in vitro by a six-amino-acid peptide that mimics the sequence around the phosphotyrosine residue in position 537 of the human ERα. The phosphorylated peptide, at nanomolar concentrations, is taken up by MCF-7 and LNCaP cells derived from human mammary and prostate cancers, respectively. In addition, to block the ER/Src interaction, the phosphopeptide inhibits Src/Erk pathway, cyclin D1 expression, and DNA synthesis induced by estradiol or androgen or triggered by epidermal growth factor. In contrast, no inhibition of the Src-mediated epidermal growth factor action on DNA synthesis is detectable in human mammary cancer cells that do not express ER (MDA-MB231), indicating that the peptide specifically targets the ER-associated Src. Remarkably, the peptide, in contrast with classic steroid antagonists, does not interfere in ER- or androgen receptor–dependent transcriptional activity. Nevertheless, it markedly inhibits the growth of MCF-7 cell xenografts induced in immunodepressed and estradiol-treated mice. The present report suggests that inhibition of association of steroid receptors with Src or other signaling effectors may have therapeutic applications for patients with ER-positive tumors. (Mol Cancer Res 2007;5(11):1213–21)
VEGF165, but not VEGF189, Stimulates Vasculogenesis and Bone Marrow Cell Migration into Ewing's Sarcoma Tumors In vivo
Authors: Zhou Zhichao , Reddy Krishna , Guan Hui , Kleinerman Eugenie S.
Published: November 2007

We previously showed that bone marrow stem cells participate in the tumor vessel expansion that supports the growth of Ewing's sarcoma tumors in vivo. The purpose of this study was to determine the relative importance of two isoforms of vascular endothelial growth factor (VEGF) in tumor vessel expansion and recruitment of bone marrow–derived cells during tumor growth. We injected VEGF165-siRNA–transfected cells (TCsi/7-1), control siRNA–transfected cells (TC/si-control), or TC71 parental Ewing's sarcoma cells into nude mice. The TCsi/7-1 tumors were then treated with adenoviral vectors expressing VEGF165 (Ad-VEGF165), VEGF189 (Ad-VEGF189), or β-galactosidase (Ad-β-gal). Bone marrow cells labeled with fluorescent tracker dye were injected into the mice 3 weeks later. The TCsi/7-1 tumors were significantly smaller (P < 0.05), had decreased vessel density, and showed significantly lower bone marrow cell migration than did TC71 parental and TC/si-control tumors. Treatment with Ad-VEGF165, but not Ad-VEGF189 or Ad-β-gal, resulted in a significant increase in bone marrow cell infiltration, tumor vessel density, and tumor growth. Immunohistochemical staining revealed that the injected bone marrow cells migrated to and incorporated into the expanding CD31+ tumor vessel network. Taken together, these data show that VEGF165 is a chemoattractant that recruits bone marrow cells into the tumor area. These data provide a mechanism by which Ewing's sarcoma cells induce vasculogenesis. (Mol Cancer Res 2007;5(11):1125–32)
Phosphatidylethanol Accumulation Promotes Intestinal Hyperplasia by Inducing ZONAB-Mediated Cell Density Increase in Response to Chronic Ethanol Exposure
Authors: Pannequin Julie , Delaunay Nathalie , Darido Charbel , Maurice Tangui , Crespy Philippe , Frohman Michael A. , Balda Maria S. , Matter Karl , Joubert Dominique , Bourgaux Jean-François , Bali Jean-Pierre , Hollande Frédéric
Published: November 2007

Chronic alcohol consumption is associated with increased risk of gastrointestinal cancer. High concentrations of ethanol trigger mucosal hyperregeneration, disrupt cell adhesion, and increase the sensitivity to carcinogens. Most of these effects are thought to be mediated by acetaldehyde, a genotoxic metabolite produced from ethanol by alcohol dehydrogenases. Here, we studied the role of low ethanol concentrations, more likely to mimic those found in the intestine in vivo, and used intestinal cells lacking alcohol dehydrogenase to identify the acetaldehyde-independent biological effects of ethanol. Under these conditions, ethanol did not stimulate the proliferation of nonconfluent cells, but significantly increased maximal cell density. Incorporation of phosphatidylethanol, produced from ethanol by phospholipase D, was instrumental to this effect. Phosphatidylethanol accumulation induced claudin-1 endocytosis and disrupted the claudin-1/ZO-1 association. The resulting nuclear translocation of ZONAB was shown to mediate the cell density increase in ethanol-treated cells. In vivo, incorporation of phosphatidylethanol and nuclear translocation of ZONAB correlated with increased proliferation in the colonic epithelium of ethanol-fed mice and in adenomas of chronic alcoholics. Our results show that phosphatidylethanol accumulation after chronic ethanol exposure disrupts signals that normally restrict proliferation in highly confluent intestinal cells, thus facilitating abnormal intestinal cell proliferation. (Mol Cancer Res 2007;5(11):1147–57)
Detection of the G34R Mutation in the 5 Alpha Reductase 2 Gene by Allele Specific PCR and Its Linkage to the 89L Allele among Egyptian Cases
Authors: Gad Y.Z. , Khairt R. , Mazen I. , Osman H.G.
Published: November 2007

The 5 alpha-reductase type 2 deficiency is an autosomal recessive disorder of sexual development among 46,XY individuals. In Egypt, there is a prevalence of a G34R disease underlying mutation. This study aimed to devise a rapid diagnostic method based on allele specific PCR (AS-PCR) and a linked polymorphism (V89L). The results showed that one set of primers was capable to differentiate between normal, heterozygous, and affected individuals efficiently. All 34R mutation carrying sequences had 100% linkage to the 89L allele, contrasting normal ones with low 89L frequencies. This linkage infers a founder effect among Egyptians having G34R mutation.
Comparative Analysis of Anti-Mouse SRY Antibodies
Authors: Bradford S.T. , Wilhelm D. , Koopman P.
Published: November 2007

The Y chromosome gene SRY is the initiator of male sexual differentiation in mammals, but the molecular and cellular mechanisms operating downstream of SRY remain undefined. A deeper understanding of these issues relies on the ability to visualize SRY protein endogenously under a number of experimental conditions. Here we compare the specificity and effectiveness of several available antibodies to mouse SRY. Two antibodies cross-reacted with other SOX proteins in immunofluorescence analyses of transfected cells, and one of these two was unable to detect SRY on Western blots. A third antibody was both avid and specific, and was able to detect endogenous SRY in developing Sertoli cells in mouse genital ridges. Our findings underline the need to distinguish between useful and spurious reagents for biochemical and immunolocalization studies involving mouse SRY protein.
Are Pruritus and Scratching the Cough of the Skin?
Authors: Misery Laurent
Published: November 2007

Pruritus is not the equivalent of the cough of the skin, but itch and scratch can certainly be defined as such. In physiological conditions, they share the same function: to exclude a foreign body. Itch/scratching and cough could be selective responses for the same diseases, mainly atopic diseases, and their pathophysiology is similar (role of C fibers and mast cells; role of histamine, substance P and tachykinins). This is an intriguing analogy rather than a pathophysiological identity. It may be inappropriate for many disease settings. Itch and cough can be triggered or enhanced by stress. This similarity is very interesting because it could give rise to many new research ideas.
Entodermoscopy: A New Tool for Diagnosing Skin Infections and Infestations
Authors: Zalaudek Iris , Giacomel Jason , Cabo Horacio , Di Stefani Alessandro , Ferrara Gerardo , Hofmann-Wellenhof Rainer , Malvehy Joseph , Puig Susana , Stolz Wilhelm , Argenziano Giuseppe
Published: November 2007

Background: There is upcoming evidence that dermoscopy facilitates the in vivo diagnosis of skin infections and infestations. As such, dermoscopy connects the research fields of dermatologists and entomologists, opening a new research field of ‘entodermoscopy’. Objective: To provide an overview on the current applications of entodermoscopy. Methods: Systematic review of the English- and German-language literature by searches of Medline, Medscape and abstracts of the 1st World Congress of the International Dermoscopy Society. Results: Dermoscopic patterns have been described for viral warts, molluscum contagiosum, scabies, pediculosis, tinea nigra, tungiasis, cutaneous larva migrans, ticks and reactions to spider leg spines. Besides the diagnostic role of dermoscopy, there is increasing evidence that it can also assist in the monitoring of treatment efficacy for some of these conditions. Conclusion: Although most of the current available literature is based on single observations and small case studies rather than controlled trials, an increasing interest in this field can be observed.
Clinical Characteristics and Psychopathological Profile of Patients with Vulvodynia: An Observational and Descriptive Study
Authors: Tribó M.J. , Andión O. , Ros S. , Gilaberte M. , Gallardo F. , Toll A. , Ferrán M. , Bulbena A. , Pujol R.M. , Baños J.E.
Published: November 2007

Background: Vulvodynia is a fairly common dermatological symptom that often interferes with the personal, social and working activities of affected women and results in a significant loss of their quality of life. It is a persistent and tedious clinical disorder which is often resistant to conventional treatments. Objectives: The aim of this study is to evaluate the main clinical signs, associated psychopathological disorders and outcome after antidepressant treatment of patients with vulvodynia. Methods: Eighty patients were included. Clinical characteristics and psychopathological profiles were determined by appropriate instruments. The improvement of clinical symptoms after combined antidepressant drug therapy was also evaluated. Results: Pain (70%), burning (63.7%), dyspareunia (57.5%) and stinging (56.2%) were the most commonly reported symptoms. Most patients (56.5%) showed anxiety, and 52.2% of them were reported as having a depression disorder. When evaluated by psychometric tools, 81.4% of patients scored >150 on the Life Event Scale, which means a risk >50% of suffering an illness in the near future, and patients’ scores in the Dermatology Life Quality Index showed higher values than the mean of the Spanish validation group. After 6 months of combined treatment with escitalopram (10–20 mg/day), perfenazine (2–4 mg/day) and amytriptiline (10 mg/day), a complete remission of the clinical symptoms was achieved in 41% of patients. In contrast, only 12% of patients who did not follow drug treatment reported a complete resolution of the clinical symptoms. Conclusions: Our results seem to confirm that vulvodynia is associated with psychiatric co-morbidity such as stress and depression. The study highlights that the psychiatric treatment may be a useful option to improve clinical symptoms. Whether these patients should be evaluated for depression or be referred to a psychiatrist, remains to be investigated.
The Venous Nevus: A Distinct Vascular Malformation Suggesting Mosaicism
Authors: Zietz Sabrina , Happle Rudolf , Hohenleutner Ulrich , Landthaler Michael
Published: November 2007

Background: Venous malformations are common vascular anomalies which only occur sporadically. Objective: We present a series of 25 patients with extratruncular venous malformations of the skin or the neighboring mucosa that are arranged in a segmental pattern. Results: All lesions were sporadic and mostly unilateral. According to the extent of the vascular malformation, two subgroups were defined: large- to medium-sized and small localized lesions (‘acrofacial distribution’). In large- or medium-sized lesions, we noted a strict midline separation of the disorder. Thus, we assume that this segmental arrangement reflects genetic mosaicism. Conclusions: This type of venous malformation originates from a postzygotic mutation that occurs at an early developmental stage. Hence, the type of vascular disorder present in our 25 patients seems to fulfil each criterion of the term ‘nevus’. This vascular nevus should be distinguished from other forms of venous malformations such as the varicose veins associated with the Klippel-Trénaunay syndrome, the dermal nodules of the blue rubber bleb nevus syndrome and the vascular skin lesions of the Maffucci syndrome. Thus, we propose the new term ‘venous nevus’ or ‘nevus venosus’.
Dew Point Effect of Cooled Hydrogel Pads on Human Stratum Corneum Biosurface
Authors: Xhauflaire-Uhoda Emmanuelle , Paquet Philippe , Piérard Gérald E.
Published: November 2007

Background: Cooled hydrogel pads are used to prevent overheating effects of laser therapy. They do not induce cold injuries to the skin, but their more subtle physiological effects have not been thoroughly studied. Purpose: To describe the changes in transepidermal water loss and electrometric properties of the skin surface following application of cooled hydrogel pads. Measurements were performed on normal forearm skin of 27 healthy volunteers and on freshly excised skin from abdominoplasty. Methods: LaserAid® hydrogel pads cooled to 4°C were placed for 15 min on the forearm skin. Measurements of transepidermal water loss (TEWL) and electrometric properties (Corneometer®, Nova DPM 900®) were performed before application and after removal of the cooled pads. Results: A consistent increase in corneometer units, dermal phase meter (DPM) values and TEWL were recorded at removal of the cooled hydrogel pads. Both the in vivo and in vitro assessments brought similar information. Discussion: The similar changes disclosed in vitro and in vivo suggest that a common physical process is operating in these conditions. The observed phenomenon is opposite to the predicted events given by the Arrhenius law probably because of the combination of cooling and occlusion by the pads. A dew point effect (air temperature at which relative humidity is maximal) is likely involved in the moisture content of the stratum corneum. Thus, the biological impact of using cooling hydrogel pads during laser therapy is different from the effect of a cryogenic spray cooling procedure. The better preservation of the water balance in the stratum corneum by the cooled hydrogel pads could have a beneficial esthetic effect on laser treated areas.
Poor Reporting of Quality of Life Outcomes in Dermatology Randomized Controlled Clinical Trials
Authors: Le Cleach Laurence , Chassany Olivier , Levy Annabelle , Wolkenstein Pierre , Chosidow Olivier
Published: November 2007

Background: Because many dermatological diseases are chronic but not life-threatening, consideration of their impact on health-related quality of life (QOL) seems essential. Objective: To analyze the use of QOL as an evaluation endpoint in randomized clinical trials concerning skin diseases. Methods: Studies identified by computerized search of 3 bibliographical databases were selected, and their data on QOL as an evaluation endpoint were collected and analyzed. Results: Among the 67 studies retained, 87% did not adequately describe the questionnaires; 75% did not address handling of missing data; 95% did not calculate the number of subjects needed to obtain the desired statistical power; 95% did not disclose before-and-after results as means of overall scores and each dimension. Conclusion: Our analysis highlighted methodological weaknesses in the use of QOL questionnaire and poor reporting of QOL outcomes in randomized clinical trials.
Fibrous Papule of the Face with Granular Cells
Authors: Jacyk W.K. , Rütten A. , Requena L.
Published: November 2007

Fibrous papule of the face is a common benign lesion located most often on the nose. It presents usually as a single small, firm, skin-coloured papule and is often misdiagnosed as melanocytic naevus, wart or small nodular basal cell carcinoma. Histopathologically, the lesions are characterized by involvement of the upper dermis by a fibrovascular proliferation and scattered triangular or stellate, often multinucleated cells. Uncommon histopathologic variants of fibrous papule of the face include hypercellular, clear-cell, pleomorphic, pigmented, inflammatory and granular-cell types. We present here a patient with the syndrome of familial cancer and fibrous papule of the face with granular cells. The granules stained strongly with PAS stain, as well as with CD68 and NKI/C3 immunostains, whereas S-100 protein resulted negative. In our patient the mutations in the 2 most often affected DNA mismatch repair genes of Muir-Torre syndrome were not found, therefore the origin of the familial cancer syndrome remains unknown. Probably the occurrence of the granular-cell fibrous papule of the face was coincidental.
Exophytic Ulcerated Tumors in HIV Patients: Diagnostic and Therapeutic Problems
Authors: Lautenschlager Stephan , Schwarzkopf Stefan , Keller Beat
Published: November 2007

Two HIV-positive male patients with a rarely documented form of genital herpes are described. In both cases the atypical clinical presentation suggested neoplastic rather than infectious lesions. This tumorous genital herpes may occur in HIV-infected patients while on antiretroviral therapy. Since therapeutic failure to nucleoside analogues is common in these cases even in the absence of phenotypical resistance, other treatment options are discussed.
Azo Pigments and a Basal Cell Carcinoma at the Thumb
Authors: Engel Eva , Ulrich Heidi , Vasold Rudolf , König Burkhard , Landthaler Michael , Süttinger Rudolf , Bäumler Wolfgang
Published: November 2007

Basal cell carcinoma is the most common malignant neoplasm of the skin, whereas the localization at the nail unit is very rare. We report the case of a 58-year-old patient with a periungual basal cell carcinoma at the thumb. The specific feature of the reported case is the frequent exposure to fishing baits that the patient had stained with an unknown colorant. The use of chromatography, mass spectrometry and infrared spectroscopy revealed the colorant as the azo pigment Solvent Red 8. Solvent Red 8 is a widespread synthetic azo pigment that is applied to stain consumer products. Compounds such as Solvent Red 8 can be cleaved to carcinogenic amines under, for example, light exposure, in particular after incorporation into the human body. As a result of the frequent skin contact to this azo pigment, this hazard compound might have induced the basal cell carcinoma in our patient.
Circulating Adipocytokines in Obese Nondiabetic Patients in Relationship with Cardiovascular Risk Factors, Anthropometry and Resting-Energy Expenditure
Authors: de Luis D.A. , Gonzalez Sagrado M. , Conde R. , Aller R. , Izaola O. , Romero E.
Published: November 2007

Background: Obesity and insulin resistance are associated with cardiovascular risk factors, including altered levels of inflammatory markers and adipocytokines. The aim of the present study was to examine the relationship between circulating adipocytokines and cardiovascular risk factors. Subjects: A population of 95 obese, nondiabetic outpatients was analyzed prospectively. A complete nutritional evaluation was performed. Results: In the multivariate analysis, with leptin as a dependent variable, only fat mass remained in the model (F = 66.6; p < 0.05), with an increase of 2.24 (95% CI 1.68–2.8) ng/ml of leptin with each 1 kg of fat mass. In a new model, with adiponectin as a dependent variable, the HDL cholesterol levels remained in the model (F = 8.46; p < 0.05), with an increase of 5.38 (95% CI 1.7–9.1) ng/ml of adiponectin with each 1 mg/dl of HDL cholesterol. In a third model, with interleukin 6 (IL-6) as a dependent variable, the resistin and C-reactive protein (CRP) levels remained in the model (F = 16.8; p < 0.01), with an increase of 0.48 (95% CI 0.27–0.85) pg/ml of IL-6 with each 1 ng/ml of resistin and an increase of 0.12 (95% CI 0.029–0.214) pg/ml with each 1 mg/dl of CRP. Conclusion: Circulating adipocytokine concentrations are associated with different cardiovascular risk factors in nondiabetic obese patients.
Three-Year Tracking of Fatty Acid Composition of Plasma Phospholipids in Healthy Children
Authors: Guerra António , Demmelmair Hans , Toschke André Michael , Koletzko Berthold
Published: November 2007

Objectives: The fatty acid composition of plasma phospholipids reflects the dietary fatty acid intake as well as endogenous turnover. We aimed at investigating the potential tracking of plasma phospholipid fatty acid composition in children that participated in a prospective cohort study. Methods: 26 healthy children participated in a longitudinal study on health risks and had been enrolled after birth. All children were born at term with birth weights appropriate for gestational age. Follow-up took place at ages 24, 36 and 60 months. At each time point a 24-hour dietary recall was obtained, anthropometric parameters were measured and a blood sample for phospholipid fatty acid analysis was taken. Results: Dietary intake of saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids at the three time points were not correlated. We found lower values for plasma MUFA and the MUFA/SFA ratio at 60 months compared to 24 months. In contrast, total PUFA, total n–6 and n–6 long-chain polyunsaturated fatty acids (LC-PUFA) were higher at 60 months. Significant averaged correlation coefficients (average of Pearson’s R for 24 versus 36 months and 36 versus 60 months) were found for n–6 LC-PUFA (r = 0.67), n–6/n–3 LC-PUFA ratio (r = 0.59) and arachidonic acid/linoleic acid ratio (r = 0.64). Partial tracking was found for the docosahexaenoic acid/α-linolenic acid ratio (r = 0.33). Body mass index and sum of skinfolds Z-scores were similar in the three evaluations. Conclusions: A significant tracking of n–6 LC-PUFA, n–6 LC-PUFA/n–3 LC-PUFA ratio, arachidonic acid/linoleic acid ratio and docosahexaenoic acid/α-linolenic acid ratio may reflect an influence of individual endogenous fatty acid metabolism on plasma concentrations of some, but not all, fatty acids.
Lifestyle of School Children: Representative Survey in Metropolitan Elementary Schools – Part One
Authors: Péter Szabolcs , Regöly-Mérei Andrea , Biró Lajos , Nagy Katalin , Arató Györgyi , Szabó Csaba , Vámos Adrienn , Martos Éva , Antal Magda
Published: November 2007

Background/Aims: The prevalence of overweight and obesity among school children is increasing dramatically. Obesity is multifactorial and depends on lifestyle as well as genetic components. The purpose of the survey was to investigate the lifestyle of 7- to 14-year-old children attending elementary schools in Budapest. Methods: The research was questionnaire-based. Children were asked to answer questions about their leisure activities, physical exercise, nutritional, eating, and smoking habits. Results: Many children live a sedentary life and are dissatisfied with their body weight. One in 5 boys and 1 in 3 girls have been on a slimming diet at least once. About two-thirds of the children regularly consumed vitamin and/or mineral supplements and at the same time just over half of them knew how much fruit should be eaten daily. School children in the upper classes did not eat 5 times a day. More than 5% of the 11- to 14-year-old boys and more than 10% of the girls smoked regularly.Conclusions: According to our results, the unfavorable lifestyle of the great majority of Hungarian school children may have implications for their health during adulthood.
Dietary Habits of School Children: Representative Survey in Metropolitan Elementary Schools – Part Two
Authors: Biró Lajos , Regöly-Mérei Andrea , Nagy Katalin , Péter Szabolcs , Arató Györgyi , Szabó Csaba , Martos Éva , Antal Magda
Published: November 2007

Background/Aims: The aim of this study was to investigate the eating habits and the nutrient intake of 11- to 14-year-old school children as part of a representative nutrition and health survey in primary schools in Budapest. Methods: A food frequency questionnaire of 875 school children, aged from 11 to 14 (449 boys and 426 girls), was recorded and evaluated. Energy and nutrient intake of 235 children (124 boys and 111 girls) was calculated in parallel by 3-day dietary record. Results: The average energy intake (MJ) was appropriate (boys: 10.40 ± 1.89; girls: 9.18 ± 1.50); protein and fat intake was somewhat higher than the Hungarian recommended dietary allowances. Sodium intake was alarmingly high. The intake of calcium and vitamin D was inadequate. The intakes of zinc, chromium, retinol, folate for both genders, and iron in the case of girls were insufficient. The daily consumption of milk and dairy products was deficient, that of vegetables and fresh fruits was rather low, while the frequency of consumption of sugar-sweetened beverages, chips, sticks and fast foods was high. Conclusions: Nutrition intervention programs should be launched among Hungarian school children.
Higher Content of C18:1 Trans Fatty Acids in Early Human Milk Fat of Roma Breast-Feeding Women
Authors: Marhol P. , Dlouhý P. , Rambousková J. , Pokorný R. , Wiererová O. , Hrnčířová D. , Procházka B. , Anděl M.
Published: November 2007

Aim: The purpose of our study was to determine the content of trans fatty acids in early human breast milk as an indicator of dietary exposure in a sample of Roma breast-feeding women and in a sample of women from the general Czech population. Methods: We collected samples of early human milk from 43 Prague women from the general population and 21 Roma women. After lipid extraction, the fatty acids were converted into methyl esters (FAMEs). Finally, gas chromatography with flame ionization detector (GC-FID) analysis on a CP-Sil 88 column was used to determine C18:1 trans monoenic fatty acid levels and total trans isomers fatty acid levels in human milk. Results: A significantly higher content of C18:1 trans fatty acid isomers was detected in human milk fat from Roma mothers than in women of the general population (2.73 vs. 2.09%, p < 0.05). Both groups monitored did not differ in the representation of total fatty acid trans isomers. Differences in the frequency of consumption of certain TFA sources (butter, fried crisps) were established. Conclusions: The study proved a higher fatty acid trans isomers content in Roma breast-feeding mothers in the Czech Republic, and this is probably related to their bad eating habits.