bluuebunny/crossref_metadata_2025 huggingface dataset:
Multisensory Enhancement in the Optic Tectum of the Barn Owl: Spike Count and Spike Timing
Authors: Zahar Yael , Reches Amit , Gutfreund Yoram
Published: March 2009

Temporal and spatial correlations between auditory and visual stimuli facilitate the perception of unitary events and improve behavioral responses. However, it is not clear how combined visual and auditory information is processed in single neurons. Here we studied responses of multisensory neurons in the barn owl's optic tectum (the avian homologue of the superior colliculus) to visual, auditory, and bimodal stimuli. We specifically focused on responses to sequences of repeated stimuli. We first report that bimodal stimulation tends to elicit more spikes than in the responses to its unimodal components (a phenomenon known as multisensory enhancement). However, this tendency was found to be history-dependent; multisensory enhancement was mostly apparent in the first stimulus of the sequence and to a much lesser extent in the subsequent stimuli. Next, a vector-strength analysis was applied to quantify the phase locking of the responses to the stimuli. We report that in a substantial number of multisensory neurons responses to sequences of bimodal stimuli elicited spike trains that were better phase locked to the stimulus than spike trains elicited by stimulating with the unimodal counterparts (visual or auditory). We conclude that multisensory enhancement can be manifested in better phase locking to the stimulus as well as in more spikes.
Microarray analysis of hepatic gene expression identifies new genes involved in steatotic liver
Authors: Guillén Natalia , Navarro María A. , Arnal Carmen , Noone Enda , Arbonés-Mainar José M. , Acín Sergio , Surra Joaquín C. , Muniesa Pedro , Roche Helen M. , Osada Jesús
Published: March 2009

Trans-10, cis-12-conjugated linoleic acid (CLA)-enriched diets promote fatty liver in mice, while cis-9, trans-11-CLA ameliorates this effect, suggesting regulation of multiple genes. To test this hypothesis, apoE-deficient mice were fed a Western-type diet enriched with linoleic acid isomers, and their hepatic gene expression was analyzed with DNA microarrays. To provide an initial screening of candidate genes, only 12 with remarkably modified expression between both CLA isomers were considered and confirmed by quantitative RT-PCR. Additionally mRNA expression of 15 genes involved in lipid metabolism was also studied. Ten genes (Fsp27, Aqp4, Cd36, Ly6d, Scd1, Hsd3b5, Syt1, Cyp7b1, and Tff3) showed significant associations among their expressions and the degree of hepatic steatosis. Their involvement was also analyzed in other models of steatosis. In hyperhomocysteinemic mice lacking Cbs gene, only Fsp27, Cd36, Scd1, Syt1, and Hsd3b5 hepatic expressions were associated with steatosis. In apoE-deficient mice consuming olive-enriched diet displaying reduction of the fatty liver, only Fsp27 and Syt1 expressions were found associated. Using this strategy, we have shown that expression of these genes is highly associated with hepatic steatosis in a genetic disease such as Cbs deficiency and in two common situations such as Western diets containing CLA isomers or a Mediterranean-type diet. Conclusion: The results highlight new processes involved in lipid handling in liver and will help to understand the complex human pathology providing new proteins and new strategies to cope with hepatic steatosis.
Uncovering multiple molecular targets for caffeine using a drug target validation strategy combining A2Areceptor knockout mice with microarray profiling
Authors: Yu Liqun , Coelho Joana E. , Zhang Xiaoling , Fu Yutao , Tillman Abigail , Karaoz Ulas , Fredholm Bertil B. , Weng Zhiping , Chen Jiang-Fan
Published: March 2009

Caffeine is the most widely consumed psychoactive substance and has complex pharmacological actions in brain. In this study, we employed a novel drug target validation strategy to uncover the multiple molecular targets of caffeine using combined A2Areceptor (A2AR) knockouts (KO) and microarray profiling. Caffeine (10 mg/kg) elicited a distinct profile of striatal gene expression in WT mice compared with that by A2AR gene deletion or by administering caffeine into A2AR KO mice. Thus, A2ARs are required but not sufficient to elicit the striatal gene expression by caffeine (10 mg/kg). Caffeine (50 mg/kg) induced complex expression patterns with three distinct sets of striatal genes: 1) one subset overlapped with those elicited by genetic deletion of A2ARs; 2) the second subset elicited by caffeine in WT as well as A2AR KO mice; and 3) the third subset elicited by caffeine only in A2AR KO mice. Furthermore, striatal gene sets elicited by the phosphodiesterase (PDE) inhibitor rolipram and the GABAAreceptor antagonist bicucullin, overlapped with the distinct subsets of striatal genes elicited by caffeine (50 mg/kg) administered to A2AR KO mice. Finally, Gene Set Enrichment Analysis reveals that adipocyte differentiation/insulin signaling is highly enriched in the striatal gene sets elicited by both low and high doses of caffeine. The identification of these distinct striatal gene populations and their corresponding multiple molecular targets, including A2AR, non-A2AR (possibly A1Rs and pathways associated with PDE and GABAAR) and their interactions, and the cellular pathways affected by low and high doses of caffeine, provides molecular insights into the acute pharmacological effects of caffeine in the brain.
Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation
Authors: Mukhopadhyay Nishit K. , Kim Jayoung , Cinar Bekir , Ramachandran Aruna , Hager Martin H. , Di Vizio Dolores , Adam Rosalyn M. , Rubin Mark A. , Raychaudhuri Pradip , De Benedetti Arrigo , Freeman Michael R.
Published: March 2009

The regulation of androgen receptor (AR) expression in prostate cancer is still poorly understood. The activation of the epidermal growth factor receptor (EGFR) in prostate cancer cells was previously shown to lower AR expression by a rapamycin-sensitive, posttranscriptional mechanism involving the AR mRNA 5′-untranslated region (5′-UTR). In a search for an intermediate within the EGFR/phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway that regulates AR at this site, we identified the nucleic acid–binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNP-K), by mass spectrometric analysis of Akt immune complexes from lipid raft–enriched subcellular fractions. We show here that hnRNP-K is a novel inhibitor of AR mRNA translation that regulates androgen-responsive gene expression and prostate cancer cell proliferation. A functional hnRNP-K binding site involved in down-regulating AR protein levels was identified in the AR mRNA 5′-UTR. Further analysis revealed that hnRNP-K is also able to inhibit AR translation in the absence of the 5′-UTR, consistent with the presence of additional predicted hnRNP-K binding sites within the AR open reading frame and in the 3′-UTR. Immunohistochemical analysis of a human prostate cancer tissue microarray revealed an inverse correlation between hnRNP-K expression and AR protein levels in organ-confined prostate tumors and a substantial decline in cytoplasmic hnRNP-K in metastases, despite an overall increase in hnRNP-K levels in metastatic tumors. These data suggest that translational inhibition of AR by hnRNP-K may occur in organ-confined tumors but possibly at a reduced level in metastases. HnRNP-K is the first protein identified that directly interacts with and regulates the AR translational apparatus. [Cancer Res 2009;69(6):2210–8]
U19/Eaf2 Binds to and Stabilizes von Hippel-Lindau Protein
Authors: Xiao Wuhan , Ai Junkui , Habermacher Geoffrey , Volpert Olga , Yang Ximing , Zhang Ai-yuan , Hahn Junghyun , Cai Xiaoyan , Wang Zhou
Published: March 2009

Studies have firmly established a key regulatory role for the tumor suppressor pVHL in the regulation of the vascular system and normal spermatogenesis. Here, we report that knockout of the newly identified tumor suppressor U19/Eaf2 also caused vascular system abnormalities and aspermatogenesis, suggesting a potential link between U19/Eaf2 and pVHL. Coimmunoprecipitation and in vitro binding assays showed an association between U19/Eaf2 and pVHL, whereas deletion mutagenesis revealed the requirement of the NH2 terminus of U19/Eaf2 and both the α and β domains of pVHL for this binding. U19/Eaf2 stabilizes pVHL, as shown by protein stability and pulse-chase studies. Testes and mouse embryonic fibroblasts (MEF) derived from U19/Eaf2 knockout mice expressed reduced levels of pVHL, indicating that full in vivo expression of pVHL indeed requires U19/Eaf2. As expected, U19/Eaf2 knockout MEF cells exhibited an increased level and activity of hypoxia-inducible factor 1α (HIF1α), a protein typically regulated via a pVHL-mediated degradation pathway. Furthermore, angiogenesis in a Matrigel plug assay was significantly increased in U19/Eaf2 knockout mice. The above observations argue that U19/Eaf2 can modulate HIF1α and angiogenesis, possibly via direct binding and stabilization of pVHL. [Cancer Res 2009;69(6):2599–606]
NKX3.1 Activates Expression of Insulin-like Growth Factor Binding Protein-3 to Mediate Insulin-like Growth Factor-I Signaling and Cell Proliferation
Authors: Muhlbradt Erin , Asatiani Ekaterina , Ortner Elizabeth , Wang Antai , Gelmann Edward P.
Published: March 2009

NKX3.1 is a homeobox gene that codes for a haploinsufficient prostate cancer tumor suppressor. NKX3.1 protein levels are down-regulated in the majority of primary prostate cancer tissues. NKX3.1 expression in PC-3 cells increased insulin-like growth factor binding protein-3 (IGFBP-3) mRNA expression 10-fold as determined by expression microarray analysis. In both stably and transiently transfected PC-3 cells and in LNCaP cells, NKX3.1 expression increased IGFBP-3 mRNA and protein expression. In prostates of Nkx3.1 gene-targeted mice Igfbp-3 mRNA levels correlated with Nkx3.1 copy number. NKX3.1 expression in PC-3 cells attenuated the ability of insulin-like growth factor-I (IGF-I) to induce phosphorylation of type I IGF receptor (IGF-IR), insulin receptor substrate 1, phosphatidylinositol 3-kinase, and AKT. The effect of NKX3.1 on IGF-I signaling was not seen when cells were exposed to long-R3-IGF-I, an IGF-I variant peptide that does not bind to IGFBP-3. Additionally, small interfering RNA–induced knockdown of IGFBP-3 expression partially reversed the attenuation of IGF-IR signaling by NKX3.1 and abrogated NKX3.1 suppression of PC-3 cell proliferation. Thus, there is a close relationship in vitro and in vivo between NKX3.1 and IGFBP-3. The growth-suppressive effects of NKX3.1 in prostate cells are mediated, in part, by activation of IGFBP-3 expression. [Cancer Res 2009;69(6):2615–22]
Association of a Germ-Line Copy Number Variation at 2p24.3 and Risk for Aggressive Prostate Cancer
Authors: Liu Wennuan , Sun Jishan , Li Ge , Zhu Yi , Zhang Scott , Kim Seong-Tae , Sun Jielin , Wiklund Fredrik , Wiley Kathleen , Isaacs Sarah D. , Stattin Pär , Xu Jianfeng , Duggan David , Carpten John D. , Isaacs William B. , Grönberg Henrik , Zheng S. Lilly , Chang Bao-Li
Published: March 2009

We searched for deletions in the germ-line genome among 498 aggressive prostate cancer cases and 494 controls from a population-based study in Sweden [CAncer of the Prostate in Sweden (CAPS)] using Affymetrix SNP arrays. By comparing allele intensities of ∼500,000 SNP probes across the genome, a germ-line deletion at 2p24.3 was observed to be significantly more common in cases (12.63%) than in controls (8.28%); P = 0.028. To confirm the association, we genotyped this germ-line copy number variation (CNV) in additional subjects from CAPS and from Johns Hopkins Hospital (JHH). Overall, among 4,314 cases and 2,176 controls examined, the CNV was significantly associated with prostate cancer risk [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.06–1.48; P = 0.009]. More importantly, the association was stronger for aggressive prostate cancer (OR, 1.31; 95% CI, 1.08–1.58; P = 0.006) than for nonaggressive prostate cancer (OR, 1.19; 95% CI, 0.98–1.45; P = 0.08). The biological effect of this germ-line CNV is unknown because no known gene resides in the deletion. Results from this study represent the first novel germ-line CNV that was identified from a genome-wide search and was significantly, but moderately, associated with prostate cancer risk. Additional confirmation of this association and functional studies are warranted. [Cancer Res 2009;69(6):2176–9]
Mitochondrial Uncoupling and the Warburg Effect: Molecular Basis for the Reprogramming of Cancer Cell Metabolism
Authors: Samudio Ismael , Fiegl Michael , Andreeff Michael
Published: March 2009

The precise mitochondrial alterations that underlie the increased dependence of cancer cells on aerobic glycolysis for energy generation have remained a mystery. Recent evidence suggests that mitochondrial uncoupling—the abrogation of ATP synthesis in response to mitochondrial membrane potential—promotes the Warburg effect in leukemia cells, and may contribute to chemoresistance. Intriguingly, leukemia cells cultured on bone marrow–derived stromal feeder layers are more resistant to chemotherapy, increase the expression of uncoupling protein 2, and decrease the entry of pyruvate into the Krebs cycle—without compromising the consumption of oxygen, suggesting a shift to the oxidation of nonglucose carbon sources to maintain mitochondrial integrity and function. Because fatty acid oxidation has been linked to chemoresistance and mitochondrial uncoupling, it is tempting to speculate that Warburg's observations may indeed be the result of the preferential oxidation of fatty acids by cancer cell mitochondria. Therefore, targeting fatty acid oxidation or anaplerotic pathways that support fatty acid oxidation may provide additional therapeutic tools for the treatment of hematopoietic malignancies. [Cancer Res 2009;69(6):2163–6]
Rethinking “Cancer as a Dynamic Developmental Disorder” a Quarter Century Later
Authors: Rubin Harry
Published: March 2009

In a Perspectives article of 1985 in Cancer Research, I discussed evidence for a nonmutational origin of teratocarcinoma, and cited related claims in liver carcinogenesis, which I later broadened to include spontaneous transformation in cell culture. Further research on spontaneous transformation cast doubt on that interpretation, and motivated re-examination of the cases for teratocarcinomas and liver cancer. This re-examination led to the conclusion that mutation and selection underlie the development of neoplasia in all three cases. At the same time, it affirmed the primary role of hierarchical tissue structure and intercellular relations in maintaining homeostasis, which was the major theme of the 1985 article. Tumor promotion disrupts intercellular relations to allow progressively selective proliferation of initiated cells and accompanying clonal accumulation of genetic change. [Cancer Res 2009;69(6):2171–5]
Tolfenamic acid enhances pancreatic cancer cell and tumor response to radiation therapy by inhibiting survivin protein expression
Authors: Konduri Santhi , Colon Jimmie , Baker Cheryl H. , Safe Stephen , Abbruzzese James L. , Abudayyeh Ala , Basha Md. Riyaz , Abdelrahim Maen
Published: March 2009

Survivin is overexpressed in most human cancers, including pancreatic adenocarcinoma. Expression of survivin is regulated by specificity protein (Sp) proteins and related to resistance to radiation therapy. Tolfenamic acid induces Sp protein degradation in several cancer cell lines. The purpose of this study is to investigate whether tolfenamic acid inhibits survivin expression and sensitizes pancreatic cancer cells/tumor to radiotherapy. Panc1 and L3.6pl cells have been used to study the effect of radiation on survivin expression and to investigate the efficacy of tolfenamic acid in enhancing the response to radiation therapy. In addition, an orthotopic model for human pancreatic cancer has been used to confirm the efficacy of tolfenamic acid to enhance tumor response to radiation in vivo. Pancreatic cancer cell lines express variable levels of survivin mRNA/protein, which correlate with their radiosensitivity. Radiation increased survivin promoter activity and protein expression in Panc1 and L3.6pl cells and tolfenamic acid inhibited both constitutive and radiation-induced survivin protein expression and enhanced the response of pancreatic cancer cells to radiation therapy. In vivo studies show that tolfenamic acid enhanced the radiation-induced apoptosis associated with decreased survivin expression in tumors and this correlates with the enhanced response of these tumors to the radiation. Thus, tolfenamic acid significantly enhances pancreatic cancer cells/tumor response to radiation therapy. The underlying mechanism includes tolfenamic acid-induced degradation of Sp proteins, which in tumor decreases expression of the Sp-dependent antiapoptotic protein survivin. These preclinical data suggest that tolfenamic acid has the potential to increase the response of pancreatic adenocarcinoma to radiation therapy. [Mol Cancer Ther 2009;8(3):533–42]
The small organic compound HMN-176 delays satisfaction of the spindle assembly checkpoint by inhibiting centrosome-dependent microtubule nucleation
Authors: DiMaio Michael A. , Mikhailov Alexei , Rieder Conly L. , Von Hoff Daniel D. , Palazzo Robert E.
Published: March 2009

HMN-176 is a potential new cancer therapeutic known to retard the proliferation of tumor cell lines. Here, we show that this compound inhibits meiotic spindle assembly in surf clam oocytes and delays satisfaction of the spindle assembly checkpoint in human somatic cells by inducing the formation of short and/or multipolar spindles. HMN-176 does not affect centrosome assembly, nuclear envelope breakdown, or other aspects of meiotic or mitotic progression, nor does it affect the kinetics of Spisula or mammalian microtubule (MT) assembly in vitro. Notably, HMN-176 inhibits the formation of centrosome-nucleated MTs (i.e., asters) in Spisula oocytes and oocyte extracts, as well as from isolated Spisula or mammalian centrosomes in vitro. Together, these results reveal that HMN-176 is a first-in-class anticentrosome drug that inhibits proliferation, at least in part, by disrupting centrosome-mediated MT assembly during mitosis. [Mol Cancer Ther 2009;8(3):592–601]
The phytochemical piceatannol induces the loss of CBL and CBL-associated proteins
Authors: Klimowicz Alexander C. , Bisson Sabine A. , Hans Karm , Long Elizabeth M. , Hansen Henrik C. , Robbins Stephen M.
Published: March 2009

Piceatannol is a naturally occurring bioactive stilbene with documented antileukemic properties. It has been extensively used as a Syk-selective protein tyrosine kinase inhibitor for the study of various signaling pathways. Herein, we show that the hydroxystilbene, piceatannol, and related catechol ring-containing compounds are able to induce the loss of the Cbl family of proteins. Normal cellular Cbl-regulatory mechanisms were not involved in this process. Screening of a small library of piceatannol-like compounds indicated that aromaticity and a catechol ring were required for the induction of Cbl loss. Further examination of these two chemical properties showed that the oxidative conversion of the catechol ring of piceatannol into a highly reactive O-benzoquinone was the cause of piceatannol-induced Cbl loss. Characterization of the Cbl selectivity of piceatannol-induced protein loss revealed that this compound was also able to induce the functional loss of specific Cbl-associated proteins involved in signaling pathways commonly associated with cancer. This work uncovers a new, piceatannol-dependent effect and shows a novel way in which this phenomenon can be exploited to inhibit disease-associated signaling pathways. [Mol Cancer Ther 2009;8(3):602–14]
Angiogenin-Stimulated rRNA Transcription Is Essential for Initiation and Survival of AKT-Induced Prostate Intraepithelial Neoplasia
Authors: Ibaragi Soichiro , Yoshioka Norie , Kishikawa Hiroko , Hu Jamie K. , Sadow Peter M. , Li Ming , Hu Guo-fu
Published: March 2009

Angiogenin (ANG), originally identified as an angiogenic ribonuclease, has recently been shown to play a direct role in prostate cancer cell proliferation by mediating rRNA transcription. ANG is up-regulated in human prostate cancer and is the most significantly up-regulated gene in AKT-driven prostate intraepithelial neoplasia (PIN) in mice. Enhanced cell proliferation in the PIN lesions requires increased ribosome biogenesis, a multistep process involving an orchestrated production of ribosomal proteins and rRNA. AKT is known to enhance ribosomal protein production through the mammalian target of rapamycin pathway. However, it was unknown how rRNA is proportionally increased. Here, we report that ANG is essential for AKT-driven PIN formation and survival. We showed that up-regulation of ANG in the AKT-overexpressing mouse prostates is an early and lasting event. It occurs before PIN initiation and lasts beyond PIN is fully developed. Knocking down ANG expression by intraprostate injection of lentivirus-mediated ANG-specific small interfering RNA prevents AKT-induced PIN formation without affecting AKT expression and its signaling through the mammalian target of rapamycin pathway. Neomycin, an aminoglycoside that blocks nuclear translocation of ANG, and N65828, a small-molecule enzymatic inhibitor of the ribonucleolytic activity of ANG, both prevent AKT-induced PIN formation and reverse established PIN. They also decrease nucleolar organizer region, restore cell size, and normalize luminal architectures of the prostate despite continuous activation of AKT. All three types of the ANG inhibitor suppress rRNA transcription of the prostate luminal epithelial cells and inhibit AKT-induced PIN, indicating an essential role of ANG in AKT-mediated cell proliferation and survival. (Mol Cancer Res 2009;7(3):415–24)
Interleukin-24 Induces Expression of β4 Integrin but Suppresses Anchorage-Independent Growth of Rat Mammary Tumor Cells by a Mechanism That Is Independent of β4
Authors: Xuan Wanli , Li You-Jun , Liu Guodong , Ben-David Yaacov , Archer Michael C.
Published: March 2009

Wistar-Furth rats develop multiple mammary adenocarcinomas following initiation with methylnitrosourea, whereas Copenhagen rats are resistant to the development of mammary tumors. We have previously isolated cell lines from tumors induced in resistant Copenhagen × Wistar-Furth F1 rats by infusion of a retrovirus harboring v-Ha-ras directly into the main mammary ducts. Some of the cell lines were able to grow in soft agar, but a significant number did not display anchorage-independent growth. Here, we compared by microarray analysis genes that are differentially expressed in these cell lines. The expression of interleukin-24 (IL-24) and β4 integrin was highly correlated with the inability of cells to grow in soft agar. Ectopic expression of IL-24 in anchorage-independent cells inhibited their growth in monolayer culture, in soft agar, and in nude mice in vivo and inhibited their ability to migrate and invade in in vitro assays. Furthermore, growth suppression by IL-24 was associated with the transcriptional up-regulation of p27Kip1 via the activation of Stat3. We showed, for the first time, that β4 integrin is a downstream target of IL-24. However, β4 does not play a direct role in regulating the proliferative capacity of rat mammary tumor cells. Our results show that IL-24 suppresses the growth of rat mammary carcinoma cells and may play a role in the resistance of Copenhagen rats to mammary carcinogenesis. (Mol Cancer Res 2009;7(3):433–42)
Akt/Protein Kinase B and Glycogen Synthase Kinase-3β Signaling Pathway Regulates Cell Migration through the NFAT1 Transcription Factor
Authors: Yoeli-Lerner Merav , Chin Y. Rebecca , Hansen Christopher K. , Toker Alex
Published: March 2009

The phosphoinositide 3-kinase (PI3K) pathway regulates a multitude of cellular processes. Deregulation of PI3K signaling is often observed in human cancers. A major effector of PI3K is Akt/protein kinase B (PKB). Recent studies have pointed to distinct roles of Akt/PKB isoforms in cancer cell signaling. Studies have shown that Akt1 (PKBα) can attenuate breast cancer cell motility, whereas Akt2 (PKBβ) enhances this phenotype. Here, we have evaluated the mechanism by which Akt1 blocks the migration of breast cancer cells through the transcription factor NFAT. A major effector of Akt/PKB is glycogen synthase kinase-3β (GSK-3β), also a NFAT kinase. Inhibition of GSK-3β using short hairpin RNA or a selective inhibitor potently blocks breast cancer cell migration concomitant with a reduction in NFAT activity. GSK-3β-mediated inhibition of NFAT activity is due to proteasomal degradation. Experiments using GSK-3β mutants, which are unresponsive to Akt/PKB, reveal that inhibition of cell migration by Akt/PKB is mediated by GSK-3β. These effects are recapitulated at the levels of NFAT degradation by the proteasome. Our studies show that activation of Akt/PKB leads to inactivation of the effector GSK-3β and the outcome of this signaling event is degradation of NFAT by the proteasome and subsequent inhibition of cell migration. (Mol Cancer Res 2009;7(3):425–32)
Bioactive Food Components, Inflammatory Targets, and Cancer Prevention
Authors: Kim Young S. , Young Matthew R. , Bobe Gerd , Colburn Nancy H. , Milner John A.
Published: March 2009

Various dietary components may modify chronic inflammatory processes at the stage of cytokine production, amplification of nuclear factor-κB–mediated inflammatory gene expression, and the release of anti-inflammatory cytokine, transforming growth factor-β. This review provides a synopsis of the strengths and weaknesses of the evidence that specific bioactive food components influence inflammation-related targets linked to cancer. A target repeatedly surfacing as a site of action for several dietary components is transforming growth factor β. Whereas the use of dietary intervention strategies offers intriguing possibilities for maintaining normal cell function by modifying a process that is essential for cancer development and progression, more information is needed to characterize the minimum quantity of the bioactive food components required to bring about a change in inflammation-mediated cancer, the ideal time for intervention, and the importance of genetics in determining the response. Unquestionably, the societal benefits of using foods and their components to prevent chronic inflammation and associated complications, including cancer, are enormous.
Effects of Vitamin D and Calcium Supplementation on Markers of Apoptosis in Normal Colon Mucosa: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial
Authors: Fedirko Veronika , Bostick Roberd M. , Flanders W. Dana , Long Qi , Shaukat Aasma , Rutherford Robin E. , Daniel Carrie R. , Cohen Vaunita , Dash Chiranjeev
Published: March 2009

To further clarify and/or develop calcium and vitamin D as chemopreventive agents against colorectal cancer in humans, understand the mechanisms by which these agents reduce risk for the disease, and develop “treatable” biomarkers of risk for colorectal cancer, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial to test the effects of calcium and vitamin D3, alone and in combination on markers of apoptosis, in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2.0 g/d calcium or 800 IU/d vitamin D3, alone or in combination, versus placebo over 6 months. Overall expression and colorectal crypt distributions of Bcl-2 (an apoptosis inhibitor) and Bax (an apoptosis promoter) in biopsies of normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, Bax expression along the full lengths of crypts increased 56% (P = 0.02) in the vitamin D group and 33% in both the calcium (P = 0.31) and calcium plus vitamin D (P = 0.36) groups relative to the placebo group. The vitamin D treatment effect was more pronounced in the upper 40%, or differentiation zone, of crypts (80%; P = 0.01). There were no statistically significant treatment effects on Bcl-2 expression. Overall, these preliminary results suggest that calcium and vitamin D, individually or together, may enhance apoptosis in the normal human colorectal epithelium, and the strongest treatment effects may be vitamin D related and in the upper sections of the colorectal crypts.
Foodstuffs for Preventing Cancer: The Preclinical and Clinical Development of Berries
Authors: Stoner Gary D.
Published: March 2009

Laboratory research involving berries is a promising example of food-based cancer prevention. Berries contain many known chemopreventive agents such as anthocyanins and ellagitannins that can be greatly concentrated in freeze-dried berry powders. Based on our program of berry research, this commentary presents the first reported stepwise scheme for the preclinical and clinical development of foodstuffs for cancer prevention. Our preclinical work within this scheme includes promising approaches for assessing the chemopreventive potential of berry powder and berry extracts in preclinical model systems, for determining the mechanisms of action of these agents, and for identifying the active constituents in berries. The commentary also presents preliminary results of clinical trials in the oral cavity, esophagus, and colon using various formulations of freeze-dried berries. The relative merits of berry powders, extracts, or individual constituents (anthocyanins) for cancer prevention are also discussed.
Role of Steroid Hormone Coregulators in Health and Disease
Authors: Thakur M.K. , Paramanik V.
Published: March 2009

The involvement of coactivators and corepressors, collectively termed as coregulators, increases the complexity of regulation of steroid hormone action. Following the interaction of the steroid hormone-receptor complex with the specific nucleotide sequences of target genes, the coregulators are recruited for activation or suppression of specific genes. The coregulators regulate a number of hormonal events during pregnancy, sex differentiation, development, reproduction and sexual behavior. They also exert equally important functions in non-reproductive tissues like heart, kidney, pancreas, bone and brain. The mutation and/or aberrant expression of these coregulators affect the normal function of steroid hormones and result in physiological abnormalities leading to the development of diseases. Therefore, understanding the role of coregulators in steroid hormone action is important and would help in developing the therapeutic strategy for the treatment of steroid-related diseases. In this review article, we describe the coregulators and their implication in health and pathogenesis of diseases. Furthermore, the possible therapeutic approach has been discussed for the treatment of steroid-related diseases, which will be of future interest in the field of medical sciences.
Screening for Associated Autoimmunity in Children and Adolescents with Type 1 Diabetes Mellitus (T1DM)
Authors: Karavanaki Kyriaki , Kakleas Kostas , Paschali Evangelia , Kefalas Nikos , Konstantopoulos Ilias , Petrou Vassilis , Kanariou Maria , Karayianni Christina
Published: March 2009

Background/Aims: Type 1 diabetes (T1DM) is associated with autoimmune thyroid, celiac, autoimmune gastric and Addison’s disease. Our aim was to investigate the prevalence of associated autoantibodies in relation to the demographic and β-cell autoantibody status (anti-GAD). Methods: Antibodies against thyroid peroxidase (anti-TPO), thyroglobulin (anti-Tg), tissue transglutaminase (anti-tTG IgA), parietal cells (APCA) and adrenal tissue (AAA) were measured in 144 children with T1DM with a mean ± SD age of 12.3 ± 4.6 years and a diabetes duration of 4.6 ± 3.8 years. Results: The prevalence of antibody positivity among our patients was: anti-GAD 53.2%, anti-thyroid (anti-TPO 17.4%, anti-Tg 11.1%); anti-tTG IgA 7.6%, APCA 4.0%, and AAA 0%. Among the children with positive anti-thyroid antibodies, 60% developed autoimmune thyroiditis, while among those anti-tTG IgA positive, 62.5% developed biopsy-confirmed celiac disease. Female gender was more frequent among anti-tTG IgA-positive patients (OR 4.47, p = 0.068), while increasing age was associated with anti-Tg positivity (OR 22.9, p = 0.041). The presence of anti-thyroid antibodies was associated with the presence of anti-GAD (OR 1.45, p = 0.01) and parietal cell antibodies (OR 4.98, p = 0.09). Conclusion: Among T1DM patients, the prevalence rates of anti-thyroid and parietal cell antibodies increased with age and diabetes duration. As the presence of anti-GAD was associated with gastric and thyroid autoimmunity, it could serve as marker for the development of additional autoimmunity in adolescents with diabetes.
Decrease in Adiponectin Levels Correlates to Growth Response in Growth Hormone-Treated Children
Authors: Andersson B. , Carlsson L.M.S. , Carlsson B. , Albertsson-Wikland K. , Bjarnason R.
Published: March 2009

Background/Aims: Adiponectin is secreted by adipose tissue and circulates in human plasma at high levels. Decreased adiponectin levels are associated with insulin resistance and obesity. The aim of this study was to investigate whether changes in serum adiponectin levels are related to the growth response, insulin levels and insulin resistance during growth hormone (GH) treatment. Methods: The study included 94 short prepubertal children (19 girls and 75 boys). The mean age at the start of daily GH injections was 9.04 ± 2.38 years. Adiponectin levels in serum were measured using an ELISA. Results: At baseline, adiponectin correlated with the first-year growth response (r = 0.26, p = 0.012). Adiponectin decreased significantly after 1 week, 3 months and 1 year from 14.5 ± 5.71 to 13.1 ± 5.22 (p < 0.0001), 10.3 ± 4.82 (p < 0.0001) and 12.5 ± 5.34 μg/ml (p < 0.0001), respectively. There were significant correlations between the first-year growth response and the decrease in adiponectin levels after 3 months and 1 year (r = –0.38, p < 0.0001 and r = –0.47, p < 0.0001, respectively). No correlations between adiponectin, insulin and the homeostasis model assessment of insulin resistance were seen. Conclusions: GH treatment in prepubertal children decreases serum adiponectin levels, and the decrease is correlated to the growth response. No correlations between adiponectin and insulin levels or insulin resistance were found.
Androgen Receptor Modulation Does Not Affect Longitudinal Growth of Cultured Fetal Rat Metatarsal Bones
Authors: Chagin Andrei S. , Vannesjö Johanna , Sävendahl Lars
Published: March 2009

Background: Systemic administration of the nonaromatizable androgen oxandrolone stimulates growth in girls with Turner syndrome and boys with a constitutional delay of growth and puberty. It is unknown if oxandrolone acts locally at the growth plate level to stimulate longitudinal bone growth. Methods: Metatarsal bones from female and male rat fetuses (day E20) were cultured for 14 days in the presence of oxandrolone, testosterone or the androgen receptor (AR) antagonist flutamide with/without insulin-like growth-factor-I (IGF-I) or charcoal-treated serum. Results: The AR was found to be expressed in both male and female fetal rat metatarsal bones. Neither oxandrolone nor testosterone had any effect on metatarsal bone growth when tested at a wide concentration range (1 nM to 10 μM), not even in the presence of IGF-I (100 ng/ml) or charcoal-treated serum (10%). Bone growth was also unaffected when the AR was blocked by flutamide. Control experiments confirmed that metatarsal bone growth was significantly stimulated by IGF-I (p < 0.001). Conclusion: Modulation of AR activity in the fetal rat growth plate does not affect linear bone growth. Extrapolating from these in vitro data, it could be speculated that oxandrolone stimulates longitudinal bone growth in treated children by acting indirectly rather than directly through AR activation in growth plate chondrocytes.
Long-Acting Lanreotide in Adolescent Girls with Constitutional Tall Stature
Authors: Carel Jean-Claude , Blumberg Joëlle , Bougeard-Julien Muriel , Rochiccioli Pierre , Chaussain Jean-Louis , Tauber Maïthé
Published: March 2009

Background/Aims: The aim of the study was to evaluate the efficacy and safety of lanreotide prolonged release (PR) 30 mg (long-acting lanreotide) in girls with constitutional tall stature (CTS). Methods: This open label prospective study included 35 girls (mean age 12.6 years) with CTS and a predicted adult height of >180 cm. Intramuscular injections of lanreotide PR 30 mg were given every 14 days, for a minimum of 12 months and up to 36 months. Adult height was compared with pretreatment predicted height. Results: The mean predicted adult height was reduced by 3.8 cm (95% CI 3.7–4.9 cm) in the restricted intent-to-treat population. Mean growth velocity decreased from 7.9 ± 1.5 cm/year at preinclusion to 1.7 ± 2.3 cm/year at the last visit on treatment (n = 35). Gastrointestinal adverse events and cholelithiasis were reported in 35/37 patients and 5/37 patients, respectively. There was 1 withdrawal due to gastrointestinal disorders. Conclusions: Biweekly intramuscular lanreotide PR 30 mg given to girls with CTS after the onset of pubertal development reduced adult height as compared with predicted height. Treatment-associated adverse events were consistent with the overall safety profile of lanreotide 30 mg PR and did not deter most patients from long-term treatment.
Discordance for X-Linked Hypophosphataemic Rickets in Identical Twin Girls
Authors: Owen Catherine J. , Habeb Abdul , Pearce Simon H.S. , Wright Michael , Ichikawa Shoji , Sorenson Andrea H. , Econs Michael J. , Cheetham Tim D.
Published: March 2009

Background: We report monozygotic twin girls with a family history consistent with X-linked hypophosphataemic rickets (XLH). One twin had a skeletal and biochemical phenotype consistent with XLH, whilst the second twin appeared normal. Complete non-penetrance in XLH has not been previously reported and our aim was to explore potential reasons for this. Methods: Serum and urine biochemistry were analysed at regular intervals. Microsatellite analysis was performed to confirm monozygosity and bi-parental inheritance of the X chromosome. The X chromosome inactivation pattern was studied in peripheral blood. Exons of the paternal PHEX and FGF23 genes were sequenced. Results: Biochemistry was persistently abnormal in the slow-growing twin 1 and normal in twin 2 who has grown normally. Maximal tubular phosphate reabsorption was 0.68 mmol/l in twin 1 and 1.64 mmol/l in twin 2 at 10.8 years of age (normal 1.15–2.58 mmol/l). Microsatellite analysis confirmed monozygosity and the X chromosome inactivation pattern was random. These studies also excluded uniparental isodisomy. The exon sequence of paternal PHEX and FGF23 genes was normal. Conclusions: Discordant X inactivation is a well-recognised phenomenon in identical twins, and we suspect that non-random expression of the normal PHEX gene in critical tissues is the most likely explanation for non-penetrance.
Tonsillar Herniation and Cervical Syringomyelia Due to Postoperative Meningitis in Case of Pineal Region Epidermoid
Authors: Muzumdar Dattatraya , Balasubramanian Srikant , Goel Atul
Published: March 2009

The occurrence of tonsillar herniation and syringomyelia in association with tumor-induced obstructive hydrocephalus has been described in literature. In midline tumors, the symptomatology is predominantly due to hydrocephalus and resultant tonsillar herniation, but the treatment is primarily directed towards the tumor. A case of a pineal region epidermoid in a 17-year-old boy – in whom postoperative meningitis resulted in hydrocephalus, symptomatic tonsillar herniation and cervical syringomyelia – is presented here. Although the tumor was resected and cerebrospinal pathways were established, a ventriculoperitoneal shunt insertion was required for persistent symptomatic hydrocephalus. At serial follow-up after 2 years, the patient was asymp- tomatic and MR imaging showed a reduction in size of the cervical syrinx, but there was no significant ascent of the tonsils. The occurrence of tonsillar herniation and syringomyelia following postoperative meningitis in a case of pineal region epidermoid is uncommon and has not been reported till now. Cerebrospinal diversion procedure will most often be required in such a situation for symptomatic relief. The resolution of tonsillar herniation and syringomyelia may not always be complete on serially documented neuroimaging in such a situation. Stabilization of the previously progressive neurological course is the realistic goal. The need for an additional surgical procedure for associated tonsillar herniation and syringomyelia is advocated only if there is progressive neurological worsening.
CNS Tumor 22 Years after Spinal Neuroblastoma IV: Diagnostic Dilemma between Recurrence and Secondary Malignancy
Authors: Gutenberg Angelika , Schulten Hans-Jürgen , Gunawan Bastian , Ludwig Hans-Christoph , Brück Wolfgang , Larsen Jörg , Rohde Veit
Published: March 2009

We present the very unusual case of a young woman suffering from a brain tumor 22 years after a stage IV spinal neuroblastoma as an infant, demonstrating the difficulties of differentiating late neuroblastoma relapse from secondary supratentorial primitive neuroectodermal tumor (sPNET). Lacking specific immunohistochemical features, the first cerebral tumor at the age of 21 was regarded as sPNET, and we pursued a therapeutic approach consisting of neurosurgical resection as well as irradiation and high-dose alkylator-based chemotherapy according to the HIT2000 protocol. Two years later the patient suffered from a diffusely infiltrating local recurrence, changing its imaging appearance as well as its immunohistochemical characteristics, now revealing disseminated positivity for neuron-specific enolase and neural cell adhesion molecule. Moreover, the lack of PNET-specific translocations (EWS/FLI1 gene fusion) in both brain tumors as well as the development of hepatic metastases was more compatible with the diagnosis of a very late relapse 22 years after initial stage IV spinal neuroblastoma.
Add-On Benefits of Amlodipine and Thiazide in Nondiabetic Chronic Kidney Disease Stage 1/2 Patients Treated with Valsartan
Authors: Kaneshiro Yuki , Ichihara Atsuhiro , Sakoda Mariyo , Kurauchi-Mito Asako , Kinouchi Kenichiro , Itoh Hiroshi
Published: March 2009

Hypertension frequently requires combination therapy to attain efficient control to prevent cardiovascular diseases effectively. This study was conducted to determine which add-on treatment is better, namely calcium channel blockers or diuretics, in improving vascular damage. In 70 nondiabetic chronic kidney disease stage 1/2 patients who had been already treated with angiotensin II type 1 receptor blocker valsartan for at least 12 months, amlodipine or hydrochlorothiazide was added to their existing medication. Pulse wave velocity (PWV), intima-media thickness (IMT) of the carotid arteries, urinary albumin excretion (UAE), and 24-hour ambulatory blood pressure (BP) were determined before and 12 months after the start of add-on treatments. Add-on amlodipine and add-on hydrochlorothiazide significantly and similarly decreased 24-hour ambulatory BP by 18 and 19 mm Hg, respectively, PWV by 206 and 184 cm/s, respectively, and UAE, but did not change the IMT. The decreases in BP significantly contributed to the decreases in PWV and UAE and suggested that the decrease in serum cholesterol level brought about by add-on amlodipine also contributed to the decrease in UAE. These results suggest that 12 months of add-on treatment with either amlodipine or hydrochlorothiazide could have beneficial effects in nondiabetic chronic kidney disease stage 1/2 patients already being treated with valsartan.
Local Hemodynamics of the Vascular Access for Hemodialysis
Authors: Malik J. , Tuka V. , Tesař V.
Published: March 2009

Vascular access is called Achilles’ heel of hemodialysis because it is associated with a substantial morbidity. A permanent vascular access is created either by a direct connection of the patient’s own artery and vein or by the interposition of a graft. Arteriolar beds are bypassed, which leads to a substantial increase in arterial (and venous) flow and the vessels adapt to it by a complex of interesting processes. These are reviewed together with some pathophysiological mechanisms of access complications.
Oxidative Challenge and Glucose-6-Phosphate Dehydrogenase Activity of Preterm and Term Neonatal Red Blood Cells
Authors: Ko Chun Hay , Wong Raymond Pui-On , Ng Pak Cheung , Li Karen , Chui Kit Man , Yuen Patrick Man-Pan , Fok Tai Fai
Published: March 2009

Background: Recent studies suggest that a low antioxidant level in preterm infants may predispose them to increased oxidative stress and results in hyperbilirubinemia, whereas glucose-6-phosphate dehydrogenase (G6PD) activity was found to be higher in preterm infants than in term infants. Objectives: To evaluate (1) the oxidative effect of α-naphthol on preterm and term red blood cells, and (2) the relationship between G6PD activity and the gestational age of these infants. Methods: G6PD activities were determined in preterm and term infants by a standard diagnostic method. Whole blood samples were incubated with α-naphthol for 2 h and their pre- and post-challenged reduced glutathione (GSH) levels were quantified. Results: The mean G6PD activity in preterm infants (n = 113; 13.52 ± 0.19 U/g Hb; gestational age 30.67 ± 0.28 weeks) was significantly higher than that in term infants (n = 100; 12.36 ± 0.16 U/g Hb; gestational age 39.82 ± 0.14 weeks; p < 0.001). A significantly negative correlation was demonstrated between gestational age and G6PD activity (r = –0.34, p < 0.001). GSH levels of preterm and term subjects were similar at baseline, but were significantly decreased upon challenge with α-naphthol (p < 0.001). The percentage reduction in GSH levels was similar in the various gestational age groups. Conclusions: Our data show that G6PD activities had a negative correlation with gestational age of G6PD-normal infants. The similar response of preterm and term erythrocytes to an α-naphthol challenge indicates the manifestation of an active anti-oxidative pathway mediated by cellular GSH.
Glutathione S-Transferase Variants in a Brazilian Population
Authors: Magno Luiz Alexandre V. , Talbot Jhimmy , Talbot Teddy , Borges Santos Alex Marques , Souza Renan P. , Marin Lauro J. , Moreli Marcos Lázaro , de Melo Paulo R.S. , Corrêa Ronan X. , Rios Santos Fabrício , Di Pietro Giuliano
Published: March 2009

Recent pharmacogenomic studies have revealed significant interethnic differences in glutathione S-transferase (GST) allelic frequencies among various ethnic groups. Therefore, we have investigated GSTM1 (gene deletion), GSTT1 (gene deletion) and GSTP1 (rs1695) polymorphism frequencies in 3 Brazilian ethnic groups (n = 203). GSTM1 and GSTT1 polymorphism analyses were performed by multiplex polymerase chain reaction, and GSTP1 (rs1695) analysis was done by polymerase chain reaction restriction fragment length polymorphism. GSTM1– polymorphism frequency was 33.2%, while GSTT1 null (GSTT1–) was 30.2%. The valine GSTP1*B (rs1695) allele was present in 35.1% subjects, while the heterozygous form (isoleucine/valine) was the most prevalent genotype (46.6%). We found a statistically significant difference in genotype frequency among Amerindians versus Caucasians (p = 0.016) and among Amerindians versus African-Americans (p = 0.033). Considerable frequency variation was found in our study, even when compared with other studies showing phylogeographical heterogeneity to the genes studied in Brazilian populations.