bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving estimates of genetic maps: a meta‐analysis‐based approach
Authors: Stewart William C. L.
Published: April 2007

Inaccurate genetic (or linkage) maps can reduce the power to detect linkage, increase type I error, and distort haplotype and relationship inference. To improve the accuracy of existing maps, I propose a meta‐analysis‐based method that combines independent map estimates into a single estimate of the linkage map. The method uses the variance of each independent map estimate to combine them efficiently, whether the map estimates use the same set of markers or not. As compared with a joint analysis of the pooled genotype data, the proposed method is attractive for three reasons: (1) it has comparable efficiency to the maximum likelihood map estimate when the pooled data are homogeneous; (2) relative to existing map estimation methods, it can have increased efficiency when the pooled data are heterogeneous; and (3) it avoids the practical difficulties of pooling human subjects data. On the basis of simulated data modeled after two real data sets, the proposed method can reduce the sampling variation of linkage maps commonly used in whole‐genome linkage scans. Furthermore, when the independent map estimates are also maximum likelihood estimates, the proposed method performs as well as or better than when they are estimated by the program CRIMAP. Since variance estimates of maps may not always be available, I demonstrate the feasibility of three different variance estimators. Overall, the method should prove useful to investigators who need map positions for markers not contained in publicly available maps, and to those who wish to minimize the negative effects of inaccurate maps.Genet. Epidemiol. 2007. © 2007 Wiley‐Liss, Inc.
A range of simple summary genome‐wide statistics for detecting genetic linkage using high density marker data
Authors: Saunders Ian W. , Hannan Garry N. , Brohede Jesper , Giles Graham G. , Jenkins Mark A. , Hopper John L. , Southey Melissa C.
Published: April 2007

A simple approach to design and analysis of genome‐wide linkage scans is described, based on an approximation to the joint distribution of likelihood ratio statistics at a large number of single nucleotide polymorphism (SNP) loci. The approximation is readily calculated and makes it feasible to study the test properties of a range of summary statistics for the entire sequence of point‐wise test values. Both the null distribution in the absence of genetic effects and the alternative distribution under various models of single or multi‐gene inheritance can readily be simulated. This allows the power of a variety of statistics to be evaluated. The most powerful statistics proved to be the “quantile statistics” defined as quantiles of the set of pointwise test statistics. As a proof of principle study, the method was applied to a small dataset of 40 individuals from 8 families known to be segregating mutations in one or other of the DNA mismatch repair genes, MLH1 and MSH2. These included seven affected sib pairs and 11 discordant sib pairs, who were genotyped at 57,429 autosomal SNPs using the Affymetrix GeneChip Human Mapping 50 k Xba 240 Array. While the sample size was not sufficient to detect the linkage, there was a clear signal at the MLH1 location indicating that relatively small sample sizes would have been adequate to detect linkage to this gene. Genet. Epidemiol. 2007. © 2007 Wiley‐Liss, Inc.
A new association test using haplotype similarity
Authors: Sha Qiuying , Chen Huann‐Sheng , Zhang Shuanglin
Published: April 2007

Association tests based on multi‐marker haplotypes may be more powerful than those based on single markers. The existing association tests based on multi‐marker haplotypes include Pearson's χ2 test which tests for the difference of haplotype distributions in cases and controls, and haplotype‐similarity based methods which compare the average similarity among cases with that of the controls. In this article, we propose new association tests based on haplotype similarities. These new tests compare the average similarities within cases and controls with the average similarity between cases and controls. These methods can be applied to either phase‐known or phase‐unknown data. We compare the performance of the proposed methods with Pearson's χ2 test and the existing similarity‐based tests by simulation studies under a variety of scenarios and by analyzing a real data set. The simulation results show that, in most cases, the new proposed methods are more powerful than both Pearson's χ2 test and the existing similarity‐based tests. In one extreme case where the disease mutant induced at a very rare haplotype (≤3%), Pearson's χ2 is slightly more powerful than the new proposed methods, and in this case, the existing similarity‐based tests have almost no power. In another extreme case where the disease mutant was introduced at the most common haplotype, the existing similarity‐based methods are slightly more powerful than the new proposed methods, and in this case Pearson's χ2 test is least powerful. The results of real data analysis are consistent with that of our simulation studies. Genet. Epidemiol. 2007. © 2007 Wiley‐Liss, Inc.
Therapeutic targets in chronic myeloid leukaemia
Authors: Heaney Nicholas B. , Holyoake Tessa L.
Published: April 2007

Chronic myeloid leukaemia (CML) is a clonal disorder of the haemopoietic stem cell arising as a consequence of the formation of the bcr‐abl oncogene. The particular molecular basis of this condition has enabled the development of therapies that selectively target diseased cells. The success of the rationally designed first‐line therapy imatinib mesylate (IM) is tempered by the problems of disease persistence and resistance. Novel strategies have been identified to take forward therapy in CML and these will be discussed in this review. This work is generated from a review of published literature and contains particular insight into the work performed by our group in this field. Copyright © 2007 John Wiley & Sons, Ltd.
SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway
Authors: Shih Yu‐Lueng , Hsieh Chung‐Bao , Lai Hung‐Cheng , Yan Ming‐De , Hsieh Tsai‐Yuan , Chao You‐Chen , Lin Ya‐Wen
Published: April 2007

Oncogenic activation of the Wnt/β‐catenin signaling pathway is common in hepatocellular carcinoma (HCC). The secreted frizzled‐related proteins (SFRPs) function as negative regulators of Wnt signaling and have important implications for carcinogenesis. Promoter hypermethylation of SFRP genes is common in human cancers. However, the role of SFRPs in HCC is not clear. Recently, we have shown that SFRP1 is frequently downregulated through promoter hypermethylation. To confirm and extend these findings, the methylation status of the other SFRP members, including SFRP2, SFRP4 and SFRP5, was examined by methylation‐specific polymerase chain reaction (MS‐PCR). Hypermethylation of SFRP genes, except for SFRP4, is frequent in HCCs and the levels found here were significantly higher than those seen in cirrhotic livers, chronic hepatitis livers and normal controls (p < 0.0001 for SFRP1 and SFRP2, p < 0.05 for SFRP5). To investigate the role of SFRP1 in HCCs, we used re‐expression of SFRP1 in β‐catenin‐dependent HCC cell lines: Huh6 and HepG2. Restoration of SFRP1 attenuated Wnt signaling in those Huh6 hepatoma cells with a β‐catenin gene point mutation, decreased abnormal accumulation of β‐catenin in the nucleus and suppressed cell growth. Conversely, restoration of SFRP1 in HepG2 hepatoma cells with truncated β‐catenin could not block the Wnt signaling pathway. Furthermore, knocking down SFRP1 by RNA interference in β‐catenin‐deficient cell lines (SK‐Hep1) stimulated Wnt signaling and promoted cell growth. Our data suggested that SFRP1 suppressed liver cancer cells growth through Wnt canonical signaling. Moreover, β‐catenin‐independent noncanonical pathway might be involved in Wnt signaling activation through unknown molecules in HCC. © 2007 Wiley‐Liss, Inc.
DOK4/IRS‐5 expression is altered in clear cell renal cell carcinoma
Authors: Al‐sarraf Nael , Reiff Johanne Nørvig , Hinrichsen Jane , Mahmood Shaukat , Teh Bin Tean , McGovern Eilish , De Meyts Pierre , O'Byrne Kenneth J. , Gray Steven G.
Published: April 2007

The insulin‐receptor substrate family plays important roles in cellular growth, signaling, and survival. We have previously shown the dysregulation of the IGF‐axis in clear cell renal cell carcinoma. In this manuscript, we examine the expression of the insulin receptor substrate family in clear cell RCC, and demonstrate that the expression of 2 members of this family are significantly altered in tumors. The most striking finding is that expression of the new IRS family member IRS‐5 is significantly upregulated in 90% of examined clear cell RCCs. Studies on this gene has shown that it is regulated through chromatin remodeling in kidney cells. © 2007 Wiley‐Liss, Inc.
A simple panel unit root test in the presence of cross‐section dependence
Authors: Pesaran M. Hashem
Published: April 2007

A number of panel unit root tests that allow for cross‐section dependence have been proposed in the literature that use orthogonalization type procedures to asymptotically eliminate the cross‐dependence of the series before standard panel unit root tests are applied to the transformed series. In this paper we propose a simple alternative where the standard augmented Dickey–Fuller (ADF) regressions are augmented with the cross‐section averages of lagged levels and first‐differences of the individual series. New asymptotic results are obtained both for the individual cross‐sectionally augmented ADF (CADF) statistics and for their simple averages. It is shown that the individual CADF statistics are asymptotically similar and do not depend on the factor loadings. The limit distribution of the average CADF statistic is shown to exist and its critical values are tabulated. Small sample properties of the proposed test are investigated by Monte Carlo experiments. The proposed test is applied to a panel of 17 OECD real exchange rate series as well as to log real earnings of households in the PSID data. Copyright © 2007 John Wiley & Sons, Ltd.
Calcium sulfate–carboxymethylcellulose bone graft binder: Histologic and morphometric evaluation in a critical size defect
Authors: Reynolds Mark A. , Aichelmann‐Reidy Mary E. , Kassolis James D. , Prasad Hari S. , Rohrer Michael D.
Published: April 2007

Calcium sulfate (CS) is widely used as a bone graft binder and expander. Recent reports indicate that carboxymethylcellulose (CMC) can improve the clinical properties of CS when used as binder for particulate bone grafts; however, limited information is available on the effects of CMC on bone regeneration. The purpose of this study was to evaluate the histologic and morphometric characteristics of bone formation in calvarial defects grafted with a CS‐based putty containing 10% CMC in combination with allogeneic demineralized bone matrix (DBM). Bone formation and graft/binder resorption were compared with a surgical grade CS and DBM in paired critical‐sized calvarial defects in 25 Wistar rats (350–450 g). Six animals each provided paired defects at 7, 14, 21, and 28 days postsurgery for nondecalcified processing and microscopic analysis. Defects grafted with CS or CS‐CMC putty as the DBM binder exhibited similar patterns and proportions of bone formation, fibrous tissue/marrow, and residual DBM particles. Comparable mean ± SD proportions of new bone formation (31.7 ± 9.5 and 33.7 ± 12.9), fibrous tissue/marrow (54.2 ± 8.3 and 53.0 ± 10.8), residual DBM particles (8.3 ± 6.8 and 10.1 ± 6.3), and residual binder material (5.5 ± 4.6 and 3.7 ± 3.5) were found at 28 days for defects grafted with CS and CS‐CMC putty, respectively. Thus, CMC was found to improve the handling characteristics of CS and, when used in conjunction with DBM, supported comparable levels bone formation and patterns of binder/scaffold resorption as CS and DBM in a calvarial defect model. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2007
Present concepts and future outlook: Function of peroxisome proliferator‐activated receptors (PPARs) for pathogenesis, progression, and therapy of cancer
Authors: Sertznig P. , Seifert M. , Tilgen W. , Reichrath J.
Published: April 2007

Peroxisome proliferator‐activated receptors (PPARs) are members of the nuclear receptor superfamily of transcriptional regulators that regulate lipid, glucose, and amino acid metabolism. In recent studies it also has been shown that these receptors are implicated in tumor progression, cellular differentiation, and apoptosis and modulation of their function is therefore considered as a potential target for cancer prevention and treatment. PPAR ligands and other agents influencing PPAR signalling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in a variety of human cancers and could represent a potential novel strategy to inhibit tumor carcinogenesis and progression. This review summarizes the currently available data on the roles of PPARs in relation to the processes of cell differentiation and carcinogenesis as well as their role as promising future therapeutic targets. J. Cell. Physiol. 212: 1–12, 2007. © 2007 Wiley‐Liss, Inc.
Altered intracellular redox status in Gaucher disease fibroblasts and impairment of adaptive response against oxidative stress
Authors: Deganuto Marta , Pittis Maria Gabriela , Pines Alex , Dominissini Silvia , Kelley Mark R. , Garcia Rodolfo , Quadrifoglio Franco , Bembi Bruno , Tell Gianluca
Published: April 2007

Gaucher disease (GD) is a lysosomal storage disorder, due to glucosylceramide (GlcCer) accumulation in several body tissues, which causes cellular failure by yet unidentified mechanisms. Several evidence indicates that GD pathogenesis is associated to an impairment in intracellular redox state. In fibroblast primary cultures, reactive oxygen species (ROS) levels and protein carbonyl content resulted significantly increased in GD patients compared to healthy donors, suggesting that GD cells, facing a condition of chronic oxidative stress, have evolved an adaptive response to survive. The ROS rise is probably due to NAD(P)H oxidase activity, being inhibited by the treatment with diphenylene iodonium chloride. Interestingly, GD cells are more sensitive to H2O2 induced cell death, suggesting a dysregulation in the adaptive response to oxidative stress in which APE1/Ref‐1 plays a central role. We found that the cytoplasmic amounts of APE1/Ref‐1 protein were significantly higher in GD fibroblasts with respect to controls, and that GD cells failed to upregulate its expression upon H2O2 treatment. Both ROS and APE1/Ref‐1 increases are due to GlcCer accumulation, being prevented by treatment of GD fibroblasts with Cerezyme® and induced in healthy fibroblasts treated with conduritol‐β‐epoxide. These data, suggesting that GD cells display an impairment in the cellular redox state and in the adaptive cellular response to oxidative stress, may open new perspectives in the comprehension of GD pathogenesis. J. Cell. Physiol. 212: 223–235, 2007. © 2007 Wiley‐Liss, Inc.
Retracted: Transcriptional activation by stimulating protein 1 and post‐transcriptional repression by muscle‐specific microRNAs of IKs‐encoding genes and potential implications in regional heterogeneity of their expressions
Authors: Luo Xiaobin , Xiao Jiening , Lin Huixian , Li Baoxin , Lu Yanjie , Yang Baofeng , Wang Zhiguo
Published: April 2007

In cardiac cells, KCNQ1 assembles with KCNE1 and forms a channel complex constituting the slow delayed rectifier current IKs. Expression of KCNQ1 and KCNE1 are regionally heterogeneous and changes with pathological states of the heart. The aims of this study were to decipher the molecular mechanisms for transcriptional and post‐transcriptional regulation expression of KCNQ1 and KCNE1 genes and to shed light on the molecular mechanisms for their spatial heterogeneity of distribution. We cloned the 5′‐flanking region and identified the transcription start sites of the KCNQ1 gene. We characterized the core promoters of KCNQ1 and KCNE1 and revealed the stimulating protein (Sp1) as a common transactivator of KCNQ1 and KCNE1 by interacting with the Sp1 cis‐acting elements in the core promoter regions of these genes. We also characterized the 3′ untranslated regions (3′UTRs) of the genes and experimentally established KCNQ1 and KCNE1 as targets for repression by the muscle‐specific microRNAs miR‐133 and miR‐1, respectively. We demonstrated spatial heterogeneity of KCNQ1 and KCNE1 distributions at three axes (interventricular, transmural and apical‐basal) and disparity between mRNA and protein expressions of these genes. We also found characteristic regional differences of expressions of Sp1 and miR‐1/miR‐133 in the heart. Our study unraveled a novel aspect of the cellular function of miRNAs and suggests that the IKs‐encoding genes KCNQ1 and KCNE1 expressions are dynamically balanced by transcription factor regulation and miRNA repression. The heterogeneities of Sp1 and miR‐1/miR‐133 offer an explanation for the well‐recognized regional differences and disparity between mRNA and protein expressions of KCNQ1 and KCNE1. J. Cell. Physiol. 212: 358–367, 2007. © 2007 Wiley‐Liss, Inc.
M‐CSF‐mediated macrophage differentiation but not proliferation is correlated with increased and prolonged ERK activation
Authors: Suzu Shinya , Hiyoshi Masateru , Yoshidomi Yuka , Harada Hideki , Takeya Motohiro , Kimura Fumihiko , Motoyoshi Kazuo , Okada Seiji
Published: April 2007

M‐CSF is a cytokine essential for both the proliferation and differentiation of monocytes/macrophages. In this study, we established a new M‐CSF‐mediated differentiation‐inducing system, and examined how the level and duration of the activation of ERK preceded M‐CSF‐mediated differentiation. TF‐1‐fms human leukemia cells rapidly proliferated in response to M‐CSF. However, in the presence of a phorbol ester, TPA, TF‐1‐fms cells definitely switched their responsiveness to M‐CSF from proliferation to differentiation, as evidenced by a more drastic morphological change and the appearance of cells with a higher level of phagocytic activity. In TF‐1‐fms cells expressing HIV‐1 Nef protein in a conditionally active‐manner, both M‐CSF‐mediated proliferation and M‐CSF/TPA‐mediated differentiation were inhibited by the activation of Nef. The Nef‐active cells showed perturbed patterns of ERK activation. Under the proliferation‐inducing conditions (TPA‐free), parental or Nef‐inactive cells showed modest ERK activation following M‐CSF stimulation, whereas Nef‐active cells showed an earlier and transient ERK activation, despite a decrease in their proliferation rate. Under the differentiation‐inducing conditions, parental or Nef‐inactive cells showed increased and prolonged ERK activation following M‐CSF stimulation, whereas Nef‐active cells showed transient ERK activation. These results supported the idea that the increased and prolonged ERK activation led to M‐CSF‐mediated macrophage differentiation but not to proliferation. J. Cell. Physiol. 212: 519–525, 2007. © 2007 Wiley‐Liss, Inc.
Thapsigargin induces biphasic fragmentation of mitochondria through calcium‐mediated mitochondrial fission and apoptosis
Authors: Hom Jennifer R. , Gewandter Jennifer S. , Michael Limor , Sheu Shey‐Shing , Yoon Yisang
Published: April 2007

Mitochondrial fission and fusion are the main components mediating the dynamic change of mitochondrial morphology observed in living cells. While many protein factors directly participating in mitochondrial dynamics have been identified, upstream signals that regulate mitochondrial morphology are not well understood. In this study, we tested the role of intracellular Ca2+ in regulating mitochondrial morphology. We found that treating cells with the ER Ca2+‐ATPase inhibitor thapsigargin (TG) induced two phases of mitochondrial fragmentation. The initial fragmentation of mitochondria occurs rapidly within minutes dependent on an increase in intracellular Ca2+ levels, and Ca2+ influx into mitochondria is necessary for inducing mitochondrial fragmentation. The initial mitochondrial fragmentation is a transient event, as tubular mitochondrial morphology was restored as the Ca2+ level decreased. We were able to block the TG‐induced mitochondrial fragmentation by inhibiting mitochondrial fission proteins DLP1/Drp1 or hFis1, suggesting that increased mitochondrial Ca2+ acts upstream to activate the cellular mitochondrial fission machinery. We also found that prolonged incubation with TG induced the second phase of mitochondrial fragmentation, which was non‐reversible and led to cell death as reported previously. These results suggest that Ca2+ is involved in controlling mitochondrial morphology via intra‐mitochondrial Ca2+ signaling as well as the apoptotic process. J. Cell. Physiol. 212: 498–508, 2007. © 2007 Wiley‐Liss, Inc.
Oxidative stress and increased eNOS and NADPH oxidase expression in mouse microvessel endothelial cells
Authors: Ding Hong , Aljofan Mohamad , Triggle Chris R.
Published: April 2007

Elevated oxidative stress plays a key role in diabetes‐associated vascular disease. In this study, we tested the hypothesis that high glucose‐induced oxidative stress was associated with changes in the expression of NADPH oxidase, superoxide dismutase (SOD) and endothelial nitric oxide synthase (eNOS). Oxidative stress was assessed in cell cultures of mouse microvessel endothelial cells (MMECs) by fluorescence labelling with dihydroethidium, lucigenin‐enhanced chemiluminescence and determining NADPH oxidase subunit and eNOS expression with real‐time polymerase chain reaction protocol and Western blotting. Oxidative stress and expression of the NADPH oxidase subunit, p22phox, were both increased, SOD1 and 3 expression lowered and eNOS significantly elevated in MMECs treated with 40 mM glucose for 72 h compared to low glucose medium. Oxidative stress, p22phox mRNA, eNOS mRNA, and protein were lowered by concurrent incubation with sepiapterin. When eNOS protein expression in endothelial cells was significantly decreased by eNOS siRNA treatment, superoxide generation was significantly higher in the MMECs grown in low glucose, but reduced in those grown in high glucose for 72 h. Thus, exposure of MMECs to high glucose results in increased oxidative stress that is associated with increased eNOS and NADPH oxidase subunit expression, notably p22phox, and decreased expression of SOD1 and 3. J. Cell. Physiol. 212:682–689, 2007. © 2007 Wiley‐Liss, Inc.
14‐3‐3 sigma isoform interacts with the cytoplasmic domain of the transmembrane BP180 in keratinocytes
Authors: Li Yunyuan , Lin Xiaoyue , Kilani Ruhangiz T. , Jones Jonathan C.R. , Ghahary Aziz
Published: April 2007

The protein bullous pemphigoid antigen‐2 (BPAG2/BP180/collagen type XVII) plays a key role in attachment of basal keratinocytes to epidermal basement membrane. The binding of BP180 with either integrin α6, integrin β4, or bullous pemphigoid antigen‐1 (BPAG1/BP230) is critical for this attachment in skin. The protein 14‐3‐3 σ, also known as stratifin and a marker for epithelial cells, is a member of a highly conserved small acidic 14‐3‐3 protein family naturally found in all eukaryotic cells. Here, we have used a 14‐3‐3σ GST pull‐down screening assay and showed that sigma (σ) isoform of the 14‐3‐3 protein family interacts with the cytoplasmic N‐terminal domain of BP180. Analysis of a series of truncated or deleted 14‐3‐3σ revealed that only intact 14‐3‐3σ molecule, but not any of its fragments can interact with BP180. This finding suggests that conformation and possible dimerization of 14‐3‐3 σ is essential for this interaction. Further, a BP180 co‐immunoprecipitation (IP) and its reverse IP assays were conducted and the results confirmed that 14‐3‐3 σ interacts with cytoplasmic domain, but not ecto‐domain of the BP180. In conclusion, the finding of this study provides evidence that 14‐3‐3σ isoform interacts with BP180 which is a major component of hemidesmosome involved in the attachment of epidermis to the basement membrane in skin. However, the significance of this interaction in hemidesmosome formation and/or attachment needs to be explored. J. Cell. Physiol. 212:675–681, 2007. © 2007 Wiley‐Liss, Inc.
Alveolar progenitor cells develop in mouse mammary glands independent of pregnancy and lactation
Authors: Booth Brian W. , Boulanger Corinne A. , Smith Gilbert H.
Published: April 2007

We have previously described pluripotent, parity‐induced mammary epithelial cells (PI‐MEC) marked by Rosa26‐lacZ expression in the mammary glands of parous females. PI‐MEC act as lobule‐limited epithelial stem/progenitor cells. To determine whether parity is necessary to generate PI‐MEC, we incubated mammary explant cultures from virgin mice in vitro with insulin alone (I), hydrocortisone alone (H), prolactin alone (Prl), or a combination of these lactogenic hormones (IHPrl). Insulin alone activated the WAP‐Cre gene. Hydrocortisone and prolactin alone did not. Any combination of hormones that included insulin was effective. Only I, H and Prl together were able to induce secretory differentiation and milk protein synthesis. In addition, EGF, IGF‐2 and IGF‐1 added individually produced activated (lacZ+) PI‐MEC in explant cultures. Neither estrogen nor progesterone induced WAP‐Cre expression in the explants. None of these positive initiators of WAP‐Cre expression in PI‐MEC were effective in mammospheres or two‐dimensional cultures of mammary epithelium, indicating the indispensability of epithelial–stromal interaction in PI‐MEC activation. Like PI‐MEC, lacZ+ cells from virgin explants proliferated and contributed progeny to mammospheres in vitro and to epithelial outgrowths in vivo after transplantation. LacZ+ cells induced in virgin mouse mammary explants were multipotent (like PI‐MEC) in impregnated hosts producing lacZ+ mammary alveolar structures comprised of both myoepithelial and luminal progeny. These data demonstrate PI‐MEC, a mammary epithelial sub‐population of lobule‐limited progenitor cells, are present in nulliparous female mice before parity and, like the PI‐MEC observed following parity, are capable of proliferation, self‐renewal and the capacity to produce progeny of diverse epithelial cell fates. J. Cell. Physiol. 212:729–736, 2007. © 2007 Wiley‐Liss, Inc.
Dual regulation of upstream binding factor 1 levels by IRS‐1 and ERKs in IGF‐1‐receptor signaling
Authors: Sun Hongzhi , Tu Xiao , Liu Mingli , Baserga Renato
Published: April 2007

The Upstream Binding Factor 1 (UBF1) is a nucleolar protein that participates in the regulation of RNA polymerase I activity and ribosomal RNA (rRNA) synthesis. In 32D myeloid cells expressing the type 1 insulin‐like growth factor receptor (IGF‐IR), the UBF1 protein (but not its mRNA) is down regulated when the cells are shifted from Interleukin‐3 (IL‐3) to IGF‐1. Ectopic expression of insulin receptor substrate‐1 (IRS‐1) in these cells inhibits the down‐regulation of UBF1. We now show that the stability of UBF1 in 32D‐derived cells requires also a signal from the extracellular regulated kinases (ERKs). When ERKs signaling is defective, as in cells over‐expressing the insulin receptor (InR) or selected mutants of the IGF‐1R, UBF1 is down‐regulated, even in the presence of IRS‐1. The down‐regulation is corrected by the expression of an activated Ha‐ras, which stimulates ERKs activity. Mutations at threonines 117 and 201 of UBF1, known to be phosphorylated by ERKs, cause its down‐regulation. However, when IRS‐2, instead of IRS‐1, is ectopically expressed in 32D InR cells, ERKs phosphorylation is increased and UBF is stabilized. Taken together, these results indicate that in 32D‐derived myeloid cells expressing either the IGF‐IR or the InR, UBF1 levels are regulated by signaling from both IRS proteins and ERKs. J. Cell. Physiol. 212:780–786, 2007. © 2007 Wiley‐Liss, Inc.
Zinc regulates the ability of Cdc25C to activate MPF/cdk1
Authors: Sun Lu , Chai Yingtao , Hannigan Robyn , Bhogaraju Venkata K. , Machaca Khaled
Published: April 2007

Zn2+ is an essential micronutrient for the growth and development of multicellular organisms, as Zn2+ deficiencies lead to growth retardation and congenital malformations (Vallee, BL, Falchuk, KH. 1993. Physiol Rev., 73:79–118). At the cellular level Zn2+ depravation results in proliferation defects in many cell types (Vallee, BL, Falchuk, KH. 1993. Physiol Rev., 73:79–118), however the molecular pathways involved remain poorly defined. Here we show that the transition metal chelator TPEN (N,N,N′,N′‐tetrakis(2‐pyridylmethyl) ethylene diamine) blocks the G2/M transition of the meiotic cell cycle by inhibiting Cdc25C‐cdk1 activation. ICP‐MS analyses reveal that Cdc25C is a Zn2+‐binding metalloprotein, and that TPEN effectively strips Zn2+ away from the enzyme. Interestingly, although apo‐Cdc25C (Zn2+‐deficient) remains fully catalytically active, it is compromised in its ability to dephosphorylate and activate MPF/cdk1. Thus, Zn2+ is an important regulator of Cdc25C function in vivo. Because of the conserved essential role of the Cdc25C‐cdk1 module in the eukaryotic cell cycle, these studies provide fundamental insights into cell cycle regulation. J. Cell. Physiol. 213: 98–104, 2007. © 2007 Wiley‐Liss, Inc.
Glutamate is a determinant of cellular proliferation through modulation of nuclear factor E2 p45‐related factor‐2 expression in osteoblastic MC3T3‐E1 cells
Authors: Uno Kyosuke , Takarada Takeshi , Hinoi Eiichi , Yoneda Yukio
Published: April 2007

Activation of particular glutamate (Glu) receptors is shown to promote cellular differentiation toward maturation during osteoblastogenesis. In the present study, we have evaluated the possible modulation by Glu of cellular proliferation in osteoblastic cells endowed to proliferate for self‐renewal and to differentiate toward matured osteoblasts. Exposure to Glu significantly suppressed the proliferation activity at a concentration over 500 µM without inducing cell death in osteoblastic MC3T3‐E1 cells before differentiation. The suppression by Glu occurred in a manner sensitive to the prevention by either cystine or reduced glutathione. Expression of mRNA was for the first time shown with the cystine/Glu antiporter composed of xCT and 4F2hc subunits in these undifferentiated osteoblastic cells. A significant decrease was seen in intracellular total glutathione levels in undifferentiated MC3T3‐E1 cells cultured with Glu, indeed, whereas the cellular proliferation activity was drastically decreased by the addition of the glutathione depleter cyclohexene‐1‐one and the glutathione biosynthesis inhibitor L‐buthionine‐[S,R]‐sulfoximine, respectively. Exposure to Glu led to a significant increase in mRNA expression of nuclear factor E2 p45‐related factor 2 (Nrf2) together with the generation of reactive oxygen species, while a significant decrease was seen in the proliferation activity in MC3T3‐E1 cells with stable overexpression of Nrf2. These results suggest that Glu could suppress the cellular proliferation toward self‐renewal through a mechanism associated with the upregulation of Nrf2 expression in association with the depletion of intracellular glutathione after promoting the retrograde operation of the cystine/Glu antiporter in undifferentiated MC3T3‐E1 cells. J. Cell. Physiol. 213: 105–114, 2007. © 2007 Wiley‐Liss, Inc.
Fak/Src signaling in human intestinal epithelial cell survival and anoikis: Differentiation state‐specific uncoupling with the PI3‐K/Akt‐1 and MEK/Erk pathways
Authors: Bouchard Véronique , Demers Marie‐Josée , Thibodeau Sonya , Laquerre Vincent , Fujita Naoya , Tsuruo Takashi , Beaulieu Jean‐François , Gauthier Rémy , Vézina Anne , Villeneuve Lisabeth , Vachon Pierre H.
Published: April 2007

Human intestinal epithelial cell survival and anoikis are distinctively regulated according to the state of differentiation. In the present study, we analyzed the roles of focal adhesion kinase (Fak)/Src signaling to the PI3‐K/Akt‐1 and mitogen‐activated protein kinase (MEK)/extracellular regulated kinases (Erk) pathways, within the context of such differentiation‐state distinctions. Anoikis was induced by inhibition of β1 integrins (antibody blocking), inhibition of Fak (pharmacologic inhibition or overexpression of dominant negative mutants), or by maintaining cells in suspension. Activation parameters of Fak, Src, Akt‐1, and Erk1/2 were analyzed. Activities of Src, Akt‐1, or Erk1/2 were also blocked by pharmacological inhibition or by overexpression of dominant‐negative mutants. We report that: (1) the loss or inhibition of β1 integrin binding activity causes anoikis and results in a down‐activation of Fak, Src, Akt‐1, and Erk1/2 in both undifferentiated, and differentiated cells; (2) the inhibition of Fak likewise causes anoikis and a down‐activation of Src, Akt‐1, and Erk1/2, regardless of the differentiation state; (3) Src, PI3‐K/Akt‐1, and MEK/Erk contribute to the survival of differentiated cells, whereas MEK/Erk does not play a role in the survival of undifferentiated ones; (4) the inhibition/loss of β1 integrin binding and/or Fak activity results in a loss of Src engagement with Fak, regardless of the state of differentiation; and (5) Src contributes to the activation of both the PI3‐K/Akt‐1 and MEK/Erk pathways in undifferentiated cells, but does not influence PI3‐K/Akt‐1 in differentiated ones. Hence, Fak/Src signaling to the PI3‐K/Akt‐1 and MEK/Erk pathways undergoes a differentiation state‐specific uncoupling which ultimately reflects upon the selective engagement of these same pathways in the mediation of intestinal epithelial cell survival. J. Cell. Physiol. 212:717–728, 2007. © 2007 Wiley‐Liss, Inc.
Root traits of different crops under rainfed conditions in the High Barind Tract of Bangladesh
Authors: Ali M. Yusuf , Ahmed Selim , Johansen Chris , Harris David , Rao J. V. D. K. Kumar
Published: April 2007

Root traits of six different crops grown on residual soil moisture in the post–rainy season in the High Barind Tract (HBT) of Bangladesh were investigated to better understand their adaptation to this moisture‐limited environment. Deep‐rooting chickpea is the currently favored rainfed crop grown after rainy‐season rice in the HBT, but it is necessary to identify alternative crops to chickpea in order to avoid buildup of pests and diseases. Averaged over 2 y, barley (1.72 Mg ha–1) produced significantly more grain than chickpea (1.4 Mg ha–1) which, in turn, yielded better than linseed (1.0 Mg ha–1), wheat (0.93 Mg ha–1), and mustard (0.77 Mg ha–1). Lentil did not produce any grain at all. Grain yield for all crops increased as total root length increased above a threshold value of 0.05 to 0.1 km m–2. In general, grain yield increased as the proportion of total root produced below 60 cm depth increased, although barley also had thin roots that could more effectively extract soil moisture. Expression of root traits varied considerably between seasons, which was attributable to the different rainfall patterns and bulk‐density characteristics of the soil profile in the 2 years of the study. Although favorable root traits, particularly rooting ability below 60 cm, are a prerequisite for acceptable yield levels of crops grown on residual soil moisture in the HBT, it is recognized that farmers' choice of a post‐rice crop will depend on its economic return or food‐security value.
Zur Interpretation erhöhter Schluffgehalte in Böden des Bayerischen und des Oberpfälzer Waldes
Authors: Förster Helmwart , Ullrich Frank
Published: April 2007

Anhand der Körnungsanalysen von insgesamt 41 repräsentativen Pedons aus verschiedenen Teillandschaften des Bayerischen und des Oberpfälzer Waldes wird die Bedeutung äolischer Beimengungen für diese Mittelgebirgsböden untersucht. Typische Lösslehm‐ bzw. Lössprofile (drei Pedons) finden sich nur in der donaunahen Vorwaldzone des Bayerischen Waldes, lösslehmbeeinflusste Böden (ein Pedon) teilweise auch im nordöstlich daran angrenzenden Vorderen Bayerischen Wald. Für die übrigen Teillandschaften (insgesamt 37 Pedons) ist dagegen kein Hinweis auf äolische Beimengungen ableitbar: Allen diesen Profilen fehlt ein Grobschluff‐Maximum in der Hauptlage, was bei der Einblasung von typischen Lösslehmen zu erwarten wäre. Siebzehn von ihnen verfügen in ihrer Hauptlage stattdessen über ein Mittelschluff‐Maximum, das als Resultat intensiver (Frost)Verwitterung interpretiert wird. Ein verbreitetes Vorkommen lösslehmbeeinflusster Böden kann demnach für den ostbayerischen Mittelgebirgsraum nicht bestätigt werden.
Synergistic effects of the inoculation with nitrogen‐fixing and phosphate‐solubilizing rhizobacteria on the performance of field‐grown chickpea
Authors: Wani Parvaze A. , Khan Mohammad Saghir , Zaidi Almas
Published: April 2007

The synergistic effects of nitrogen‐fixing and phosphate‐solubilizing rhizobacteria on plant growth, yield, grain protein, and nutrient uptake of chickpea plants were determined in a sandy clay‐loam soil. Legume grain yield and concentration and uptake of nitrogen (N) and phosphorus (P) were significantly increased as a result of co‐inoculation with Mesorhizobium and P‐solubilizing Pseudomonas and Bacillus spp. The inoculation with M. ciceri RC4 + A. chroococuum A10 + Bacillus PSB9 tripled the seed yield and resulted in highest grain protein (295 mg g–1) at 145 d after sowing (DAS). An 8% increase in P concentration above the uninoculated control was observed in case of a single inoculation with Pseudomonas PSB 5, while the P uptake was highest (2.14‐fold above the uninoculated control) with a combined inoculation with [M. ciceri RC4 + A. chroococcum A10 + Bacillus PSB 9] at 145 DAS. The highest N concentration and N uptake at 145 DAS (81% and 16% above the uninoculated control, respectively) were observed with the triple inoculation of [M. ciceri RC4 + A. chroococcum A10 + Pseudomonas PSB 5). These findings show that multiple inoculations with rhizospheric microorganisms can promote plant growth and grain yield and increase concentrations and uptake of N and P by field‐grown chickpea.
The influence of plant growth–promoting rhizobacteria on growth and enzyme activities in wheat and spinach plants
Authors: Çakmakçı Ramazan , Erat Mustafa , Erdoğan Ümmügülsüm , Dönmez Mesude Figen
Published: April 2007

A pot experiment in a greenhouse was conducted in order to investigate the effect of different N2‐fixing, phytohormone‐producing, and P‐solubilizing bacterial species on wheat and spinach growth and enzyme activities. Growth parameters and the activities of four enzymes, glucose‐6‐phosphate dehydrogenase (G6PD; EC 1.1.1.49), 6‐phosphogluconate dehydrogenase (6PGD; EC 1.1.1.44), glutathione reductase (GR; EC 1.8.1.7), and glutathione S‐transferase (GST; EC 2.5.1.18) were determined in the leaves of wheat (Triticum aestivum L., Konya) and spinach (Spinacia oleracea L.), noninoculated and inoculated with nine plant growth–promoting rhizobacteria (PGPR: Bacillus cereus RC18, Bacillus licheniformis RC08, Bacillus megaterium RC07, Bacillus subtilis RC11, Bacillus OSU‐142, Bacillus M‐13, Pseudomonas putida RC06, Paenibacillus polymyxa RC05 and RC14). Among the strains used in the present study, six PGPR exhibited nitrogenase activity and four were efficient in phosphate solubilization; all bacterial strains were efficient in indole acetic acid (IAA) production and significantly increased growth of wheat and spinach. Inoculation with PGPR increased wheat shoot fresh weight by 16.2%–53.8% and spinach shoot fresh weight by 2.2%–53.4% over control. PGPR inoculation gave leaf area increases by 6.0%–47.0% in wheat and 5.3%–49.3% in spinach. Inoculation increased plant height by 2.2%–24.6% and 1.9%–36.8% in wheat and spinach, respectively. A close relationship between plant growth and enzyme activities such as G6PD, 6PGD, GR, and GST was demonstrated. Plant‐growth response was variable and dependent on the inoculant strain, enzyme activity, plant species, and growth parameter evaluated. In particular, the N2‐fixing bacterial strains RC05, RC06, RC14, and OSU‐142 and the P‐solubilizing strains RC07 and RC08 have great potential in being formulated and used as biofertilizers.
A multivariate analysis of adhesion molecules expression in assessment of colorectal cancer
Authors: Ngan Chew Yee , Yamamoto Hirofumi , Seshimo Iwao , Ezumi Koji , Terayama Motokazu , Hemmi Hideyuki , Takemasa Ichiro , Ikeda Masataka , Sekimoto Mitsugu , Monden Morito
Published: April 2007

Background and Objectives

Adhesion molecules are implicated in the progression of colorectal cancer (CRC). Despite the evidence of association between their expression and patients' prognosis, the data have not been examined simultaneously in a same study; thus, the relative clinical value remained largely unknown. The aim of this study was to identify the adhesion factors that display the most significant prognostic value for CRC patients to guide clinical decision‐making regarding appropriate treatment.

Patients and Methods

We examined by immunohistochemistry, the expression of E‐cadherin and its associated catenins, alpha(α)‐catenin and beta(β)‐catenin, DCC, and CD44 and its partner, MT1‐MMP in a series of 140 CRC tissues at intermediate Stage II and Stage III to determine their prognostic significance.

Results

Clinicopathological survey indicated an inverse relationship between E‐cadherin expression and tumor differentiation, and an association between CD44 expression and venous invasion. Univariate and multivariate analyses showed that loss of expression of E‐cadherin and CD44 significantly correlated to poor survival, especially in Stage II. Combination studies indicated that loss of E‐cadherin and loss of CD44 had the worst impact on patient prognosis, particularly in colon cancer.

Conclusion

Immunohistochemical staining of E‐cadherin and CD44 may help to identify a subgroup of high‐risk patients with Stage II CRC, especially in colon cancer, who may need intensive follow‐up and appropriate therapeutic strategy. J. Surg. Oncol. 2007;95:652–662. © 2007 Wiley‐Liss, Inc.
“Wide local ablation” of localized breast cancer using high intensity focused ultrasound
Authors: Wu Feng , Wang Zhi‐Biao , Cao You‐De , Zhu Xue‐Qiang , Zhu Hui , Chen Wen‐Zhi , Zou Jiang‐Zhong
Published: April 2007

Background and Objective

High intensity focused ultrasound (HIFU) is a non‐invasive technique for tumor ablation. The goal of this study was to investigate the feasibility of performing wide local ablation using ultrasound‐guided HIFU in the treatment of patients with localized breast cancer.

Methods

Twenty‐three patients with histologically proven breast cancer were enrolled in this prospective clinical trial. They underwent HIFU treatment for breast cancer including the tumor and 1.5–2.0 cm normal breast tissue surrounding the tumor, followed by modified mastectomy 1–2 weeks after HIFU. Radiological examination, histological, and terminal deoxynucleotidyl transferase‐mediated nick end labeling (TUNEL) methods were performed to evaluate therapeutic effects in the treated region.

Results

Thermal ablation was confirmed in all 23 patients. It included tumor and normal breast tissue surrounding the tumor. Mean values of the largest parallel and perpendicular dimensions, and volume of HIFU lesions in excised breasts were significantly larger than those of the targeted tumors respectively (P < 0.001). Hematoxylin and eosin (H & E) staining showed clear evidence of complete coagulation necrosis in the treated regions. However, no apoptotic cells were detected in either treated tumor or normal breast tissue.

Conclusion

As a non‐invasive therapy, ultrasound‐guided HIFU can induce wide local ablation in the treatment of patients with localized breast cancer. J. Surg. Oncol. 2007;96:130–136. © 2007 Wiley‐Liss, Inc.
MDR1 gene polymorphisms and risk of recurrence in patients With hepatocellular carcinoma after liver transplantation
Authors: Wu Liming , Xu Xiaobo , Shen Juwei , Xie Haiyang , Yu Songfeng , Liang Tingbo , Wang Weilin , Shen Yan , Zhang Min , Zheng Shusen
Published: April 2007

Background and Objectives

Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major cause of post‐LT death. However, currently there is still lacking the markers to reliably predict recurrence. This study was undertaken to evaluate the association between three polymorphisms (C1236T, G2677A/T, C3435T) of Multidrug resistance 1 (MDR1) gene and the risk of recurrence after LT.

Methods

Genomic DNA of 99 HCC patients undergoing LT was extracted from peripheral blood lymphocytes and genotyping was performed using polymerase chain reaction‐restriction fragment length polymorphism assay. Cox proportional hazard model was used to estimate the hazard ratios associated with polymorphisms.

Results

During a mean follow‐up of 14.9 months, 49 patients experienced recurrence. The association between recurrence‐free and 2677A carrier (carrying at least one variant A allele) was significant (P = 0.019). However, no significant association was observed in other polymorphisms. Patients with 2677A carrier conferred a 63% reduction in recurrence risk compared with 2677A non‐carrier (odds ratio: 0.374; 95% confidence interval: 0.177–0.788;P = 0.010). The median recurrence‐free survival for 2677A carrier group was significantly longer than that for 2677A non‐carrier group (44.2 vs. 10.5 months,P = 0.015).

Conclusion

The polymorphism of MDR1 gene may be a valuable molecular marker for HCC recurrence after LT. J. Surg. Oncol. 2007;96:62–68. © 2007 Wiley‐Liss, Inc.
The incidence, indications and outcome for the non‐operative management of breast cancer
Authors: Atkin Gary K. , Scott Mike A. , Wiggins Joan E. , Callam Michael J.
Published: April 2007

Background and Objectives

This study aimed to identify the proportion of patients with breast cancer who do not undergo primary operative treatment, to identify the reasons surgery is not performed, and to determine the outcome for this group of patients.

Methods

Data was obtained from the Bedford Breast Cancer Registry for all non‐metastatic patients presenting between January 1990 and December 2004 who were initially treated non‐operatively. Robust diagnostic, therapeutic, and follow‐up data on all patients was collected prospectively during this period.

Results

One hundred and eighty‐five out of 2110 episodes of breast cancer were treated non‐operatively during this period. Sixty‐eight percent of patients were unfit for surgery, 15% had inoperable tumours, and 17% refused surgical intervention. Median survival and 5‐year survival rate for all non‐operative patients were 3.7 years and 41.2%. Median survival for inoperable patients was 3.7 years, compared with 3.5 years for those unfit for surgery and 4.2 years for those who refused surgery. The 5‐year survival rate for patients refusing surgery was 43%, compared with 61% for a matched group of patients undergoing standard surgical therapy.

Conclusions

This study provides useful data on the reasons for, and outcome of, the non‐operative management of breast cancer. J. Surg. Oncol. 2007;96:137–143. © 2007 Wiley‐Liss, Inc.