bluuebunny/crossref_metadata_2025 huggingface dataset:
Xq27–28 deletions in prostate carcinoma
Authors: Kibel Adam S. , Faith Dennis A. , Bova G. Steven , Isaacs William B.
Published: June 2003

Linkage studies have implicated a prostate cancer susceptibility locus at Xq27–28 (termed HPCX), estimated to be responsible for approximately 16% of hereditary prostate cancer cases. To date, this region has not been investigated in sporadic disease. In this study, we examined tumor DNA samples prepared from patients with sporadic prostate cancer, prostate cancer cell lines, and prostate cancer xenografts for evidence of genomic alterations within the Xq27–28 region. To facilitate the detection of nullizygosity, we examined a unique series of highly tumor‐enriched DNA samples prepared from men with multi‐sampled metastatic prostate cancer, as well as a series of prostate cancer xenografts and cell lines. PCR amplification of carcinoma and normal DNA templates was performed for 11 loci spanning an Xq27–28 interval of ∼16 cM. Among 19 patients studied, somatic deletions in this region were found in two cases. Within these two cases, each independent metastatic tumor sample available from an individual (n = 4 sites and 8 sites, respectively) showed the same reduction to nullizygosity, suggesting a pre‐metastatic origin for the deletion events in both. Mapping of the deletion boundaries with eight additional sets of markers indicated that both deletions had breakpoints within an ∼500‐ to 800‐kb interval containing FMR1; however, the deletions were non‐overlapping. The lack of a common region of deletion suggests one of three possibilities: (1) that these two deletions are unrelated, (2) that the deletions affect the opposite ends of an as yet unknown gene, or (3) that each deletion has inactivated a single copy of an unknown gene arranged in cis in the region of interest. These data clearly indicate that deletions do occur within the HPCX locus in a subset of sporadic prostate cancers and therefore raises the possibility that the gene at this locus may prove to play a role in sporadic disease. © 2003 Wiley‐Liss, Inc.
Identification of candidate tumor‐suppressor genes in 6q27 by combined deletion mapping and electronic expression profiling in lymphoid neoplasms
Authors: Steinemann Doris , Gesk Stefan , Zhang Yanming , Harder Lana , Pilarsky Christian , Hinzmann Bernd , Martin‐Subero Jose Ignacio , Calasanz Maria Jose , Mungall Andrew , Rosenthal André , Siebert Reiner , Schlegelberger Brigitte
Published: June 2003

Deletions in the long arm of chromosome 6 (6q) are among the most frequent chromosome aberrations in lymphoid neoplasms. Recently, the region of minimal deletion (RMD1) in 6q27 was narrowed down to 5–9 Mb. In the present study, we aimed to define the distal border of the commonly lost region in 6q27 more precisely and to identify and investigate tumor‐suppressor genes (TSGs) from this region. Twenty‐nine cases, in which our previous fluorescence in situ hybridization (FISH) screening that used a set of 36 YAC probes revealed loss in 6q25–27, were further investigated by means of FISH. In all cases, deletions of 6q27 extended from yeast artificial chromosome (YAC) 977e10 spanning the proximal border of RMD1 to the most telomeric YAC 933f7 within the recently established YAC‐contig of this region. An interstitial homozygous deletion, flanked by the telomeric probe TelVysion6q and YAC 971g12, was detected, which substantially narrows down the RMD1. To identify candidate TSGs down‐regulated in malignant lymphomas from this region of homozygous loss, we performed electronic profiling of expressed sequences mapped to this region. This analysis suggested the gene PDCD2 originally thought to be involved in programmed cell death to be probably down‐regulated in malignant B‐cell lymphomas compared to normal B lymphocytes. Nevertheless, mutation analyses failed to identify mutations in the coding region of PDCD2 in nine lymphomas with FISH‐proved 6q27 deletions. Furthermore, epigenetic studies in these nine and an additional 48 lymphomas did not show altered methylation of the PDCD2 locus in these tumors. Possibly haploinsufficiency is effectual in accelerating tumor progression. © 2003 Wiley‐Liss, Inc.
Non‐muscle myosin heavy chain (MYH9): A new partner fused to ALK in anaplastic large cell lymphoma
Authors: Lamant Laurence , Gascoyne Randy D. , Duplantier Marie Michèle , Armstrong Florence , Raghab Ashraf , Chhanabhai Mukesh , Rajcan‐Separovic Evica , Raghab Janie , Delsol Georges , Espinos Estelle
Published: June 2003

In anaplastic large cell lymphoma, the ALK gene at 2p23 is known to be fused to NPM, TPM3, TPM4, TFG, ATIC, CLTC, MSN, and ALO17. All of these translocations result in the expression of chimeric ALK transcripts that are translated into fusion proteins with tyrosine kinase activity and oncogenic properties. We report a case showing a restricted cytoplasmic staining pattern of ALK and a novel chromosomal abnormality, t(2;22)(p23;q11.2), demonstrated by fluorescence in situ hybridization analysis. The result of 5′ RACE analysis showed that the ALK gene was fused in‐frame to a portion of the non‐muscle myosin heavy chain gene, MYH9. Nucleotide sequence of the MYH9‐ALK chimeric cDNA revealed that the ALK breakpoint was different from all those previously reported. It is localized in the same exonic sequence as MSN‐ALK, but 6 bp downstream, resulting in an in‐frame fusion of the two partner proteins. In contrast to the previously reported ALK fusion proteins, MYH9‐ALK may lack a functional oligomerization domain. However, biochemical analysis showed that the new fusion protein is tyrosine phosphorylated in vivo but seems to lack tyrosine kinase activity in vitro. If further investigations confirm this latter result, the in vivo tyrosine phosphorylation of MYH9‐ALK protein could involve mechanisms different from those described in the other ALK hybrid proteins. © 2003 Wiley‐Liss, Inc.
Prenatal chromosomal diversification of leukemia in monozygotic twins
Authors: Kempski Helena , Mensa‐Bonsu Karen A. , Kearney Lyndal , Jalali G. Reza , Hann Ian , Khurshid Mohammed , Greaves Mel
Published: June 2003

Previous studies on concordant acute lymphoblastic leukemia (ALL) in identical twins have identified the leukemia as monoclonal with MLL or ETV6‐RUNX1 gene fusion as early or initiating events in utero. In the latter case, postnatal latency is associated with secondary genetic events such as ETV6 deletion. We describe here a pair of infant twins with concordant acute monoblastic leukemia (AML). They are a unique pair in that their leukemia blasts display extensive intraclonal chromosomal diversity. Comparison of the leukemic cells between the two twins by karyotype and fluorescence in situ hybridization identifies a common or shared stem line and extensive subclonal diversity for which the twins' leukemic populations are divergent. This case of leukemia illustrates in utero initiation with early imposition of chromosomal instability, the progressively divergent evolution of which can be mapped in the twins into pre‐ and postnatal periods. © 2003 Wiley‐Liss, Inc.
Torsional Motion in (tert‐Butyl)ammonium Hemispheraplexes: Rotational Barriers and Energy of Binding
Authors: Maverick Emily F. , Knobler Carolyn B. , Khan Saeed , Canary James W. , Dicker Ira B. , Trueblood Kenneth N.
Published: June 2003

The ADPs (ADPs=atomic anisotropic displacement parameters) from the single‐crystal X‐ray studies of nine related TBA+ (TBA+=(tert‐butyl)ammonium) hemispheraplexes are analyzed, and the results compared to the free energy of binding of this guest by the nine hosts. The lipophilic hosts (Fig. 1) were synthesized over a number of years, with increasing pre‐organization for and specificity of binding. Structural studies for six of the complexes have been published, but the remaining three structures, including those of the strongest binders of TBA+, are disordered and have only now been completed.

New area‐detector data has been analyzed for the TBA+ClO$\rm{_{4}^{-}}$ complexes of 5 and of 8 at two temperatures, while the original data for 9⋅TBA+SCN− has been treated with a disorder model. In addition, improved models are presented for the complexes of 6 and 7. Methods for assessing the precision of the ADP analyses are discussed. Although most of the structures are imprecise, the TBA+ groups do demonstrate some of the characteristics of independent motion. The general trend in calculated libration amplitudes for the TBA+ group suggests that the guests with the greatest free energy of binding, and the shortest distances from N+ to the ligand plane, are those with the highest barriers to internal rotation.
Noncovalent Bond Lengths and Their Cooperative Shortening: Dimers of Vancomycin Group Antibiotics in Crystals and in Solution
Authors: Shiozawa Hideyuki , Zerella Rosa , Bardsley Ben , Tuck Kellie L. , Williams Dudley H.
Published: June 2003

A wide range of dimerisation constants (Kdim ca. 101–106 M−1) for various glycopeptide antibiotics have been determined. We consider these dimerisation constants in the light of the published X‐ray structures of the antibiotics, in particular, the relationship between Kdim and the length of a specified distance at the dimer interface. In the crystals, we find that this distance is smaller for strongly dimerising antibiotics and larger for weakly dimerising antibiotics. Thus, the dimerisation constant is correlated with tightness at the dimer interface. Despite the crystal‐packing forces exerted between adjacent dimer molecules in the crystals, the noncovalent bond distances at the dimer interface are correlated with the distances in solution (inferred from solution NMR data). These observations can account for the benefits in enthalpy, and costs in entropy, associated with positively cooperative binding.
Syntheses and CD‐Spectroscopic Investigations of Longer‐Chain β‐Peptides: Preparation by Solid‐Phase Couplings of Single Amino Acids, Dipeptides, and Tripeptides
Authors: Arvidsson Per I. , Frackenpohl Jens , Seebach Dieter
Published: June 2003

The synthesis and CD‐spectroscopic analysis of eleven water‐soluble β‐peptides composed of all‐β3 or alternating β2‐ and β3‐amino acids is described. Different approaches for the efficient syntheses of longer‐chain β‐peptides (>9 residues) were investigated. They were synthesized on solid phase with Fmoc‐protected amino acids or Fmoc‐protected di‐ or tripeptide fragments (assembled using solution‐phase synthesis). The use of preformed fragments significantly increased the purity of the crude peptides and facilitated purification. Especially, the use of Fmoc‐protected β2/β3‐dipeptides for the synthesis of a ‘mixed' β2/β3‐nonapeptide proved to be remarkably effective, yielding the crude peptide in 95% purity and without detectable epimerization of the β2‐amino acid residues. This is a significant improvement over previously reported procedures for the solid‐phase synthesis of β‐peptides, and foreshadows that the field of β‐peptide research will now switch from synthesis to the design and study of complex functional ‘β‐proteins'.
From Crystal Structures and Their Analysis to the in silico Prediction of Toxic Phenomena
Authors: Dobler Max , Lill Markus A. , Vedani Angelo
Published: June 2003

While the development of potential drug molecules based on the known three‐dimensional structure of the macromolecular target is doubtless one of the more‐potent approaches to rational drug design, the estimation of associated changes in the free energy of ligand binding is all but trivial. Major obstacles include the treatment of long‐range electrostatic effects and charge transfer, the calculation of solvation energies, the treatment of entropic effects, and the quantification of induced fit. In the last decade, a number of computational concepts have nonetheless matured into powerful tools for the development of drug‐candidate molecules. These concepts have mainly focussed on the binding of the small molecule to a bioregulator. More recently, need has arisen to develop tools for a safe prediction of more‐complex phenomena such as metabolism, toxicity, and bioavailability. We describe the ongoing development of a virtual laboratory on the Internet to allow for a reliable in silico estimation of harmful effects triggered by drugs, chemicals, and their metabolites. For this, we used our recently developed underlying technology (5D‐QSAR, based on five‐dimensional quantitative structure‐activity relationships) and compiled a pilot project, including the models of five receptor systems known to mediate adverse effects (the aryl hydrocarbon (Ah), 5 HT2A, cannabinoid, GABAA, and estrogen receptor, resp.) which were already validated against 280 compounds (drugs, chemicals, toxins). Within this setup, we could demonstrate that our virtual laboratory is able both to recognize toxic compounds substantially different from those used in the training set as well as to classify harmless compounds as being nontoxic. The results suggest that our approach can be used for the prediction of adverse effects of drug molecules and chemicals and, thus, bears a significant potential to recognize hazardous compounds early in the development process hence improving resource and waste management and reducing animal testing. It is the aim to provide free access to this technology – particularly to universities, hospitals, and regulatory bodies.
Theory of Stereomutation Dynamics and Parity Violation in Hydrogen Thioperoxide Isotopomers 1,2,3HSO1,2,3H
Authors: Quack Martin , Willeke Martin
Published: June 2003

We present quantitative calculations of the mode‐selective stereomutation tunneling and parity violation in chiral hydrogen thioperoxide (‘oxadisulfane') isotopomers XSOY with X, Y=H, D, and T. The torsional tunneling stereomutation dynamics are investigated with a quasi‐adiabatic channel quasi‐harmonic reaction path Hamiltonian approach, which treats the torsional motion anharmonically in detail and all remaining coordinates as harmonic (but anharmonically coupled to the reaction coordinate). We predict how stereomutation is catalyzed or inhibited by excitation of various vibrational modes compared to the corresponding stereomutation dynamics of the vibrational ground state. Parity‐violating potentials were calculated with our recent multiconfiguration linear response (MC‐LR) approach in the random phase approximation (RPA). We find that, in agreement with general scaling expectations, the parity‐violating energy difference for the equilibrium structures of the two HSOH enantiomers (ca. 5×10−12J mol−1) is situated intermediate between HOOH and HSSH. Our results on the stereomutation dynamics and the influence of parity violation on these are discussed in relation to investigations for the analogous molecules H2O2, H2S2, and Cl2S2. As expected in XSOY (X, Y=H, D, and T), this influence is much larger than in the corresponding H2O2 isotopomers, but smaller than in H2S2 or Cl2S2.
Structure and Function of the Ribosomal Frameshifting Pseudoknot RNA from Beet Western Yellow Virus
Authors: Egli Martin , Sarkhel Sanjay , Minasov George , Rich Alexander
Published: June 2003

Many viruses reprogram ribosomes to produce two different proteins from two different reading frames. So‐called −1 frameshifting often involves pairwise alignment of two adjacent tRNAs at a ‘slippery' sequence in the ribosomal A and P sites such that an overlapping codon is shifted upstream by one base relative to the zero frame. In the majority of cases, an RNA pseudoknot located downstream stimulates this type of frameshift. Crystal structures of the frameshifting RNA pseudoknot from Beet Western Yellow Virus (BWYV) have provided a detailed picture of the tertiary interactions stabilizing this folding motif, including a minor‐groove triplex and quadruple‐base interactions. The structure determined at atomic resolution revealed the locations of several magnesium ions and provided insights into the role of structured water stabilizing the RNA. Systematic in vitro and in vivo mutational analyses based on the structural results revealed specific tertiary interactions and regions in the pseudoknot that drastically change frameshifting efficiency. Here, we summarize recent advances in our understanding of pseudoknot‐mediated ribosomal frameshifting on the basis of the insights gained from structural and functional studies of the RNA pseudoknot from BWYV.
Gas‐Phase Electron‐Diffraction Investigation and Quantum‐Chemical Calculations of the Structure of 1,5‐Dimethylsemibullvalene‐2,4,6,8‐tetracarboxylic Dianhydride
Authors: Samdal Svein , Richardson Alan D. , Hedberg Kenneth , Gadgil Vijay R. , Meyer Matthew M. , Williams Richard Vaughan
Published: June 2003

The bridged homotropilidines have been of interest for decades because their molecules offer the potential for homoaromaticity. Although many of these have been shown not to be homoaromatic, the energy differences of the delocalized (homoaromatic) forms and the localized (nonhomoaromatic) ones, and the barriers to the interconversion of the localized forms via a Cope rearrangement, have been found to vary greatly. The title compound is a strong candidate for homoaromaticity, and, since the structures of the possible localized and delocalized forms could differ significantly, we have carried out an electron‐diffraction investigation of it augmented by quantum‐mechanical calculations with different basis sets at several levels of theory. Three models were explored: one representing a localized form of Cs symmetry, one a delocalized form of C2v symmetry, and one a 2 : 1 mixture of the localized/delocalized forms. Although none of the models could be ruled out, the experimental evidence slightly favors the Cs form. These results are consistent with those from the DFT B3PW91 calculations with basis sets ranging from 6‐31G(d) to cc‐pVTZ, which, surprisingly, predict essentially equal thermally corrected free energies for each. The results are discussed.
Potent New Heterogeneous Asymmetric Catalysts
Authors: Rouzaud Jacques , Jones Matthew D. , Raja Robert , Johnson Brian F. G. , Meurig Thomas John , Duer Melinda J.
Published: June 2003

A set of new, air‐stable, RhI‐based heterogeneous asymmetric hydrogenation catalysts have been synthesised, characterised, and tested. Individual members of this new family all exhibit good enantioselectivity.
Cadherin switching in ovarian cancer progression
Authors: Patel Ila S. , Madan Pavneesh , Getsios Spiro , Bertrand Monique A. , MacCalman Colin D.
Published: June 2003

The roles of the cadherins in the progression of ovarian cancer to the late stages of the disease state when malignant cells have disseminated within the peritoneal cavity remain poorly understood. In view of these observations, we have undertaken a comprehensive survey of the cadherin subtypes present in normal ovarian surface epithelium and peritoneum and in the tumors and peritoneal effusions of women diagnosed with Stage I or Stage II primary ovarian cancer using a degenerate cloning strategy for sequences highly conserved among this family of cell adhesion molecules. On the basis of the nucleotide sequences of the resultant PCR products, multiple cadherin subtypes (E‐, N‐, P‐cadherin, and cadherin‐4, ‐6, and ‐11) were found to be present in these normal and malignant tissues and cells. P‐cadherin was determined to be the predominant cadherin subtype in normal peritoneum, peritoneal effusions and Stage II tumor masses. An increase in P‐cadherin mRNA and protein expression levels in ovarian tumor masses with progression to later stages of the disease state was confirmed by Northern and Western blot analysis, respectively. In addition, we have determined that the cadherin‐associated protein, known as β‐catenin, is expressed in normal peritoneum, ovarian tumors and malignant cell effusions obtained from women with Stage I or Stage II cancer. Immunoprecipitation studies demonstrated that P‐cadherin was capable of interacting with β‐catenin in these normal and malignant tissues and cells. Collectively, these findings suggest that the regulated expression of P‐cadherin/β‐catenin complexes in ovarian tumor cells may represent a key step in disease progression. © 2003 Wiley‐Liss, Inc.
c‐Kit is preferentially expressed in MYCN‐amplified neuroblastoma and its effect on cell proliferation is inhibited in vitro by STI‐571
Authors: Vitali Roberta , Cesi Vincenzo , Nicotra Maria Rita , McDowell Heather P. , Donfrancesco Alberto , Mannarino Olga , Natali Pier Giorgio , Raschellà Giuseppe , Dominici Carlo
Published: June 2003

Coexpression for c‐Kit receptor and its ligand stem cell factor (SCF) has been described in neuroblastoma (NB) cell lines and tumors, suggesting the existence of an autocrine loop modulating tumor growth. We evaluated c‐Kit and SCF expression by immunohistochemistry in a series of 75 primary newly diagnosed neuroblastic tumors. Immunostaining for c‐Kit was found in 10/75 and for SCF in 17/75, with 5/10 c‐Kit–positive tumors also expressing SCF. For both, c‐Kit and SCF staining were predominantly found in the most aggressive subset of tumors, i.e., those amplified for MYCN: c‐Kit was detected in 8/14 amplified vs. 2/61 single copy (p<0.001), and SCF in 9/14 amplified vs. 8/61 single copy tumors (p<0.001). Furthermore, the association of c‐Kit expression with advanced stage (3 or 4) (p=0.001) and of SCF expression with adrenal primary (p=0.03) was substantiated. The in vitro activity of the tyrosine kinase inhibitor STI‐571 (imatinib mesylate, Gleevec, Glivec) on NB cell lines positive or negative for c‐Kit was also assessed. When cells were grown in 10% fetal calf serum, the 4 c‐Kit‐positive cell lines tested were sensitive to STI‐571 growth inhibition to a different extent (ranging from 30 to 80%); also the c‐Kit‐negative cell line GI‐CA‐N was slightly affected, suggesting that other STI‐571 targets operate in regulating NB proliferation. In addition, c‐Kit‐positive cell lines SK‐N‐BE2(c) and HTLA230, grown in SCF only, remained sensitive (40 and 70% of growth inhibition, respectively), while, in the same conditions, proliferation of the c‐Kit‐negative cell line GI‐CA‐N was not affected. Immunoprecipitation of c‐Kit from cell lysates of SK‐N‐BE2(c) and HTLA230 cells grown in SCF and subsequent western blot analysis of the immunoprecipitates revealed a sharp decrease of c‐Kit phosphorylation after STI‐571 treatment. These data demonstrate that both c‐Kit and SCF are preferentially expressed in vivo in the most aggressive neuroblastic tumors and that their signaling is active in promoting in vitro NB cell proliferation that can be selectively inhibited by treatment with STI‐571. © 2003 Wiley‐Liss, Inc.
Capsaicin consumption, Helicobacter pylori positivity and gastric cancer in Mexico
Authors: López‐Carrillo Lizbeth , López‐Cervantes Malaquías , Robles‐Díaz Guillermo , Ramírez‐Espitia Armando , Mohar‐Betancourt Alejandro , Meneses‐García Abelardo , López‐Vidal Yolanda , Blair Aaron
Published: June 2003

Gastric cancer (GC) incidence has not declined in Mexico. We assessed whether the intake of capsaicin (CAP), the pungent compound of chili peppers, increases the risk of GC independently of H. pylori positivity (Hp). From 1994 to 1996, a hospital‐based case‐control study was performed in 3 areas of Mexico; 234 cases of GC and 468 matched controls were enrolled and their diet and other characteristics were inquired. Chili pepper intake was queried by interview and CAP content of chilies was determined in a separate analysis by gas chromatography to estimate CAP intake; IGg Hp serum antibodies were determined by ELISA. The risk of GC was increased (OR = 1.71; 95% CI = 0.76–3.88) among high‐level consumers of CAP (90–250 mg of capsaicin per day, approximately 9–25 jalapeño peppers per day) as compared to low‐level consumers (0–29.9 mg of capsaicin per day, approximately 0 to less than 3 jalapeño peppers per day; p for trend p = 0.026); this effect was independent of Hp status and other potential GC determinants and was higher among diffuse GC cases (OR = 3.64; 95% CI = 1.09–12.2; p for trend = 0.002) compared to intestinal GC cases (OR = 1.36; 95% CI = 0.31–5.89; p for trend = 0.493). No significant interaction was found between CAP intake and Hp on GC risk. Chili pepper consumption might be an independent determinant of GC in Mexico. © 2003 Wiley‐Liss, Inc.
Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: Relationships with abnormal E‐cadherin and catenin expression and microsatellite instability
Authors: Sarrió David , Moreno‐Bueno Gema , Hardisson David , Sánchez‐Estévez Carolina , Guo Mingzhou , Herman James G. , Gamallo Carlos , Esteller Manel , Palacios José
Published: June 2003

The causes and functional consequences of E‐cadherin (E‐CD) loss in breast cancer are poorly understood. E‐CD loss might act in concert with alterations in the APC/β‐catenin pathway to permit oncogenic β‐catenin signaling. To test this hypothesis, we have analyzed the presence of genetic and epigenetic alterations affecting E‐CD (CDH1), APC and β‐catenin (CTNNB1) genes and the immunohistochemical expression of E‐CD, β‐ and γ‐catenin in a series of 46 infiltrating lobular breast carcinomas (ILCs). Since 80% of ILCs featured complete loss of E‐CD expression, we analyzed the molecular alterations responsible for E‐CD inactivation in these tumors. We found that 10 of 46 (22%) cases harbored mutations in CDH1, including 1 case with 2 different mutations (1 of which was germline). CDH1 was also inactivated by loss of heterozygosity (LOH; 30/41, 73%) and promoter hypermethylation (19/46, 41%). Interestingly, LOH and mutations were also detected in the corresponding in situ lesions of the ILCs, implying that these alterations are early events in lobular cancer tumorogenesis. Additionally, the presence of a polymorphism in the CDH1 promoter was found to be inversely correlated with CDH1 mutations, but not with E‐CD levels. We next examined whether alterations in the APC/β‐catenin pathway also occurred in the same series of ILCs. Although no CTNNB1 or APC mutations were detected, promoter methylation (25/46, 52%) and LOH (7/30, 23%) of APC were found. Moreover, methylation of APC and CDH1 occurred concordantly. However, β‐ and γ‐catenin were severely reduced or absent in 90% of these tumors, implying that alterations in CDH1 and APC genes do not promote β‐catenin accumulation in ILC. These molecular alterations were not associated with microsatellite instability. In summary, several different mechanisms (mutations, LOH, methylation) are involved in the frequent CDH1 inactivation in invasive and in situ lobular breast cancer. The same tumors also show genetic and epigenetic alterations of APC gene. However, altered CDH1 and APC genes do not promote β‐catenin accumulation in this tumor type. © 2003 Wiley‐Liss, Inc.
Characterization of several leukemia‐associated antigens inducing humoral immune responses in acute and chronic myeloid leukemia
Authors: Greiner Jochen , Ringhoffer Mark , Taniguchi Masanori , Hauser Thomas , Schmitt Anita , Döhner Hartmut , Schmitt Michael
Published: June 2003

To design a specific immunotherapy for leukemia patients, the identification of leukemia‐associated antigens (LAAs) is a pivotal step. Antileukemic effects after hematopoetic stem cell transplantation for myeloid leukemias are observed and might be related to the recognition of LAAs. Using the serological screening of an expression library (SEREX) of K562 cells, we identified 16 different clones encoding LAAs eliciting a humoral immune response, among them the heat shock proteins HSJ2 and HSP70, the M‐phase phosphoprotein 11 (MPP11), the BRCA1‐associated protein (BRAP), the Jκ recombination binding protein (RBPJκ) and the receptor for hyaluronic acid mediated motility (RHAMM). Serological responses to MPP11 were observed in 7/19 (37%) of patients with acute myeloid leukemia (AML) and 6/16 (38%) of patients with chronic myeloid leukemia (CML), but not in healthy volunteers (0/20). IgG antibodies directed against MPP11 were also detected in 25–50% of the sera of patients with solid tumors such as melanoma, renal cell, ovarian and breast carcinoma. mRNA expression of MPP11 was detected in 20/20 AML patients and 7/10 patients with CML. In normal tissues, strong mRNA expression of MPP11 was only detected in testis. By real‐time PCR, we detected upregulation of MPP11 in leukemic blasts. Simultaneous humoral immune responses to 2 or more of the 16 LAAs identified here was observed, suggesting the feasibility of a polyvalent vaccination as an option for immunotherapies in leukemia patients. © 2003 Wiley‐Liss, Inc.
Induced and spontaneous abortion and breast cancer risk: Results from the E3N cohort study
Authors: Paoletti Xavier , Clavel‐Chapelon Françoise
Published: June 2003

Recent reviews reach conflicting conclusions on breast cancer risk after spontaneous or induced abortion. E3N is a large‐scale cohort study collecting detailed information on environmental and reproductive factors. We investigated the relation between breast cancer and a history of induced and/or spontaneous abortion, using the data from the 100,000 women aged 40–65 at entrance in 1990. Among them, over 2,600 new invasive breast cancers had been diagnosed by June 2000. Multivariate analysis, adjusted for known potential confounders, showed no association between a history of induced abortion and breast cancer risk either in the whole population (relative risk [RR] = 0.91, 95% confidence interval [CI] 0.82–0.99) or in subgroups defined by parity or by menopausal status. Overall, the association between spontaneous abortion and breast cancer was not significant (RR = 1.05, 95% CI 0.95–1.15). However, there is a suggestion of increased risk with increased number of miscarriages (RR = 1.20, 95% CI 0.92–1.56 after 3 or more). Moreover, an interaction with menopausal status was observed. In premenopause, the risk decreased with increasing number of spontaneous abortions, whereas it increased in postmenopause. Among nulliparous and parous women, the relative risk estimates were respectively equal to 1.16 (95% CI 1.04–1.30, p trend < 0.0008) and 1.14 (95% CI 1.01–1.28, p trend = 0.005). Premenopausal breast cancer, on the other hand, appeared to be less frequent in women who had had repeated miscarriages. We conclude that there is no relationship between breast cancer and induced abortion but that an association with spontaneous abortion is possible and may depend on menopausal status. © 2003 Wiley‐Liss, Inc.
Dietary influences on survival after ovarian cancer
Authors: Nagle Christina M. , Purdie David M. , Webb Penelope M. , Green Adèle , Harvey Philip W. , Bain Christopher J.
Published: June 2003

We evaluated the effects of various food groups and micronutrients in the diet on survival among women who originally participated in a population‐based case‐control study of ovarian cancer conducted across 3 Australian states between 1990 and 1993. This analysis included 609 women with invasive epithelial ovarian cancer, primarily because there was negligible mortality in women with borderline tumors. The women's usual diet was assessed using a validated food frequency questionnaire. Deaths in the cohort were identified using state‐based cancer registries and the Australian National Death Index (NDI). Crude 5‐year survival probabilities were estimated using the Kaplan‐Meier technique, and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained from Cox regression models. After adjusting for important confounding factors, a survival advantage was observed for those who reported higher intake of vegetables in general (HR = 0.75, 95% CI = 0.57–0.99, p‐value trend 0.01 for the highest third, compared to the lowest third), and cruciferous vegetables in particular (HR = 0.75, 95% CI = 0.57–0.98, p‐value trend 0.03), and among women in the upper third of intake of vitamin E (HR = 0.76, 95% CI = 0.58–1.01, p‐value trend 0.04). Inverse associations were also seen with protein (p‐value trend 0.09), red meat (p‐value trend 0.06) and white meat (p‐value trend 0.07), and modest positive trends (maximum 30% excess) with lactose (p‐value trend 0.04), calcium and dairy products. Although much remains to be learned about the influence of nutritional factors after a diagnosis of ovarian cancer, our study suggests the possibility that a diet high in vegetable intake may help improve survival. © 2003 Wiley‐Liss, Inc.
Aberrant methylation of TMS1 in small cell, non small cell lung cancer and breast cancer
Authors: Virmani Arvind , Rathi Asha , Sugio Kenji , Sathyanarayana Ubaradka G. , Toyooka Shinichi , Kischel Frank C. , Tonk Vijay , Padar Asha , Takahashi Takashi , Roth Jack A. , Euhus David M. , Minna John D. , Gazdar Adi F.
Published: June 2003

TMS1 (target of methylation‐induced silencing) is a CpG island‐associated gene that functions in the regulation of apoptosis and encodes a caspase recruitment domain, a recently described motif found in apoptotic signaling molecules. Recent evidence suggests that silencing of genes in the apoptotic pathway contribute to human carcinogenesis. We examined the DNA methylation status of the TMS1 promoter in lung and breast tumor tissues, tumor cell lines and nonmalignant tissues by methylation‐specific polymerase chain reaction (MSP) and its mRNA expression by reverse transcription PCR. Aberrant methylation of TMS1 was present in 70% (40 of 57) of small cell lung cancer (SCLC) cell lines and 41% (13 of 32) of SCLC tumor tissues, 48% (29 of 61) of non small cell lung cancer (NSCLC) cell lines and 40% (28 of 70) of NSCLC tumor tissues and 46% (12 of 26) of breast cancer cell lines and 32% (20 of 63) of breast tumor tissues. Methylation was absent in the peripheral blood lymphocytes and buccal epithelium from healthy volunteers, as well as in nonmalignant lung tissues and was rare in nonmalignant breast tissues 7% (2 of 30). DNA methylation was confirmed by sequence analysis and the methylation status correlated inversely with TMS1 RNA expression in 18 cell lines tested. RNA expression was restored by treatment with the demethylating agent 5‐aza‐2′‐deoxycytidine, in 4 of 4 methylated cell lines that lacked the TMS1 transcript. Our results suggest that methylation of TMS1 may play a role in the pathogenesis of small cell and non small lung and breast cancers. © 2003 Wiley‐Liss, Inc.
Novel tumor antigens identified by autologous antibody screening of childhood medulloblastoma cDNA libraries
Authors: Behrends Uta , Schneider Inken , Rössler Sabine , Frauenknecht Heinrich , Golbeck Anja , Lechner Brigitte , Eigenstetter Gerhard , Zobywalski Colette , Müller‐Weihrich Stephan , Graubner Ulrike , Schmid Irene , Sackerer Dieter , Späth Manfred , Goetz Claudia , Prantl Franz , Asmuss Hans‐Peter , Bise Karl , Mautner Josef
Published: June 2003

Medulloblastoma is an embryonal childhood malignancy with poor prognosis. By screening 4 medulloblastoma cDNA expression libraries (SEREX) with autologous sera, 15 different antigens were identified. These antigens were encoded by 3 novel genes, genes of unknown function (KIAA0445, KIAA1853, KIAA0665, FLJ13942, HSPC213), a proto‐oncogene (rab18), candidate tumor suppressor genes (BAP1, PRDM13) and genes encoding a motor protein (kinesin‐2), a histone (H2A1.2), the ankyrin residue‐rich nasopharyngeal cancer susceptibility protein (NZ16) and the transcription factor TZP, which is homologous to the tumor‐associated antigens HCA58 and GLEA2. In a consecutive analysis of serum antibody titers and tumor load, a more than 10‐fold increase in serum antibodies against PRDM13 preceded the clinical diagnosis of recurrent tumor growth in a patient with aggressive large cell medulloblastoma. When sera of pediatric patients with cancer (n = 40) and healthy controls (n = 40) were tested for humoral responses against the SEREX‐defined antigens, 5 antigens were exclusively recognized by sera from cancer patients. These antigens included a novel rab18 gene product translated from mRNA sequences formerly described as 3′ untranslated region. Humoral responses against 2 of the remaining 10 antigens were found preferentially in cancer patients. Antibodies against these antigens were detected in 8/40 and 12/40 cancer patients, respectively, but in only 1 healthy control. The 2 antigens were characterized by a tumor‐specific deletion and a tumor‐specific mutation, respectively. These findings indicate that the humoral immune response against medulloblastoma is directed against diverse antigens that may be useful as diagnostic markers or targets for immunotherapy. © 2003 Wiley‐Liss, Inc.
Spontaneously formed tumorigenic hybrids of Meth A sarcoma cells and macrophages in vivo
Authors: Busund Lill‐Tove R. , Killie Mette K. , Bartnes Kristian , Seljelid Rolf
Published: June 2003

We have recently demonstrated that malignant cells can hybridize with tissue macrophages in vitro, giving rise to tumorigenic hybrids. We now demonstrate that this can occur spontaneously in vivo as a result of fusion between inoculated Meth A sarcoma cells and host cells, presumably macrophages. Thus, from tumor cell suspensions prepared by collagenase perfusion and density centrifugation, hybrid cells could be isolated that were neoplastic but in contrast to Meth A expressed macrophage markers and had phagocytic capacity. Their morphologic features were intermediate between Meth A and macrophages. By taking advantage of a semiallogeneic experimental system by inoculation of Meth A cells from BALB/c (H‐2 Kd) into (BALB.K × BALB/c) F1 (H‐2k/d), hybrid cells from these tumors could be shown to express MHC antigens of both the Meth A and the host haplotypes. Hybrid cells grew faster than Meth A cells in vivo, indicating acquisition of growth‐promoting properties through heterotypic cell fusion. © 2003 Wiley‐Liss, Inc.
Homozygous deletions scanning in tumor cell lines detects previously unsuspected loci
Authors: Pineau Pascal , Marchio Agnès , Cordina Emilie , Tiollais Pierre , Dejean Anne
Published: June 2003

High rates of loss of heterozygosity commonly affect multiple chromosomes in individual tumor types, yet the number of known tumor suppressor genes (TSGs) systematically mutated in the corresponding tumors is usually low. The search for homozygously deleted genome segments in tumor samples or cell lines has become a method of choice to identify major TSGs or to reveal their influence on the development of a given tumor type. Here, we report a detailed homozygous deletion (HD) profiling for 246 critical loci on a panel of 89 tumor cell lines containing significant subsets of lung, ovarian and head and neck squamous cell carcinomas. We found a total of 53 HDs affecting 17 loci. The major target for HDs was p16‐INK4A/p14‐ARF (23/89, 26% of cases). Among the remaining alterations, HDs affecting TP73 or telomeric markers have never been previously described, whereas other HDs represent the first examples associating lesions of certain TSGs with a given tumor type (NF2 in lung and ovarian cells, STK11 in HELA cells). Overall, tumor cell lines established from ovarian or lung carcinomas displayed a surprising diversity of loci targeted by HDs with 7 and 6 loci involved, respectively. Our data suggest that, beside allelotyping or transcriptome/proteome studies, extensive HD profiling represents a promising approach for the detection of hitherto not implicated signalling pathways of tumorigenesis. © 2003 Wiley‐Liss, Inc.
Expression profiling of CC531 colon carcinoma cells reveals similar regulation of β‐catenin target genes by both butyrate and aspirin
Authors: Germann Anja , Dihlmann Susanne , Hergenhahn Manfred , von Knebel Doeberitz Magnus , Koesters Robert
Published: June 2003

The CC531 cell line has been widely used to study different aspects of tumor growth and metastasis and provides an excellent experimental platform to develop novel antitumor strategies. To characterize the CC531 model at the molecular level, we screened for mutations in genes covering important signal‐transduction pathways that are known to play major roles during colon carcinogenesis, the wnt and the ki‐ras signaling pathways. We found both a prototypic β‐catenin (Ctnnb1) mutation (Thr41Ile) and a ki‐ras (G12D) mutation, providing unambiguous evidence for the constitutive activation of these pathways in CC531 cells. We further established comprehensive gene expression profiles of CC531 cells and investigated the molecular response to 2 antitumor drugs, butyrate and aspirin. Using oligonucleotide microarrays, we screened the expression levels of 7,700 genes and identified a total of 398 genes whose expression was significantly changed upon treatment with butyrate. When using aspirin, 121 genes were significantly altered. Interestingly, 36 genes were regulated by both butyrate and aspirin and 35 of them were regulated in the same direction. We found 7 differentially expressed genes, cyclin D1, cyclin E, c‐myc, Fosl1, c‐fos, Cd44 and follistatin, which are known targets of the β‐catenin and/or the ras pathway. In all cases, butyrate and aspirin reversed the changes in expression normally found in response to active signaling of these oncogenic pathways. The microarray data are available (http://ncbi.nlm.nih.gov/geo/). © 2003 Wiley‐Liss, Inc.
Visual speech, a trajectory in viseme space
Authors: Kalberer Gregor A. , Müller Pascal , Gool Luc Van
Published: June 2003

Efficient, realistic face animation is still a challenge. A system is proposed that yields realistic animations for speech. It starts from real 3D face dynamics, observed at frame rate for thousands of points on the faces of speaking actors. When asked to animate a face it replicates the visemes that it has learned, and adds the necessary coarticulation effects. The speech animation could be based on as few as 16 modes, extracted through independent component analysis from the observed face dynamics. Rather than animating via verbatim copying the deformation fields that come with the different visemes are adapted to the shape of the given face. By localizing the face to be animated in a face space, where also the locations of the example faces are known, visemes are adapted automatically according to the relative distance with respect to these examples. © 2003 Wiley Periodicals, Inc. Int J Imaging Syst Technol 13: 74–84, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ima.10044
Robust full‐motion recovery of head by dynamic templates and re‐registration techniques
Authors: Xiao Jing , Moriyama Tsuyoshi , Kanade Takeo , Cohn Jeffrey F.
Published: June 2003

This article presents a method to recover the full‐motion (3 rotations and 3 translations) of the head from an input video using a cylindrical head model. Given an initial reference template of the head image and the corresponding head pose, the head model is created and full head motion is recovered automatically. The robustness of the approach is achieved by a combination of three techniques. First, we use the iteratively reweighted least squares (IRLS) technique in conjunction with the image gradient to accommodate nonrigid motion and occlusion. Second, while tracking, the templates are dynamically updated to diminish the effects of self‐occlusion and gradual lighting changes and to maintain accurate tracking even when the face moves out of view of the camera. Third, to minimize error accumulation inherent in the use of dynamic templates, we re‐register images to a reference template whenever head pose is close to that in the template. The performance of the method, which runs in real time, was evaluated in three separate experiments using image sequences (both synthetic and real) for which ground truth head motion was known. The real sequences included pitch and yaw as large as 40° and 75°, respectively. The average recovery accuracy of the 3D rotations was about 3°. In a further test, the method was used as part of a facial expression analysis system intended for use with spontaneous facial behavior in which moderate head motion is common. Image data consisted of 1‐min of video from each of 10 subjects while engaged in a two‐person interview. The method successfully stabilized face and eye images allowing for 98% accuracy in automatic blink recognition. © 2003 Wiley Periodicals, Inc. Int J Imaging Syst Technol 13: 85–94, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ima.10048
Effect of textile waste water on the spermatogenesis of male albino rats
Authors: Gupta R. S. , Sharma Rakhi , Chaudhary Rakesh , Yadav Rajesh Kumar , Khan T. I.
Published: June 2003

Textile waste water released from dyeing and printing industries situated in Sanganer, Jaipur (India), brought about inhibition of spermatogenesis in male rats. Water analysis showed the presence of heavy metals at more than permissible limits. Oral administration of waste water to the rats at the dose level of 26.6 ml kg−1 body wt. significantly reduced the weights of testes, epididymides and seminal vesicle. Treated animals showed a notable depression of various stages of spermatogenesis. The production of spermatids was inhibited by 70.8% in waste‐water‐treated rats. The populations of spermatogonia, preleptotene spermatocytes and secondary spermatocytes were decreased by 67.2, 71.1 and 73.2%, respectively. The total number of Sertoli cells was affected after waste water treatment. Reduced sperm count and motility resulted in treated groups.

A significant fall in the content of various biochemical parameters of reproductive tissues was observed after water treatment. Copyright © 2003 John Wiley & Sons, Ltd.
Life history parameters of the Two‐spotted Spider Mite (Tetranychus urticae Koch) feeding on bean leaves treated with pyrrolizidine alkaloids
Authors: Pietrosiuk Agnieszka , Furmanowa Mirosława , Kropczyńska Danuta , Kawka Beata , Wiedenfeld Helmut
Published: June 2003

In this study we assess the effect of pyrrolizidine alkaloids (PAs) extracted from Lithospermum canescens on the biology of the two‐spotted spider mite (Tetranychus urticae Koch). Lithospermum canenscens (Michaux) Lehm. (Boraginaceae) is a common prairie plant also known as Indian paint or hoary puccoon. A mixture of seven PAs with known chemical structures was used in this investigation. Mites treated with PAs showed a high mortality of juveniles, a decrease in female fecundity and a shortened longevity. The intrinsic rate of population increase (rm) was used as an indicator of T. urticae population performance after treatment with PAs. The rm value obtained with alkaloid‐treated leaves was lower than that for mites developing on untreated leaves, which indicates that the mite population would develop much slower on treated plants. The results suggest that further studies should be performed to assess the possible use of PA extracts for spider mite control. Copyright © 2003 John Wiley & Sons, Ltd.
Leadership competence and political control: The influential factors
Authors: Itzhaky Haya , York Alan S.
Published: June 2003

This study considers the impact of social support upon the psychological empowerment of community activists. Although it has been clearly shown that the human and personal resources that individual activists bring to their voluntary activity and the inputs of the agencies and associations in which they are active both contribute to the activists' empowerment, little research has considered the effect of the support given by family, friends, and significant others. One hundred twenty‐two community activists in the lower socioeconomic neighborhoods of a city in the center of Israel filled in questionnaires at the conclusion of a year's training program. The questionnaires included scales of social support (family and friends), satisfaction with the course (practical and learning), leadership competence, policy control, self‐esteem, and mastery. The variables were of importance in their contribution to leadership competence and policy control, but in different ways. Both forms of satisfaction from the course, self‐esteem, and family support, contributed to leadership competence, while both mastery and self‐esteem, and the support of friends contributed to policy control. The differences between leadership competence and policy control are discussed in the light of these findings. © 2003 Wiley Periodicals, Inc. J Comm Psychol 31: 371–381, 2003.