bluuebunny/crossref_metadata_2025 huggingface dataset:
Familial risks of cancer as a guide to gene identification and mode of inheritance
Authors: Hemminki Kari , Li Xinjun
Published: March 2004

Occurrence of cancer in parents and offspring may be due to dominant causes, whereas cancer affecting only siblings may indicate a recessive causation. Systematic comparisons of mode of inheritance have not been available for most types of cancer. Using the Swedish Family‐Cancer Database, standardized incidence ratios (SIR) were calculated for offspring whose parents or siblings were diagnosed with the same cancer. The degree of environmental causation was assessed by spouse correlation and by comparing risks among siblings of different ages. We identified reliable familial risks for all common neoplasms, SIRs ranging from 1.6 to 4.3 when only a parent was affected and up to 8.5 when only a sibling was effected. Risks between siblings were particularly high for renal cancer. Spouse correlation was found only for lung and stomach cancer, but the analysis of sibling risks by their age difference suggested that even for some other cancers environmental effects in childhood may contribute to familial aggregation. The results from these analysis suggest that familial cluster of cancer at most sites is heritable, caused by dominant effects; for renal cancer recessive effects may be most important. © 2004 Wiley‐Liss, Inc.
Case‐control study of anthropometric measures and prostate cancer risk
Authors: Friedenreich Christine M. , McGregor S. Elizabeth , Courneya Kerry S. , Angyalfi Steven J. , Elliott Frederick G.
Published: March 2004

A population‐based case‐control study of 988 stage T2 or greater prostate cancer cases and 1,063 controls was conducted in Alberta from November 1997 to December 2000 to examine the influence of anthropometric risk factors on the risk of prostate cancer using several different measures. An in‐person interview was conducted, and all anthropometric measurements were taken using standardized methods. Respondents also recalled their body weight at each decade from age 20 to the referent year. Several anthropometric variables were derived, and unconditional logistic regression analyses were performed. The multivariable odds ratios, when comparing the highest to the lowest quartile were: for body mass index, OR = 1.12 (95% CI 0.85–1.47); for waist‐hip ratio, OR = 1.07 (0.83–1.38); for height, OR = 0.78 (0.60–1.02); for weight, OR = 0.91 (0.70–1.18); for weight gain since age 20, OR = 0.91 (0.70–1.19); and for difference between minimum and maximum adult weight, OR = 0.89 (0.69–1.16). Our study provides evidence for no association between any measures of anthropometry including several derived measures of changes in weight over lifetime and prostate cancer risk. © 2004 Wiley‐Liss, Inc.
Attenuated type II TGF‐β receptor signalling in human malignant oral keratinocytes induces a less differentiated and more aggressive phenotype that is associated with metastatic dissemination
Authors: Huntley Suzy P. , Davies Maria , Matthews John B. , Thomas Gareth , Marshall John , Robinson C. Max , Eveson John W. , Paterson Ian C. , Prime Stephen S.
Published: March 2004

We examined the effect of stable transfection of dominant negative TβR‐II (dn TβR‐II) cDNA in a human oral carcinoma cell line that contained normal Ras and was growth inhibited by TGF‐β1. Two clonal cell lines containing dn TβR‐II were isolated and compared to the vector‐only control and parent cell line. The treatment of cells with exogenous TGF‐β1 resulted in a decrease in ligand‐induced growth inhibition and loss of c‐myc downregulation in test cells compared to controls; transcriptional activation of certain genes including fra‐1 and collagenase was retained. Cells containing dn TβR‐II grew faster in monolayer culture, expressed less keratin 10 and exhibited increased motility and invasion in vitro compared to control cell lines. Endogenous TGF‐β1 production and the regulation of MMP‐2 and MMP‐9 by TGF‐β1 remained unchanged. After orthotopic transplantation to the floor of the mouth in athymic mice, cells containing dn TβR‐II formed comparable numbers of primary tumours at the site of inoculation as controls but the tumours were less differentiated as demonstrated by the absence of keratin 10 immunostaining. Further, metastatic dissemination to the lungs and lymphatics was more evident in grafts of cells containing dn TβR‐II than controls. Taken together, the results demonstrate that attenuation of TGF‐β signalling through transfection of dn TβR‐II cDNA leads to an enhanced growth rate, a loss of tumour cell differentiation and an increase in migration and invasion, characteristics that corresponded to the development of the metastatic phenotype. © 2004 Wiley‐Liss, Inc.
Trafficking of tumor peptide‐specific cytotoxic T lymphocytes into the tumor microcirculation
Authors: Ali Selman , Ahmad Murrium , Lynam June , Rees Robert C. , Brown Nicola
Published: March 2004

The major histocompatibility complex class I‐restricted CD8+ cytotoxic T‐lymphocyte (CTL) effector arm of the adaptive immune response can specifically recognize and destroy tumor cells expressing peptide antigens. Although adoptive T‐cell therapy has been successfully used for the treatment of viral and malignant diseases, little is known of the trafficking and fate of adoptively transferred antigen‐specific T cells. In the present study, splenocytes derived from mice that rejected their tumors (CT26 or CT26‐clone 25 tumors) in response to direct intratumor injection of disabled infectious single‐cycle herpes simplex virus (DISC‐HSV) encoding murine GM‐CSF were restimulated with peptide in vitro. CTLs specific for the AH‐1 and β‐gal peptides expressed by CT26 and CT26‐clone 25 tumor cells, respectively, were generated and used for adoptive cellular therapy and trafficking studies. Intravenous administration of AH‐1‐specific CTLs 3 days following i.v. injection of CT26 cells resulted in significant tumor growth inhibition, whereas administration of control CTLs generated against a bacterial β‐gal peptide did not inhibit the growth of tumors. Trafficking of AH‐1‐specific lymphocytes and their interaction with the CT26 tumor microcirculation was analyzed using real‐time in vivo microscopy (IVM). AH‐1‐specific but not β‐gal‐specific CTLs adhered and localized in the CT26 tumor microvasculature, but neither population adhered to the endothelium of the normal microcirculation. This study provides direct visual evidence suggesting that AH‐1‐specific CTLs that mediate a therapeutic response traffic to and localize within the tumor microenvironment. © 2004 Wiley‐Liss, Inc.
Association of metabolic gene polymorphisms with tobacco consumption in healthy controls
Authors: Smits Kim M. , Benhamou Simone , Garte Seymour , Weijenberg Matty P. , Alamanos Yannis , Ambrosone Christine , Autrup Herman , Autrup Judith L. , Baranova Helena , Bathum Lisa , Boffetta Paolo , Bouchardy C. , Brockmoller Jurgen , Butkiewicz Dorota , Cascorbi Ingolf , Clapper Margie L. , Coutelle Christiane , Daly Ann K. , Muzi Giacomo , Dolzan Vita , Duzhak Tatyana G. , Farker Katrin , Golka Klaus , Haugen Aage , Hein David W. , Hildesheim Allan , Hirvonen Ari , Hsieh Ling L. , Ingelman‐Sundberg Magnus , Kalina Ivan , Kang Daehee , Katoh Takahiko , Kihara Masahiro , Ono‐Kihara Masako , Kim Heon , Kiyohara Chikako , Kremers Pierre , Lazarus Philip , Le Marchand Loic , Lechner Maria C. , London Stephanie , Manni Johannes J. , Maugard Christine M. , Morgan Gareth J. , Morita Shunji , Nazar‐Stewart Valle , Kristensen Vessela Nedelcheva , Oda Yoshio , Parl Fritz F. , Peters Wilbert H.M. , Rannug Agneta , Rebbeck Timothy , Pinto Luis F. Ribeiro , Risch Angela , Romkes Marjorie , Šalagovic Jan , Schoket Bernadette , Seidegard Janeric , Shields Peter G. , Sim Edith , Sinnett Daniel , Strange Richard C. , Stucker Isabelle , Sugimura Haruhiko , To‐Figueras Jordi , Vineis Paolo , Yu Mimi C. , Zheng Wei , Pedotti Paola , Taioli Emanuela
Published: March 2004

Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case‐control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20,938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected. © 2004 Wiley‐Liss, Inc.
Imatinib mesylate effectively combines with chaperone‐rich cell lysate‐loaded dendritic cells to treat bcr‐abl+ murine leukemia
Authors: Zeng Yi , Graner Michael W. , Feng Hanping , Li Gang , Katsanis Emmanuel
Published: March 2004

Imatinib mesylate has become an effective agent for the treatment of chronic myeloid leukemia (CML). However, the development of drug resistance has led to examination of combination therapies. In this study, we investigated the effects of combining imatinib with immunotherapy against a murine bcr‐abl+ leukemia, 12B1. We have previously shown that multiple chaperone proteins may be enriched into a vaccine form from tumor cell lysates by a free‐solution isoelectric focusing method. We refer to these vaccines as chaperone‐rich cell lysates (CRCLs) and have found that they are potent immunologic agents against a variety of murine tumors, including 12B1. We now demonstrate that the combination of imatinib with dendritic cells loaded with 12B1‐derived CRCL yields high activation of anti‐12B1‐specific T cells and potent antitumor activity, resulting in tumor‐free survival in up to 63% of mice with bcr‐abl+ 12B1 tumors. Our data suggest that immunotherapy can be effectively combined with imatinib for the treatment of CML. © 2004 Wiley‐Liss, Inc.
Histone deacetylase inhibitors FK228, N‐(2‐aminophenyl)‐4‐[N‐(pyridin‐3‐yl‐methoxycarbonyl)amino‐ methyl]benzamide and m‐carboxycinnamic acid bis‐hydroxamide augment radiation‐induced cell death in gastrointestinal adenocarcinoma cells
Authors: Zhang Yubin , Adachi Masaaki , Zhao Xudong , Kawamura Rina , Imai Kohzoh
Published: March 2004

HDAC inhibitors induce histone hyperacetylation by a relative increase of histone acetyltransferase activity. Histone hyperacetylation may affect chromatin structure and susceptibility to DNA‐damaging stress, such as IR. We here investigate whether these inhibitors can radiosensitize human gastric MKN45 and colorectal DLD1 adenocarcinoma cells. In both cells, FK228 pretreatment at minimally toxic concentrations clearly augmented IR‐induced cell death, DNA fragmentation and caspase‐3/‐8 activation. In contrast, 5‐FU did not clearly augment IR‐induced cell death and caspase‐3 activation. FK228 increased expression of proapoptotic BH3‐only Bim proteins, and gene transfer–mediated overexpression of Bimα radiosensitized DLD1 cells. These data suggest that the FK228‐mediated increase of Bim expression may at least partially contribute to its augmentation of radiation‐induced apoptosis. However, FK228 did not distinctly affect IR‐induced phosphorylation of H2AX, which is an initial event followed by DNA damage. FK228 strongly augmented IR‐induced growth suppression of MKN45 tumor xenografts. In addition, other HDAC inhibitors, MS275 and CBHA, similarly augmented IR‐induced cell death in both cell types. Our results suggest that these HDAC inhibitors may enhance the efficacy of radiation therapy in gastrointestinal cancer cells. © 2004 Wiley‐Liss, Inc.
Sarcoendoplasmic reticulum Ca2+ ATPase type 2 downregulated in human oral squamous cell carcinoma
Authors: Endo Yosuke , Uzawa Katsuhiro , Mochida Yoshiyuki , Shiiba Masashi , Bukawa Hiroki , Yokoe Hidetaka , Tanzawa Hideki
Published: March 2004

Mice with a heterozygous deletion of the Atp2a2 gene (Atp2a2+/−) encoding SERCA2 spontaneously develop SCCs of the skin and upper digestive tract, including the oral cavity. To elucidate the contribution of ATP2A2 to human oral carcinogenesis, we analyzed genetic and epigenetic changes as well as mRNA and protein expression in primary OSCCs and OPLs. With the exception of one OSCC‐derived cell line showing a 12 bp deletion of ATP2A2, we found no mutations in the coding sequence of the gene in primary OSCCs (n = 52), OPLs (n = 32) and cell lines (n = 8). In immunohistochemistry, however, high frequencies of ATP2A2 downregulation were evident not only in primary OSCCs (42%, 42/100) but also in OPLs (31%, 10/32). Real‐time quantitative RT‐PCR data were consistent with the protein expression status. Aberrant DNA methylation within ATP2A2 also was detected in 9 of 30 ATP2A2‐downregulated OSCCs. Moreover, restoration or elevated expression of the ATP2A2 protein was induced in most of the cell lines showing ATP2A2 methylation after treatment with 5‐aza‐2′‐dC, a DNA demethylating agent. These results suggest that inactivation of the ATP2A2 gene is a frequent and early event during oral carcinogenesis and that loss of expression may be regulated partly by an epigenetic mechanism. © 2004 Wiley‐Liss, Inc.
Identification of an HLA‐A*0201 cytotoxic T lymphocyte epitope specific to the endothelial antigen Tie‐2
Authors: Ramage Judith M. , Metheringham Rachael , Conn Andrew , Spendlove Ian , Moss Robert S. , Patton Daniel T. , Murray J. Clifford , Rees Robert C. , Durrant Lindy G.
Published: March 2004

Tie‐2 stabilises pericyte–endothelial interactions during angiogenesis and is highly expressed on endothelium during several diseases, including arthritis, age‐related macular degeneration and cancer. A vaccine that targets endothelium overexpressing Tie‐2 may result in vessel damage and stimulate an inflammatory cascade resulting in disease regression. We have identified a region unique to Tie‐2 (amino acids 1–196) that is homologous in humans and mice. Using computer algorithms, several HLA‐A*0201 epitopes that are identical in mice and humans were predicted within this region; however, binding assays showed that the majority of these epitopes were of low affinity. Modification of the anchor residues of 4 epitopes enhanced HLA binding. These epitopes were incorporated by site‐directed mutagenesis into a Tie‐2 DNA construct. Immunisation of HLA*0201 transgenic mice with one of the modified Tie‐2 constructs stimulated CTLs that recognised both wild‐type and modified peptide‐pulsed target cells. In contrast, no CTLs were generated in mice immunised with wild‐type Tie‐2 construct, demonstrating that the modified epitope was necessary in the generation of CTLs. Moreover, CTLs from mice immunised with the modified construct killed HLA‐A*0201 endothelial cells overexpressing Tie‐2. Our study demonstrates that it is possible to break tolerance to the endothelial antigen Tie‐2, suggesting that it may be feasible to design a vaccine to activate CTLs to kill endothelial cells overexpressing Tie‐2. © 2004 Wiley‐Liss, Inc.
Molecular alterations associated with cyclin d1 overexpression in endometrial cancer
Authors: Moreno‐Bueno Gema , Rodríguez‐Perales Sandra , Sánchez‐Estévez Carolina , Marcos Raquel , Hardisson David , Cigudosa Juan C. , Palacios José
Published: March 2004

Cyclin D1 is frequently overexpressed in human neoplasias by gene rearrangement and amplification. In addition, Ras, PTEN and β‐catenin appear to modulate cyclin D1 levels. Since the causes of cyclin D1 overexpression are poorly understood in EC, we investigated whether or not this alteration is due to cyclin D1 gene amplification or to RAS, PTEN and β‐catenin mutation. We analyzed cyclin D1 expression in 18 AEHs, 65 EECs and 27 NEECs by immunohistochemistry as well as CCND1 gene amplification by FISH. In EECs, mutations in K‐RAS, PTEN, β‐catenin and CCND1 were studied by PCR‐SSCP and sequencing and MSI was evaluated by analyzing BAT‐25 and BAT‐26 microsatellites. Contingency tests were used to evaluate the relationships between variables. Cyclin D1 overexpression was not observed in AEHs but was present in 13.8% of EECs and 11.2% of NEECs (p = 0.031). CCND1 amplification was more frequent in NEECs (26.3%) than in EECs (2.1%) (p = 0.002). In EECs, cyclin D1 overexpression was not associated with mutations in K‐RAS, PTEN or β‐catenin. However, in EECs with β‐catenin mutations, cyclin D1 was expressed mainly by cells expressing β‐catenin in the cytoplasm and nucleus but not in those with membranous expression. Finally, cyclin D1 overexpression was associated with MSI (p = 0.047). The molecular alterations associated with cyclin D1 overexpression differ in the 2 clinicopathologic types of EC. Cyclin D1 overexpression is associated with gene amplification in NEECs and with nucleocytoplasmic expression of β‐catenin and MSI in EECs. © 2004 Wiley‐Liss, Inc.
Bovine lactoferrin inhibits tumor‐induced angiogenesis
Authors: Shimamura Mariko , Yamamoto Yukio , Ashino Hiromi , Oikawa Tsutomu , Hazato Tadahiko , Tsuda Hiroyuki , Iigo Masaaki
Published: March 2004

Recent studies have demonstrated that bovine lactoferrin (bLF) suppresses tumor growth and metastasis in the mouse and rat and moreover may inhibit angiogenesis. To determine whether angiogenesis inhibition might contribute to antitumor activity, we examined the influence of bLF on tumor‐induced angiogenesis and endothelial cell functions as well as angiogenesis‐related cytokine production. Bovine LF exhibited dose‐dependent inhibition of angiogenesis on 4–6‐day‐old chick embryo chorioallantoic membranes (CAMs) that lack a mature immune response. This inhibition was reversed when bLF was simultaneously treated with basic fibroblast growth factor (bFGF). It also inhibited in vitro formation of tube‐like structures of mouse endothelial KOP2.16 cells. Moreover, it potently suppressed bFGF‐ or VEGF‐induced proliferation of mouse endothelial KOP2.16 cells, but not of mouse fibroblast A31 cells and Lewis lung carcinoma (3LL) cells. In mice, both orally and intraperitoneally administered bLF significantly and dose‐dependently suppressed 3LL cell‐induced angiogenesis in a dorsal air sac assay. As orally administered bLF was reported to exhibit antitumor activity through production of interferon (IFN)‐γ and interleukin (IL)‐18 in intestinal mucosa (Kuhara T et al., Nutr Cancer 2000;38:192–9), production of these cytokines in mouse serum and peritoneal macrophages by bLF was examined. IFN‐γ was not detected in serum by bLF administration. However, bLF markedly elevated IL‐18 concentration in serum by oral administration, but not by intraperitoneal administration. It also induced IL‐18 in peritoneal macrophages in vitro. These results suggest that bLF participates as a regulator of angiogenesis, possibly explained by blocking endothelial function and inducing IL‐18 production. Antitumor activity of bLF may thus be partly mediated by angiogenesis inhibition. © 2004 Wiley‐Liss, Inc.
Epstein‐Barr virus seroreactivity among unaffected individuals within high‐risk nasopharyngeal carcinoma families in Taiwan
Authors: Pickard Amy , Chen Chien‐Jen , Diehl Scott R. , Liu Mei‐Ying , Cheng Yu‐Juen , Hsu Wan‐Lun , Sun Brenda , Hsu Mow‐Ming , Chen I‐How , Chen Jen‐Yang , Yang Czau‐Siung , Mittl Beth L. , Chou Sheng‐Ping , Ruggles Deborah D. , Goldstein Alisa M. , Hildesheim Allan
Published: March 2004

Most adults have been infected with EBV. Many studies have indicated that antibodies against specific EBV antigens, particularly IgA antibodies, can be predictive or prognostic of EBV‐associated malignancies, such as NPC. We hypothesized that healthy individuals from families with a history of multiple members affected with NPC (who therefore might be genetically susceptible to NPC themselves) might have an EBV antibody profile that is distinct from that seen in healthy individuals from the community at large. To explore this possibility and examine determinants of anti‐EBV antibody levels in healthy, high‐risk individuals, we evaluated data from 2 parallel studies of NPC in Taiwan, which included 1,229 healthy members of families in which 2 or more individuals were affected with NPC and 320 controls from the community at large. Blood collected from participants was tested for IgA antibodies against EBV VCA and EBNA‐1 and for neutralizing antibodies against EBV DNase using standard assays. We observed evidence of familial aggregation of EBV seroreactivity among individuals from high‐risk, multiplex NPC families. Anti‐VCA IgA and anti‐EBNA‐1 IgA antibody seroprevalence in unaffected family members of NPC cases was 5–6 times higher than in members of the community (p < 0.01). This elevated seroprevalence among unaffected individuals from high‐risk families was observed regardless of the relationship of the unaffected individual to the closest affected relative (siblings, parents, children or spouses). No sociodemographic or environmental factors examined were found to strongly and consistently correlate with elevated seroprevalence, but patterns emerged of increasing seroprevalence among older individuals and among females. Unaffected individuals from high‐risk NPC families have elevated anti‐EBV IgA antibody titers. The etiologic and clinical implications of this finding remain to be established. © 2004 Wiley‐Liss, Inc.
Detection of occult tumour cells in lymph nodes of colorectal cancer patients using real‐time quantitative RT‐PCR for CEA and CK20 mRNAS
Authors: Öberg Åke N.V. , Lindmark Gudrun E. , Israelsson Anne C.E. , Hammarström Sten G. , Hammarström Marie‐Louise K.C.
Published: March 2004

The purpose of our study was to develop specific, sensitive, objective assays for early detection of disseminated tumour cells in patients with colorectal cancer (CRC). Carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20) were chosen as markers because they are selectively expressed in epithelial cells with maintained expression in CRC. Real‐time quantitative RT‐PCR assays with RNA copy standards were constructed. Regional lymph nodes were collected from patients with CRC (n = 51) and benign intestinal disease (n = 10). Results were compared to routine histopathology and anti‐CEA immunohistochemistry. Lymph node levels of CEA and CK20 mRNA correlated strongly (p < 0.0001, r = 0.8). Lymph nodes from non‐CRC patients had <0.01 CEA and <0.001 CK20 mRNA copies/18S rRNA unit. Lymph nodes from 3/6 Dukes' A, 17/26 Dukes' B, 10/10 Dukes' C and 7/9 Dukes' D patients had CEA mRNA levels above cut‐off. Corresponding figures for CK20 mRNA were 3/6, 10/26, 9/10 and 5/9, respectively. CEA mRNA levels varied from 0.001 to 100 copies/18S rRNA unit in Dukes' A and B, and 50% of the Dukes' B patients had CEA mRNA levels within the range of Dukes' C patients. Three Dukes' B patients have died from CRC or developed distant metastases. All 3 had high CEA and CK20 mRNA levels. Determination of mRNA was superior to immunohistochemistry in showing CEA expression in lymph nodes. The present qRT‐PCR assay for CEA mRNA seems to be a superior tool to identify individuals with disseminated tumour cells. Future extended studies will establish the clinically most relevant cut‐off level. © 2004 Wiley‐Liss, Inc.
Loss of cyclin E requirement in cell growth of an oral squamous cell carcinoma cell line implies deregulation of its downstream pathway
Authors: Yamada Shumpei , Sumrejkanchanakij Piyamas , Amagasa Teruo , Ikeda Masa‐Aki
Published: March 2004

Cyclin E and Cdk2 have been shown to play an important role in G1/S transition of the cell cycle. Two E‐type cyclins (E1 and E2) have been identified to date and share functionally similarities. Upregulation of these cyclins has been observed frequently in human cancers. We examined the expression profile of cyclin E1 and E2 in cell lines derived from human oral squamous cell carcinoma (SCC), and found that the expression of cyclin E1 protein was hardly detected in HSC‐2 cells. Although cyclin E2 was abundantly expressed, histone H1 kinase activities of both E‐type cyclins were virtually undetectable in this cell line. Inhibition of cyclin E1, but not that of E2, by using vectors expressing antisense‐oriented their cDNAs induced drastic growth suppression on HOC313 cells that express both E‐type cyclins. Inhibition of neither cyclin E1 nor E2 suppressed the growth of HSC‐2 cells, and compensatory elevation of cyclin E1 was not evident in cyclin E2‐inhibited HSC‐2 cells. In contrast, HSC‐2 cells expressed cyclin D1 and hyperphosphorylated forms of Rb family proteins, and were arrested in G1 by overexpression of p16INK4, a specific inhibitor against D‐type cyclin activity. These results indicate that HSC‐2 cells lost proper growth control specifically mediated by cyclin E and suggest that deregulation of its downstream pathway may contribute to tumorigenesis of oral SCC. © 2004 Wiley‐Liss, Inc.
Interferon receptor expression regulates the antiproliferative effects of interferons on cancer cells and solid tumors
Authors: Wagner T. Charis , Velichko Sharlene , Chesney Steven K. , Biroc Sandra , Harde Dean , Vogel David , Croze Ed
Published: March 2004

In addition to antiviral effects, Type I interferons (IFN) have potent antiproliferative and immunomodulatory activities. Because of these properties IFNs have been evaluated as therapeutics for the treatment of a number of human diseases, including cancer. Currently, IFNs have been shown to be efficacious for the treatment of only a select number of cancers. The reason for this is unclear. Recent evidence has demonstrated that some cancer cell types seem to be defective in their ability to respond to IFN. It has been suggested that defects in IFN signaling is one mechanism by which cancer cells escape responsiveness to Type I IFNs and growth control in general. We report that transfection and enhanced expression of the Type I IFN receptor chain (IFNAR2c) in 3 different human cancer cell lines markedly increases the sensitivity of these cells to the antiproliferative effects of IFNs. In cancer cells transfected with IFNAR2c, dose response curves demonstrate a significant decrease in the concentrations of IFN required to achieve maximum cell death. Furthermore, in these transfected cells, we observe a significant increase in the number of cells undergoing apoptosis, as measured by DNA fragmentation and Caspase 3 activation. In addition, using an in vivo xenograft tumor model we show an increase in the effectiveness of systemically delivered Betaseron™ in decreasing tumor burden in animals in which solid tumors were generated from IFNAR2c transfected cells. These data show that specific regulation of IFN receptor expression can play a major role in determining the clinical outcome of IFN‐based cancer therapeutics by regulating the relative sensitivity of cancer cells to IFN‐dependent growth control. © 2004 Wiley‐Liss, Inc.
Increased cancer risk of heterozygotes with NBS1 germline mutations in poland
Authors: Steffen Jan , Varon Raymonda , Mosor Maria , Maneva Galina , Maurer Martin , Stumm Markus , Nowakowska Dorota , Rubach Maryna , Kosakowska Ewa , Ruka Włodzimierz , Nowecki Zbigniew , Rutkowski Piotr , Demkow Tomasz , Sadowska Małgorzata , Bidziński Mariusz , Gawrychowski Krzysztof , Sperling Karl
Published: March 2004

It has been suggested based on familial data that Nijmegen breakage syndrome (NBS) heterozygotes have an increased risk of malignant tumors. We found 15 carriers of the 657del5 mutation and 8 carriers of the R215W molecular variant of the NBS1 gene among 1,289 consecutive patients from Central Poland with various cancers and only 10 and 4 such carriers, respectively, in 1,620 controls from this region. Most of the 657del5 mutation carriers were found among patients with melanoma (4/105), non‐Hodgkin lymphoma (2/42) and breast cancer (4/224) and of the 234 patients with colorectal carcinoma 3 carried the 657del5 mutation and 3 others the R215W molecular variant. The frequencies of 657del5 mutation carriers among patients with melanoma and non‐Hodgkin lymphoma and of R215W carriers in patients with colorectal cancer were significantly higher than in controls (p < 0.01, < 0.05 and < 0.05 respectively). The pooled frequencies of 657del5 and R215W mutations in all cancer patients were also significantly higher than in controls (p < 0.05). Two carriers of the 657del5 mutation had second primary tumors. Malignant tumors among parents and siblings of 657del5 mutation carriers (14/77) were twice more frequent than in population controls. Three carriers of this mutation (2 probands with melanoma) reported melanoma in relatives. These results suggest strongly that NBS1 heterozygosity may be associated with elevated risk of some cancers. Larger studies are needed to evaluate the impact of the high frequency of germline NBS1 mutations on the cancer burden in the Slav populations. © 2004 Wiley‐Liss, Inc.
Colorectal cancer risk in adenoma patients: A nation‐wide study
Authors: Loeve F. , van Ballegooijen M. , Boer R. , Kuipers E.J. , Habbema J.D.F.
Published: March 2004

Colorectal cancer incidence after adenoma removal has been studied in selected populations of adenoma patients. Our study estimates the trend in colorectal cancer incidence after adenoma removal in actual clinical practice. From PALGA, a nationwide network and registry of histo‐ and cytopathology in the Netherlands, we extracted data of all patients diagnosed with colorectal adenomas between 1 January 1988 and 1 October 1998. The data were used to calculate population‐based colorectal cancer incidence rates after adenoma removal. A total of 78,473 adenoma patients were followed for a mean of 4.5 years after the first adenoma removal. The colorectal cancer incidence ratio compared with the general population matched by age and gender was 38.4 (37.3–39.5) in the first year after adenoma removal and 1.5 (95% confidence interval (CI): 1.4–1.6) after Year 1. The incidence ratio decreased from 2.8 (2.5–3.1) in Year 2 to 0.9 (0.6–1.2) in Years 9–11. This time trend is the opposite of the upward time trend that was expected after adenoma removal. Adenoma patients in the Netherlands are at increased risk for colorectal cancer compared to the general population. The high cancer incidence in Years 1–5 after polypectomy can be explained by a colonoscopic sensitivity for cancer of approximately 90%. © 2004 Wiley‐Liss, Inc.
Understanding the effect of prizes on response rates
Authors: Porter Stephen R. , Whitcomb Michael E.
Published: March 2004

A controlled experiment is used in a survey of high school students to investigate the effect on response rates of prizes awarded for responding to a survey.
Multiple surveys of students and survey fatigue
Authors: Porter Stephen R. , Whitcomb Michael E. , Weitzer William H.
Published: March 2004

This chapter reviews the literature on survey fatigue and summarizes a research project that indicates that administering multiple surveys in one academic year can significantly suppress response rates in later surveys.
Conducting longitudinal studies
Authors: Bauer Karen W.
Published: March 2004

Although time and resource intensive, longitudinal studies offer the ability to examine the direction and magnitude of causal relationships that cannot be accomplished through cross‐sectional design.
Pros and cons of paper and electronic surveys
Authors: Porter Stephen R.
Published: March 2004

This chapter describes the different types of paper and electronic surveys currently available and their costs and benefits in terms of equipment and printing costs, demands on staff time, and ease of use.
Raising response rates: What works?
Authors: Porter Stephen R.
Published: March 2004

This chapter discusses the theoretical literature on why people choose to respond to a survey and reviews the latest empirical research on how survey administration and the characteristics of a survey affect response rates.
Web surveys: Best practices
Authors: Umbach Paul D.
Published: March 2004

This chapter summarizes the most recent literature on the best practices of Web survey implementation and offers practical advice for researchers.
Conducting surveys on sensitive topics
Authors: Pryor John H.
Published: March 2004

Many institutions are surveying students about sensitive topics such as alcohol and drug use, sexual behavior, and academic dishonesty. Yet these can be some of the most difficult surveys to administer successfully, given reluctance on the part of respondents both to participate and to provide truthful answers.
Molecular responses of vascular smooth muscle cells to paclitaxel‐eluting bioresorbable stent materials
Authors: Nguyen Kytai Truong , Shaikh Nishat , Wawro Debra , Zhang Sheng , Schwade Nathan D. , Eberhart Robert C. , Tang Liping
Published: April 2004

We studied the influence of paclitaxel, eluted from poly(L‐lactic acid) (PLLA), on cultured vascular smooth muscle cell (VSMC) proliferation as a model of bioresorbable stent‐induced restenosis. We blended paclitaxel in cast PLLA films (P‐PLLA), demonstrating controlled release of the drug, then studied VSMC adhesion, proliferation, and gene expression profiles. No difference in cell adhesion was found between P‐PLLA and PLLA controls (105 ± 12% of PLLA controls). However, P‐PLLA significantly reduced VSMC proliferation (40 ± 15% of PLLA controls, p < 0.05). Using cDNA microarray technology, we identified major effects of P‐PLLA, including: upregulation of genes related to apoptosis, anti‐proliferation and antioxidation; and suppression of cell cycle regulators and cell survival markers. The expression patterns indicate that P‐PLLA regulates gene expression and cell functions via new pathways, including receptor tyrosine kinase (RTKs), mitogen‐activated protein kinase (MAPKs), and protein kinase (PKs, e.g., PKA) pathways, in addition to the stabilization of polymerized‐microtubules. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 69A: 513–524, 2004
Efficient approximate all‐atom solvent accessible surface area method parameterized for folded and denatured protein conformations
Authors: Guvench Olgun , Brooks Charles L.
Published: March 2004

Continuing advances in computer hardware and software are permitting atomic‐resolution molecular simulations for longer time scales and on larger systems. Despite these advances, routinely performing atomistic simulations with explicit water for even small proteins, which reach the folding time of such proteins, remains intractable for the foreseeable future. An implicit approximation of the solvent environment using a solvent accessible surface area (SASA) term in a molecular mechanics potential function allows exclusion of the explicit water molecules in protein simulations. This reduces the number of particles by approximately an order of magnitude. We present a fast and acceptably accurate approximate all‐atom SASA method parameterized using a set of folded and heat‐denatured conformations of globular proteins. The parameters are shown to be transferable to folded and heat‐denatured conformations for another set of proteins. Calculation of the approximate SASA and the associated derivatives with respect to atomic positions for a 4644 atom protein requires only 1/11th the CPU time required for calculation of the nonbonded interactions for this system. On a per atom basis, this algorithm is three times faster than the fastest previously published approximate SASA method and achieves the same level of accuracy. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1005–1014, 2004
Stability issues of covalently and noncovalently bonded peptide subunits
Authors: Perczel András , Hudáky Péter , Füzéry Anna K. , Csizmadia Imre G.
Published: March 2004

The present study focuses on important questions associated with modeling of peptide and protein stability. Computing at different levels of theory (RHF, B3LYP) for a representative ensemble of conformers of di‐ and tripeptides of alanine, we found that the Gibbs Free Energy values correlate significantly with the total electronic energy of the molecules (0.922 ≤ R2). For noncovalently attached but interacting peptide subunits, such as [For‐NH2]2 or [For‐L‐Ala‐NH2]2, we have found, as expected, that the basis set superimposition error (BSSE) is large in magnitude for small basis set but significantly smaller when larger basis sets [e.g., B3LYP/6‐311++G(d,p)] are used. Stability of the two hydrogen bonds of antiparallel β‐pleated sheets were quantitatively determined as a function of the molecular structure, S10 and S14, computed as 4.0 ± 0.5 and 8.1 ± 1.1 kcal/mol, respectively. Finally, a suitable thermoneutral isodesmic reaction was introduced to scale both covalently and noncovalently attached peptide units onto a common stability scale. We found that a suitable isodesmic reaction can result in the total electronic energy as well as the Gibbs free energy of a molecule, from its “noninteracting” fragments, as accurate as a few tenths of a kcal per mol. The latter observation seems to hold for peptides regardless of their length (1 ≤ n ≤ 8) or the level of theory applied. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1084–1100, 2004
A semi‐implicit solvent model for the simulation of peptides and proteins
Authors: Basdevant Nathalie , Borgis Daniel , Ha‐Duong Tap
Published: March 2004

We present a new model of biomolecules hydration based on macroscopic electrostatic theory, that can both describe the microscopic details of solvent–solute interactions and allow for an efficient evaluation of the electrostatic hydration free energy. This semi‐implicit model considers the solvent as an ensemble of polarizable pseudoparticles whose induced dipole describe both the electronic and orientational solvent polarization. In the presented version of the model, there is no mutual dipolar interaction between the particles, and they only interact through short‐ranged Lennard–Jones interactions. The model has been integrated into a molecular dynamics code, and offers the possibility to simulate efficiently the conformational evolution of biomolecules. It is able to provide estimations of the electrostatic solvation free energy within short time windows during the simulation. It has been applied to the study of two small peptides, the octaalanine and the N‐terminal helix of ribonuclease A, and two proteins, the bovine pancreatic trypsin inhibitor and the B1 immunoglobin‐binding domain of streptococcal protein G. Molecular dynamics simulations of these biomolecules, using a slightly modified Amber force field, provide stable and meaningful trajectories in overall agreement with experiments and all‐atom simulations. Correlations with respect to Poisson–Boltzmann electrostatic solvation free energies are also presented to discuss the parameterization of the model and its consequences. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1015–1029, 2004
Diffusion–collision model algorithms for protein folding kinetics
Authors: Vasilkoski Zlatko , Weaver David L.
Published: March 2004

The diffusion–collision model (DCM) of protein folding is described qualitatively and quantitatively. The input parameters required to perform a calculation are explained, and the output data are outlined. Three examples are given of calculating DCM folding kinetics: the Engrailed Homeodomain (a three‐helix bundle with three helical microdomains, pdb code 1ENH), protein G (with three microdomains having a β‐hairpin‐α‐helix‐β‐hairpin motif, pdb code 1PGA), and apomyoglobin (with eight helices and seven strong microdomain–microdomain pairings). © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1101–1107, 2004
Evaluation of the protein solvent‐accessible surface using reduced representations in terms of critical points of the electron density
Authors: Becue A. , Meurice N. , Leherte L. , Vercauteren D.P.
Published: March 2004

The aim of our study is the development of a method for calculating the interface of dimerization of protein–protein complexes based on simplified medium‐resolution structures. In particular, we wished to evaluate if the existing concepts for the computation of the Solvent‐Accessible Surface Area (SASA) of macromolecules could be applied to medium‐resolution models. Therefore, we selected a set of 140 protein chains and computed their reduced representations by topological analysis of their electron density maps at 2.85 Å crystallographic resolution. This procedure leads to a limited number of critical points (CPs) that can be identified and associated to backbone and side‐chain parts. To evaluate the SASA and interfaces of dimerization of the reduced representations, we chose and modified two existing programs that calculate the SASA of atomic representations, and tested (1) several radii tables of amino acids, (2) the influence of the backbone and side‐chain points, and (3) the radius of the solvent molecule, which rolls over the surface. The results are shown in terms of relative error compared to the values calculated on the corresponding atomic representations of the proteins. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1117–1126, 2004
Geometry optimization in density functional methods
Authors: Reveles J. Ulises , Köster Andreas M.
Published: March 2004

The geometry optimization in delocalized internal coordinates is discussed within the framework of the density functional theory program deMon. A new algorithm for the selection of primitive coordinates according to their contribution to the nonredundant coordinate space is presented. With this new selection algorithm the excessive increase in computational time and the deterioration of the performance of the geometry optimization for floppy molecules and systems with high average coordination numbers is avoided. A new step selection based on the Cartesian geometry change is introduced. It combines the trust radius and line search method. The structure of the new geometry optimizer is described. The influence of the SCF convergence criteria and the grid accuracy on the geometry optimization are discussed. A performance analysis of the new geometry optimizer using different start Hessian matrices, basis sets and grid accuracies is given. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1109–1116, 2004
A method to obtain a near‐minimal‐volume molecular simulation of a macromolecule, using periodic boundary conditions and rotational constraints
Authors: Bekker Henk , Van Den Berg Jur P. , Wassenaar Tsjerk A.
Published: March 2004

If the rotational motion of a single macromolecule is constrained during a molecular dynamics simulation with periodic boundary conditions it is possible to perform such simulations in a computational box with a minimal amount of solvent. In this article we describe a method to construct such a box, and test the approach on a number of macromolecules, randomly chosen from the protein databank. The essence of the method is that the molecule is first dilated with a layer of at least half the cut‐off radius. For the enlarged molecule a near‐densest lattice packing is calculated. From this packing the simulation box is derived. On average, the volume of the resulting box proves to be about 50% of the volume of standard boxes. In test simulations this yields on average a factor of about two in simulation speed. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1037–1046, 2004
Weaving hadamard matrices with maximum excess and classes with small excess
Authors: Craigen R. , Kharaghani H.
Published: April 2004

Weaving is a matrix construction developed in 1990 for the purpose of obtaining new weighing matrices. Hadamard matrices obtained by weaving have the same orders as those obtained using the Kronecker product, but weaving affords greater control over the internal structure of matrices constructed, leading to many new Hadamard equivalence classes among these known orders. It is known that different classes of Hadamard matrices may have different maximum excess. We explain why those classes with smaller excess may be of interest, apply the method of weaving to explore this question, and obtain constructions for new Hadamard matrices with maximum excess in their respective classes. With this method, we are also able to construct Hadamard matrices of near‐maximal excess with ease, in orders too large for other by‐hand constructions to be of much value. We obtain new lower bounds for the maximum excess among Hadamard matrices in some orders by constructing candidates for the largest excess. For example, we construct a Hadamard matrix with excess 1408 in order 128, larger than all previously known values. We obtain classes of Hadamard matrices of order 96 with maximum excess 912 and 920, which demonstrates that the maximum excess for classes of that order may assume at least three different values. Since the excess of a woven Hadamard matrix is determined by the row sums of the matrices used to weave it, we also investigate the properties of row sums of Hadamard matrices and give lists of them in small orders. © 2004 Wiley Periodicals, Inc. J Combin Designs 12: 233–255, 2004.
Hepatocyte growth factor/scatter factor stimulates migration of muscle precursors in developing mouse tongue
Authors: Bandow Kenjiro , Ohnishi Tomokazu , Tamura Masato , Semba Ichiro , Daikuhara Yasushi
Published: March 2004

Hepatocyte growth factor (HGF) stimulates the migration of myogenic cells during the development of skeletal muscles. The inactivation of HGF genes or that of its receptor, c‐met, in mice causes hypoplasia of skeletal muscle organs, such as the tongue. Basic fibroblast growth factor (FGF‐2) also induces migration of skeletal myoblasts. A comparison of the functions of HGF and FGF‐2 in myogenesis revealed the crucial effect of HGF in the development of skeletal muscles. Unlike FGF‐2, HGF induced migration of myoblasts from the developing mouse tongue. The differences between the activities of HGF and FGF‐2 were determined by comparing their effects on the expression of matrix metalloproteinase‐9 (MMP‐9) in myoblasts, C2C12 cells, cultured in collagen‐coated dishes. The results showed that HGF, but not FGF‐2, stimulated MMP‐9 expression, and that the stimulation was mediated through the activation of phosphoinositide 3‐kinase (PI3K) which was not associated with FGF‐2 signal transduction. Nevertheless, both growth factors exerted almost the same effect on the reduction of myogenin expression in, and on the proliferation of, C2C12 cells, suggesting that HGF, rather than FGF‐2, plays a crucial role in the generation of skeletal muscles, including the tongue. Moreover, the specific role of HGF through the PI3K signal pathway is the induction of MMP‐9 expression in, and the migration of, myoblasts. © 2004 Wiley‐Liss, Inc.