bluuebunny/crossref_metadata_2025 huggingface dataset:
Mammography benefit in the Canadian National Breast Screening Study‐2: A model evaluation
Authors: Rijnsburger Adriana J. , van Oortmarssen Gerrit J. , Boer Rob , Draisma Gerrit , To Teresa , Miller Anthony B. , de Koning Harry J.
Published: April 2004

The CNBSS‐2 among women aged 50–59 did not show any significant difference in breast cancer mortality between a control arm screened annually by CBE and a study arm screened by CBE and mammography. Because of this design, the benefit of screening compared to no screening could not be evaluated. We therefore conducted a modeling effort to estimate the benefit of mammography or CBE compared to no screening. We incorporated demographic, epidemiologic and screening characteristics of the CNBSS‐2 in MISCAN. Stage‐specific sensitivities of CBE, with and without mammography, and breast cancer incidence rate in the trial were estimated by comparing observed trial data with model predictions. We predicted the number of breast cancer deaths for both study arms of the CNBSS‐2 and in the absence of screening, assuming improvement in prognosis by early detection. We estimated a 24–29% higher breast cancer incidence rate in the CNBSS‐2 than the average Canadian rate. Estimated sensitivity of CBE (control arm) varied from 0.29 to 0.48 for stage T1c and from 0.6 to 0.65 for stage T2+. Estimated sensitivity of CBE supplemented with mammography (study arm) varied from 0.5 to 0.79 for stage T1c and was 0.95 for stage T2+. Expected breast cancer mortality reduction by annual CBE screening is 20.5% compared to no screening. Estimated breast cancer mortality reduction by mammography screening compared to no screening for the CNBSS‐2 fell within the range 13.6–34.1%. Enrolled women had above average risk. Screening sensitivity in both arms was high. A benefit of mammography screening is supported by our modeling of the CNBSS‐2 results. © 2004 Wiley‐Liss, Inc.
Serum insulin‐like growth factor‐I, insulin‐like growth factor binding protein‐3, and the risk of pancreatic cancer death
Authors: Lin Yingsong , Tamakoshi Akiko , Kikuchi Shogo , Yagyu Kiyoko , Obata Yuki , Ishibashi Teruo , Kawamura Takashi , Inaba Yutaka , Kurosawa Michiko , Motohashi Yutaka , Ohno Yoshiyuki
Published: April 2004

Recent epidemiological studies have shown that high serum levels of insulin‐like growth factor‐I (IGF‐I) are associated with an increased risk of lung, colon, breast and prostate cancer. Since very few studies have addressed the role of serum levels of IGF‐I in the development of pancreatic cancer, we conducted a nested case‐control study to examine this association. The analysis involved 69 case subjects who died from pancreatic cancer during the follow‐up period of the study, and 207 control subjects matched for sex, age(±1 year) and study area, selected randomly from a cohort of 10,364 individuals. Serum levels of IGF‐I and IGF binding protein‐3 (IGFBP‐3) were measured by immunoradiometric assay, using commercially available kits. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic models. The levels of IGF‐I were positively correlated with IGFBP‐3 (r=0.55). There was a positive, but statistically insignificant association between serum levels of IGF‐I and risk of death from pancreatic cancer, with subjects in the highest quartile having an OR of 2.31 (95% CI=0.70–2.64) compared to those in the lowest quartile. The risk of pancreatic cancer death increased significantly with increasing serum levels of IGFBP‐3 (trend p=0.03). Further adjustment for IGFBP‐3 or IGF‐I slightly attenuated the positive associations. This nested case‐control study showed that high serum levels of IGF‐I and IGFBP‐3 may be associated with an increased risk of death from pancreatic cancer. © 2004 Wiley‐Liss, Inc.
Linear relationship between Wnt activity levels and apoptosis in colorectal carcinoma cells exposed to butyrate
Authors: Lazarova Darina L. , Bordonaro Michael , Carbone Rocco , Sartorelli Alan C.
Published: April 2004

We have reported that butyrate, a fatty acid produced by dietary fiber that induces cell cycle arrest, differentiation and/or apoptosis in colorectal carcinoma (CRC) cells in vitro, modulates Wnt activity in 2 CRC cell lines (Bordonaro et al., Int. J. Cancer, 2002; 97:42–51). Our study determines how changes in the levels of Wnt activity induced by butyrate relate to the effects of butyrate on apoptosis, cell cycle arrest and differentiation of CRC cells. In 10 human CRC cell lines a direct relationship was shown between apoptosis and butyrate‐induced increase in Wnt activity, as well as between suppressed clonal growth and increased Wnt activity. No correlation existed between butyrate‐induced increase in Wnt activity and differentiation. The direct relationship between apoptosis and Wnt activity was supported by analyses of DLD‐1 and HCT‐116 cells expressing a dominant negative form of Tcf4, and therefore, with repressed Wnt activity, as well as by measuring the ratio of apoptotic to live cells in flow cytometry‐sorted cell fractions with high and low Wnt activity. Novel flow cytometric methodology was utilized to show that butyrate differentially increases the number of cells with Wnt activity in different CRC cell lines. Thus, CRC cell lines in which butyrate upregulated Wnt activity to relatively high levels were most susceptible to the apoptotic effects of butyrate, whereas cell lines in which butyrate modestly modulated Wnt activity were less affected. © 2004 Wiley‐Liss, Inc.
GST, NAT, SULT1A1, CYP1B1 genetic polymorphisms, interactions with environmental exposures and bladder cancer risk in a high‐risk population
Authors: Hung Rayjean J. , Boffetta Paolo , Brennan Paul , Malaveille Christian , Hautefeuille Agnès , Donato Francesco , Gelatti Umberto , Spaliviero Massimiliano , Placidi Donatella , Carta Angela , Scotto di Carlo Antonio , Porru Stefano
Published: April 2004

Tobacco smoking and occupation are major risk factors of bladder cancer via exposure to polycyclic aromatic hydrocarbons (PAHs) and aromatic amines. Glutathione S‐transferase (GST) M1, T1 and P1 are involved in the detoxification of PAH reactive metabolites. Two N‐acetyltransferase isozymes, NAT2 and NAT1, have major roles in catalyzing the N‐acetylation and O‐acetylation of aromatic amines. Cytochrome P450 1B1 (CYP1B1) and sulfotransferase 1A1 (SULT1A1) are also involved in the metabolism of PAHs and aromatic amines. It is hypothesized that the genetic polymorphisms of these metabolic enzymes have an effect on the individual susceptibility to bladder cancer in particular by interacting with relevant environmental exposures. A hospital‐based case‐control study among men in Brescia, Northern Italy recruited 201 incidence cases and 214 controls from 1997–2000. Occupational exposures were blindly coded by occupational physicians. Genotyping of polymorphisms were carried out with PCR‐RFLP method. Unconditional multivariate logistic regression was applied to model the association between genetic polymorphisms and bladder cancer risk. Effect modifications by age of onset, smoking and occupational exposures to PAHs and aromatic amines were evaluated. We also conducted an analysis of interaction between genetic factors. GSTM1 and GSTT1 null genotype were associated with an increased risk of bladder cancer with an odds ratio (OR) of 1.69 (95% confidence interval [CI] = 1.11–2.56) and 1.74 (95% CI = 1.02–2.95), respectively. The effect of GSTM1 null was seen particularly in heavy smokers, and there was a combined effect with occupational exposure of aromatic amines (OR = 2.77, 95% CI = 1.08–7.10). We observed a trend (p‐value < 0.01) of increasing cancer risk comparing subjects with normal GSTM1 and T1 activity to subjects with one (OR = 1.82, 95% CI = 1.16–2.85) or both null genotypes (OR = 2.58, 95% CI = 1.27–5.23). NAT2 slow acetylator was associated with marginally increased risk of bladder cancer (OR = 1.50, 95% CI = 0.99–2.27), and the OR for the joint effect with occupational exposure of aromatic amines was 3.26 (95% CI = 1.06–9.95). SULT1A1 Arg213His polymorphism showed a marginal protective effect. These findings suggest that individual susceptibility to bladder cancer may be modulated by GSTM1, GSTT1 and NAT2 polymorphisms. © 2004 Wiley‐Liss, Inc.
Association between war and cervical cancer among Vietnamese women
Authors: Huynh My Linh D. , Raab Stephen S. , Suba Eric J.
Published: April 2004

Decades ago, cervical cancer was the leading form of cancer among women in both North Vietnam and South Vietnam. Currently, cervical cancer rates are considerably lower in the northern region of the country. We performed a case‐control study to measure factors associated with the development of cervical cancer among Vietnamese women. Questionnaire‐based interviews were conducted with 202 women in southern Vietnam and 97 women in northern Vietnam. Case subjects were women hospitalized with cervical cancer. Control subjects were women hospitalized with extrauterine neoplasms. Data were analyzed using logistic regression, and odds ratios for the development of invasive cervical cancer were measured. The development of invasive cervical cancer was significantly associated with military service by husbands during the Second Indochinese War and with parity status. Odds ratio for the development of cervical cancer among southern Vietnamese women whose husbands had served in the armed forces was 2.6 (95% CI = 1.2–5.5). Odds ratio for the development of cervical cancer among northern women whose husbands had served in the armed forces was 3.9 (95% CI = 1.5–10.4) if their husbands had been stationed in South Vietnam during the war years. Northern women whose husbands had served in the military experienced no significant increase in cervical cancer risk if their husbands had been stationed in North Vietnam during the war years. Geographic and temporal variation in cervical cancer rates among Vietnamese women was associated with the movement of soldiers. These findings may be useful for cervical cancer prevention efforts in Vietnam and in other countries. © 2004 Wiley‐Liss, Inc.
Analysis of HIC‐1 methylation and transcription in human ependymomas
Authors: Waha Anke , Koch Arend , Hartmann Wolfgang , Mack Heike , Schramm Johannes , Sörensen Niels , Berthold Frank , Wiestler Otmar D. , Pietsch Torsten , Waha Andreas
Published: April 2004

Ependymomas are among the most common brain tumors in children. They develop from ependymal cells lining the ventricular system of the CNS. Previous studies have demonstrated a significant rate of allelic loss at chromosome 17p13.3. The HIC‐1 putative tumor‐suppressor gene, which exhibits hypermethylation and loss of expression in various tumor entities including medulloblastomas and gliomas, maps to the affected region. In the present study, we analyzed HIC‐1 in ependymomas. Therefore, we applied methylation‐specific PCR of the 5′‐untranslated region as well as of a central region of HIC‐1 and bisulfite sequencing to determine the methylation status in 52 ependymomas of different histologic subtypes, grades and locations. In addition, we used a competitive RT‐PCR approach for sensitive assessment of HIC‐1 transcripts. Hypermethylation of at least one of the 2 analyzed regions was found in 43/52 (83%) cases. There was a significant correlation between hypermethylation of HIC‐1 and nonspinal localization (p = 0.019) as well as age. Of 27 ependymomas, 22 (81%) showed absent or low expression of HIC‐1. The elevated methylation of HIC‐1 in nonspinal ependymomas supports the hypothesis that spinal and nonspinal ependymomas represent genetically distinct entities. © 2004 Wiley‐Liss, Inc.
High fat and alcohol intakes are risk factors of postmenopausal breast cancer: A prospective study from the Malmö diet and cancer cohort
Authors: Mattisson Irene , Wirfält Elisabet , Wallström Peter , Gullberg Bo , Olsson Håkan , Berglund Göran
Published: April 2004

Associations between intakes of relative fat, total alcohol and alcoholic beverages and risk of breast cancer were examined in a subsample of 11,726 postmenopausal women from the MDC cohort. The MDC conducted baseline examinations from 1991 to 1996; the end of follow‐up was 31 December 2001. Data were obtained by an interview‐based diet history method, a structured questionnaire, anthropometric measurements and national and regional cancer registries. During 89,602 person‐years of follow‐up, 342 incident cases were documented. Cox regression analysis examined breast cancer risks adjusted for potential confounders. Two energy‐adjustment approaches (i.e., adjusting for total energy vs. adjusting for nonalcohol energy) were used. High total alcohol intake was associated with a nonsignificantly elevated risk. High wine intake was associated with a significantly elevated breast cancer risk (relative risk = 2.12, 95% CI 1.24–3.60). There were significant trends of increased breast cancer risk across quintiles of relative fat intake. Mutual adjustment did not affect risk estimates for total alcohol or relative fat intakes. The specific energy‐adjustment approach did not influence associations differentially. © 2004 Wiley‐Liss, Inc.
Passive smoking and breast cancer risk among non‐smoking Chinese women
Authors: Shrubsole Martha J. , Gao Yu‐Tang , Dai Qi , Shu Xiao‐Ou , Ruan Zi‐Xian , Jin Fan , Zheng Wei
Published: April 2004

Our purpose was to evaluate whether passive exposure to cigarette smoke may be related to breast cancer risk. Data from the Shanghai Breast Cancer Study, a large population‐based study of 1,459 breast cancer cases and 1,556 controls aged 25–64 years, were analyzed. Respective response rates were 91.1% and 90.3%. Passive smoking questions were added to all face‐to‐face interviews 7 months into the study. Women were asked about exposure to their husbands' smoke at home as well as exposure in the workplace. Analyses were restricted to the 1,013 cases and 1,117 controls with passive tobacco smoke exposure data who had never actively smoked. Over 60% of controls reported some exposure to a husband's smoke and over 40% reported exposure to passive smoke in the workplace. Overall, there was no apparent association between any passive smoke exposure or exposure to a husband's smoke and breast cancer risk. There was some evidence of an elevated breast cancer risk associated with passive smoking exposure of 5 hr or more per day in the workplace (OR = 1.6, 95% confidence interval 1.0–2.4; p for trend = 0.02). This association warrants further investigation. © 2004 Wiley‐Liss, Inc.
Serologic detection of diffuse large B‐cell lymphoma‐associated antigens
Authors: Liggins Amanda P. , Guinn Barbara A. , Hatton Chris S. , Pulford Karen , Banham Alison H.
Published: April 2004

Diffuse large B‐cell lymphoma (DLBCL) accounts for 30–40% of all adult non‐Hodgkin's lymphomas, yet the understanding of its underlying genetic abnormalities remains poor. Our present study used the serological analysis of recombinant cDNA expression libraries (SEREX) technique to identify DLBCL‐associated antigens. SEREX screening of testis libraries has previously identified cancer‐testis antigens (CTAs) that may act as disease‐specific targets for immunotherapy. Screening a testis cDNA expression library with serum from a DLBCL patient identified a total of 94 positive clones, representing 28 distinct antigens. Two of these antigens were novel, 8 were previously uncharacterised, and the remainder were proteins of known function. Screening of the antigens with sera from DLBCL (n = 10), acute myeloid leukaemia (AML, n = 10) and chronic myeloid leukaemia (CML, n = 10) patients, alongside normal healthy donor controls (n = 20), revealed that 7 of the antigens were recognised by DLBCL sera but not normal donor sera, whilst 2 of these antigens were also recognised by leukaemic sera. Some of the genes identified here were already known to be transcribed in DLBCL. The mRNA expression of the majority of the remaining antigens was confirmed in DLBCL cell lines using reverse‐transcriptase PCR (RT‐PCR). Our study identified a number of DLBCL associated antigens that may be suitable as prognostic/diagnostic markers and/or for the immunotherapy of haematologic malignancies. © 2004 Wiley‐Liss, Inc.
Low‐fat milk promotes the development of 7,12‐dimethylbenz(A)anthracene (DMBA)‐induced mammary tumors in rats
Authors: Qin Li‐Qiang , Xu Jia‐Ying , Wang Pei‐Yu , Ganmaa Davaasambuu , Li Jue , Wang Jing , Kaneko Takashi , Hoshi Kazuhiko , Shirai Tomoyuki , Sato Akio
Published: April 2004

Commercial cow milk contains considerable amounts of estrogens. Our study assessed the effect of commercial low‐fat milk on the development of 7,12‐dimethylbenz(a)anthracene (DMBA)‐induced mammary tumors in rats. Eighty 6‐week‐old female Sprague‐Dawley rats received a single oral dose of 5 mg DMBA. Twenty‐four hours later, the animals were divided into 4 groups of 20 animals each and given 1 of 4 test solutions for 20 weeks as their drinking liquid: low‐fat (1%) milk (M), artificial milk (A), estrone sulfate solution (0.1 μg/ml, E), or tap water (W). The artificial milk was formulated to supply essentially the same calories as the milk. The low‐fat milk contained 378 pg/ml estrone sulfate. Tumor incidence, the cumulative number of tumors and the sum of tumor diameters were higher in the M and E groups than in the A or W groups. Overall, the development of mammary tumors was in the order: M = E > A = W. Whereas the plasma 17β‐estradiol concentration in the M group was the 2nd highest after the E group, the plasma level of insulin‐like growth factor (IGF‐I) was significantly higher in the M group than in the other 3 groups. In conclusion, commercially available low‐fat milk promotes the development of DMBA‐induced mammary tumors in rats. The degree of the promotion is almost comparable to that of 0.1 μg/ml estrone sulfate. The high estrogen content in the milk may be responsible for the promotional effects, acting in concert with other hormones such as IGF‐I. © 2004 Wiley‐Liss, Inc.
Definition of candidate low risk APC alleles in a Swedish population
Authors: Zhou Xiao‐Lei , Eriksson Ulrika , Werelius Barbro , Kressner Ulf , Sun Xiao‐Feng , Lindblom Annika
Published: April 2004

Many families experience an apparently inherited increased risk of colorectal cancer (CRC) similar to the known syndromes familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). Besides these high‐risk syndromes, approximately 10% of all CRC cases come from families with 2 affected 1st‐degree relatives, and even 1st‐degree relatives to a single case of CRC are at increased risk. Risk subjects from these families frequently show polyps at colonoscopy, which suggests the APC gene as a good candidate susceptibility gene for these attenuated polypotic syndromes. We used the sensitive DHPLC technique to search for possible predisposing germline mutations in the entire APC gene in 91 risk subjects from these high‐ and low‐risk syndromes with unknown predisposing genes. Most exons were also screened for mutations in 96 normal controls and 96 colorectal cancer cases. In our study we probably have identified the most common APC variants in a Swedish population. Among 30 germline variants identified, 1 clearly pathogenic nonsense mutation and 11 putative pathogenic variants (10 missense and one 3′ UTR) were found in 20 index patients (22%). Twelve silent as well as 5 intronic variants were considered nonpathogenic. Two of the missense variants found here, E1317Q and D1822V, have previously been related to a difference in risk of colorectal cancer. One variant, 8636C>A, located within the 3′ UTR region of the APC gene, was suggested to constitute an additional low risk allele with a similar relative risk as the Jewish I1307K mutation (OR = 1.8; 95% CI, 0.96–3.40). The question of whether all the other variants confer an increased colorectal cancer risk warrants future large association studies. © 2004 Wiley‐Liss, Inc.
In vivo administration of liposomal vincristine sensitizes drug‐resistant human solid tumors
Authors: Leonetti Carlo , Scarsella Marco , Semple Sean C. , Molinari Agnese , D'Angelo Carmen , Stoppacciaro Antonella , Biroccio Annamaria , Zupi Gabriella
Published: April 2004

Here we evaluated the antitumor efficacy of vincristine (VCR) encapsulated in sphingomyelin/cholesterol liposomes (SM/Chol) on drug‐resistant human solid tumors. We firstly used the M14 human melanoma line and the counterpart resistant derivative, M14/R. The M14/R, selected after doxorubicin exposure, was cross resistant to VCR: the in vitro treatment with free VCR reduced the survival of M14, while M14/R line was completely resistant to VCR. Encapsulation in liposomes improved the efficacy of VCR in M14 cells and sensitized the M14/R line to the drug. Experiments in vivo confirmed these results. The treatment of M14 bearing mice with VCR resulted in marked reduction of tumor growth, while no antitumoral effect was observed in M14/R tumors. The administration of VCR encapsulated in liposomes was able to sensitize M14/R tumors to the drug, the antitumoral effect being comparable to that observed in M14 tumors after the same treatment. By injecting animals with the same dose of liposomal VCR fractionated into 3 daily injections and administering repeated cycles of treatment, to a marked improvement of the antitumor activity of liposomal VCR was observed. TUNEL assay in tumor sections indicated that the improved efficacy of liposomal VCR was related to the induction of massive necrosis and apoptosis. To confirm the efficacy of liposomal VCR on drug‐resistant tumors, MCF7 breast and LoVo colon carcinomas, sensitive and resistant to VCR treatment, were also employed. The results showed that the treatment with liposomal VCR of mice bearing breast or colon resistant tumors reduced the tumor mass and delayed the tumor regrowth to the same extent observed in the sensitive counterpart. Together, these results demonstrate the ability of VCR encapsulated in liposomes in sensitizing drug resistant tumors of different histotypes. © 2004 Wiley‐Liss, Inc.
Stromal cell‐derived factor‐1α‐induced cell proliferation and its possible regulation by CD26/dipeptidyl peptidase IV in endometrial adenocarcinoma
Authors: Mizokami Yayoi , Kajiyama Hiroaki , Shibata Kiyosumi , Ino Kazuhiko , Kikkawa Fumitaka , Mizutani Shigehiko
Published: April 2004

CD26/dipeptidylpeptidase IV (DPPIV) is a 110 kD membrane‐bound extracellular peptidase with ubiquitous expressions, and has a variety of functional properties in the development of human malignancies as well as T‐cell biology. According to recent reports, stromal cell derived factor‐1α (SDF‐1α), which is a good substrate for CD26/DPPIV, is expressed in various solid tumors and is involved in tumor development or metastasis. We investigated the expression of SDF‐1α and its corresponding receptor, CXCR4, in human endometrial carcinoma (EMCA) tissues and the function of SDF‐1α on EMCA cells with its regulation by CD26/DPPIV. We demonstrated that SDF‐1α and CXCR4 were expressed in human EMCA, and these immunoreactivities were significantly low in Grade 3 EMCA, which was similar to that of CD26/DPPIV, compared to those in Grade 1 and Grade 2. Additionally, exogenous SDF‐1α concentration was significantly lower in CD26/DPPIV‐transfected EMCA cells than that in vector‐transfected cells. Moreover, exogenous SDF‐1α significantly stimulated cell proliferation in vector‐transfected cells in a concentration dependent manner. In contrast, in CD26/DPPIV‐transfected cells, there was no apparent effect on proliferation shown by the addition of exogenous SDF‐1α. This is the first report showing a direct link between the SDF‐1α/CXCR4 pathway with CD26/DPPIV in solid tumors, suggesting that CD26/DPPIV is likely to directly modulate various SDF‐1α induced functions. © 2004 Wiley‐Liss, Inc.
Aberrant methylation of the adenomatous polyposis coli promoter 1A in bronchial aspirates from patients with suspected lung cancer
Authors: Grote Hans J. , Schmiemann Viola , Kiel Sibylle , Böcking Alfred , Kappes Rainer , Gabbert Helmut E. , Sarbia Mario
Published: April 2004

Promoter hypermethylation is a major mechanism for gene silencing and offers a promising starting point for developing molecular biomarkers. The purpose of our study was to determine aberrant methylation of the adenomatous polyposis coli (APC) gene promoter 1A with respect to its prevalence and quantitative level in bronchial aspirates from patients with suspected lung cancer. Applying quantitative methylation‐specific PCR, 155 bronchial aspirates from patients with non‐small cell cancer (NSCLC) and small cell cancer (SCLC) of the lung as well as 67 bronchial aspirates from patients diagnosed for nonneoplastic lung disease were examined in a retrospective case‐control study. Aberrant APC promoter 1A methylation was seen in 71% of NSCLCs, 38% of SCLCs and 42% of patients with nonneoplastic lung disease, being therefore not specific for the presence of primary lung cancer. In contrast, quantitative analysis showed a significantly higher methylation level of bronchial aspirates from NSCLC as compared to patients without neoplastic lung disease. Introducing a cutoff point that defined high level of APC hypermethylation NSCLC could be discriminated from cases without neoplastic disease with a specificity of 98.5% and a sensitivity of 39%. The data suggest that quantitative analysis of APC hypermethylation may serve as a biomarker of primary lung cancer. © 2004 Wiley‐Liss, Inc.
Induction of cyclooxygenase‐2 mRNA and protein expression by dentin bonding agents in human gingival fibroblasts
Authors: Huang Fu‐Mei , Chang Yu‐Chao
Published: April 2004

An ideal dentin bonding agent should be nonirritating to surrounding tissues. Unfortunately, all histological investigations have demonstrated that dentin bonding agents can induce mild to severe inflammatory alterations. However, there is little information on the precise mechanisms about dentin bonding agents‐induced inflammatory reaction. Cyclooxygenase‐2 (COX‐2) is an inducible enzyme believed to be responsible for prostaglandin synthesis at the site of inflammation. The aim of the present study was to investigate the effects of three dentin bonding agents, Clearfil SE Bond, Prime & Bond NT, and Single Bond on the expression of COX‐2 mRNA gene and protein in cultured human gingival fibroblasts. The exposure of quiescent human gingival fibroblasts to dentin bonding agents resulted in the induction of COX‐2 mRNA expression. The investigations of the time‐dependent on COX‐2 mRNA expression in dentin bonding agent‐treated human gingival fibroblasts revealed different patterns. The influence of COX‐2 mRNA depended on the tested materials. In addition, all dentin bonding agents also induced COX‐2 protein expression in human gingival fibroblasts. Taken together, the activation of COX‐2 expression may be one of the potential mechanisms of dentin bonding agent‐induced gingival inflammation. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 70B: 297–302, 2004
Effect of molar mass of an experimental primer on shear bond strength to dentin
Authors: Richards Nicola D. , Söderholm Karl‐Johann , Batich Christopher D.
Published: April 2004

A novel oligomer was synthesized in different molecular masses and used as a primer in dentin bonding. The hypothesis was that an intermediate molecular mass would optimize the conflicting needs for diffusion into etched dentin (low Mw) and high mechanical properties (high Mw). The initial oligomer synthesized was tert butylmethacrylate‐co‐maleic anhydride, which was further reacted to add hyrdoxyethyl methacrylate (HEMA) across the anhydride. The oligomer was synthesized in a series of molecular masses from ∼800–6000 amu. The oligomer with an average Mw of ∼1000 amu provided the highest bond strength (16 MPa), with both lower and higher molar mass oligomers producing lower bond strengths. A polynomial model was fitted to the data with an R2 = 0.606, while a linear model only had an R2 = 0.534. This implies that the graph of molar mass to bond strength has a maximum in the range of molar masses examined, and that an optimum molar mass can be found between 800 and 6000 amu. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 70B: 384–388, 2004
Molecular diffusion in tissue‐engineered cartilage constructs: Effects of scaffold material, time, and culture conditions
Authors: Leddy Holly A. , Awad Hani A. , Guilak Farshid
Published: April 2004

Diffusion is likely to be the primary mechanism for macromolecular transport in tissue‐engineered cartilage, and providing an adequate nutrient supply via diffusion may be necessary for cell proliferation and extracellular matrix production. The goal of this study was to measure the diffusivity of tissue‐engineered cartilage constructs as a function of scaffold material, culture conditions, and time in culture. Diffusion coefficients of four different‐sized fluorescent dextrans were measured by fluorescence recovery after photobleaching in tissue‐engineered cartilage constructs seeded with human adipose‐derived stem cells or acellular constructs on scaffolds of alginate, agarose, gelatin, or fibrin that were cultured for 1 or 28 days in either chondrogenic or control conditions. Diffusivities in the constructs were much greater than those of native cartilage. The diffusivity of acellular constructs increased 62% from Day 1 to Day 28, whereas diffusivity of cellular constructs decreased 42% and 27% in chondrogenic and control cultures, respectively. The decrease in diffusivity in cellular constructs is likely due to new matrix synthesis, which may be enhanced with chondrogenic media, and matrix contraction by the cells in the fibrin and gelatin scaffolds. The increase in diffusivity in the acellular constructs is probably due to scaffold degradation and swelling. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 70B: 397–406, 2004
Development and testing of a general amber force field
Authors: Wang Junmei , Wolf Romain M. , Caldwell James W. , Kollman Peter A. , Case David A.
Published: April 2004

We describe here a general Amber force field (GAFF) for organic molecules. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited number of atom types, but incorporates both empirical and heuristic models to estimate force constants and partial atomic charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallographic structures were compared to GAFF minimized structures, with a root‐mean‐square displacement of 0.26 Å, which is comparable to that of the Tripos 5.2 force field (0.25 Å) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 Å, respectively). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermolecular energies were compared to MP2/6‐31G* results. The RMS of displacements and relative energies were 0.25 Å and 1.2 kcal/mol, respectively. These data are comparable to results from Parm99/RESP (0.16 Å and 1.18 kcal/mol, respectively), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to experiment) is about 0.5 kcal/mol. GAFF can be applied to wide range of molecules in an automatic fashion, making it suitable for rational drug design and database searching. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1157–1174, 2004
Hypoxia suppresses runx2 independent of modeled microgravity
Authors: Ontiveros Christopher , Irwin Regina , Wiseman Robert W. , McCabe Laura R.
Published: April 2004

Bone loss is a consequence of skeletal unloading as seen in bed rest and space flight. Unloading decreases oxygenation and osteoblast differentiation/function in bone. Previously we demonstrated that simulation of unloading in vitro, by culturing differentiating mouse osteoblasts in a horizontal rotating wall vessel (RWV), results in suppressed expression of runx2, a master transcriptional regulator of osteoblast differentiation. However, the RWV is able to reproduce in a controlled fashion at least two aspects of disuse that are directly linked, model microgravity and hypoxia. Hypoxia in the RWV is indicated by reduced medium oxygen tension and increased expression of GAPDH and VEGF. To uncouple the role of model microgravity from hypoxia in suppressed runx2 expression, we cultured osteoblasts under modeled microgravity (oxygenated, horizontal RWV rotation), hypoxia (vertical RWV rotation), or both conditions (horizontal RWV rotation). The expression, DNA binding activity and promoter activity of runx2, was suppressed under hypoxic but not normoxic modeled microgravity RWV conditions. Consistent with a role for hypoxia in suppression of runx2, direct exposure to hypoxia alone is sufficient to suppress runx2 expression in osteoblasts grown in standard tissue culture plates. Taken together, our findings indicate that hypoxia associated with skeletal unloading could be major suppressor of runx2 expression leading to suppressed osteoblast differentiation and bone formation. © 2004 Wiley‐Liss, Inc.
The role of substance P in inflammatory disease
Authors: O'Connor Terence M. , O'Connell Joseph , O'Brien Darren I. , Goode Triona , Bredin Charles P. , Shanahan Fergus
Published: April 2004

The diffuse neuroendocrine system consists of specialised endocrine cells and peptidergic nerves and is present in all organs of the body. Substance P (SP) is secreted by nerves and inflammatory cells such as macrophages, eosinophils, lymphocytes, and dendritic cells and acts by binding to the neurokinin‐1 receptor (NK‐1R). SP has proinflammatory effects in immune and epithelial cells and participates in inflammatory diseases of the respiratory, gastrointestinal, and musculoskeletal systems. Many substances induce neuropeptide release from sensory nerves in the lung, including allergen, histamine, prostaglandins, and leukotrienes. Patients with asthma are hyperresponsive to SP and NK‐1R expression is increased in their bronchi. Neurogenic inflammation also participates in virus‐associated respiratory infection, non‐productive cough, allergic rhinitis, and sarcoidosis. SP regulates smooth muscle contractility, epithelial ion transport, vascular permeability, and immune function in the gastrointestinal tract. Elevated levels of SP and upregulated NK‐1R expression have been reported in the rectum and colon of patients with inflammatory bowel disease (IBD), and correlate with disease activity. Increased levels of SP are found in the synovial fluid and serum of patients with rheumatoid arthritis (RA) and NK‐1R mRNA is upregulated in RA synoviocytes. Glucocorticoids may attenuate neurogenic inflammation by decreasing NK‐1R expression in epithelial and inflammatory cells and increasing production of neutral endopeptidase (NEP), an enzyme that degrades SP. Preventing the proinflammatory effects of SP using tachykinin receptor antagonists may have therapeutic potential in inflammatory diseases such as asthma, sarcoidosis, chronic bronchitis, IBD, and RA. In this paper, we review the role that SP plays in inflammatory disease. J. Cell. Physiol. 201: 167–180, 2004. © 2004 Wiley‐Liss, Inc.
Epithelial mesenchymal transition is a characteristic of hyperplasias and tumors in mammary gland from MMTV‐Cripto‐1 transgenic mice
Authors: Strizzi Luigi , Bianco Caterina , Normanno Nicola , Seno Masaharu , Wechselberger Christian , Wallace‐Jones Brenda , Khan Nadia I. , Hirota Morihisa , Sun Youping , Sanicola Michele , Salomon David S.
Published: April 2004

Epithelial‐mesenchymal transition (EMT) facilitates migration and invasion of epithelial tumor cells. Cripto‐1 (CR‐1), a member of the epidermal growth factor‐CFC protein family increases migration of cells in vitro. Here the expression of molecular markers and signaling molecules characteristic of EMT were assessed in mammary gland hyperplasias and tumors from mice expressing the human CR‐1 transgene by the MMTV promoter (MMTV‐CR‐1) and in mouse mammary epithelial cell line HC‐11 overexpressing CR‐1 (HC‐11/CR‐1). Western blot analysis showed decreased expression of E‐cadherin in MMTV‐CR‐1 tumors and in HC‐11/CR‐1 cells. The expression of N‐cadherin, vimentin, cyclin‐D1, and of the zinc‐finger transcription factor, snail, was increased in MMTV‐CR‐1 tumors. Increased snail mRNA was also found in HC‐11/CR‐1 cells. Expression of phosphorylated (P)‐c‐Src, P‐focal adhesion kinase (FAK), P‐Akt, P‐glycogen synthease kinase 3β (GSK‐3β), dephosphorylated (DP)‐β‐catenin, and various integrins such as, alpha 3, alpha v, beta 1, beta 3, and beta 4 was also increased in MMTV‐CR‐1 tumors. Immunohistochemistry showed positive staining for vimentin, N‐cadherin, cyclin‐D1, smooth muscle actin, fibronectin, snail, and β‐catenin in MMTV‐CR‐1 tumor sections. HC‐11/CR‐1 cells treated with the c‐Src inhibitor PP2 reduced the expression of P‐c‐Src and of P‐FAK, P‐Akt, P‐GSK‐3β, DP‐β‐catenin all known to be activated by c‐Src. Migration of HC‐11/CR‐1 cells was also reduced by PP2 treatment. These results suggest that CR‐1 may play a significant role in promoting the increased expression of markers and signaling molecules associated with EMT. © 2004 Wiley‐Liss, Inc.
Preparation and Thermosensitivity of Naturally Occurring Polypeptide Poly(γ‐glutamic acid) Derivatives Modified by Propyl Groups
Authors: Shimokuri Taiki , Kaneko Tatsuo , Serizawa Takeshi , Akashi Mitsuru
Published: April 2004

Summary: Poly(γ‐glutamic acid) (γ‐PGA) is a biosynthetic polymer, and the carboxyl groups are able to undergo a chemical modification. In this study, poly(α‐propyl γ‐glutamate) (γ‐PGA propylate) was synthesized by the esterification of these carboxyl groups to yield a thermosensitive and biodegradable polymer. In aqueous solution, the γ‐PGA propylate can impart thermosensitivity by controlling the hydrophobic‐hydrophilic balance of the γ‐PGA polymeric chains.

Temperature dependence of light transmittance of an aqueous solution of γ‐PGA and γ‐PGA propylate.

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Temperature dependence of light transmittance of an aqueous solution of γ‐PGA and γ‐PGA propylate.
Enhanced Biocompatibility in Biostable Poly(carbonate)urethane
Authors: Hsu Shan‐hui , Kao Yu‐Chih , Lin Zu‐Chang
Published: April 2004

Summary: In this work, we synthesized two MDI‐based polyurethanes, including a poly(ether)urethane (PEU) and a poly(carbonate)urethane (PCU), by using different soft segments, poly(tetramethylene oxide) and poly(hexyl, ethyl)carbonate diol ($\overline M$ ∼ 2 000). We demonstrated that, in addition to the enhanced biostability of PCU over PEU, the biological performances of PCU in vitro were also improved in general. These included, better cellular attachment and proliferation, less platelet activation, as well as reduced monocyte activation. The unusual wide‐ranging enhancement in biocompatibility for PCU was believed to be related to the larger micro‐phase separation in PCU (∼25 nm) that caused distinct protein adsorption on the surface.

The total number of adherent monocytes (nonactivated and activated) on the bare sample surfaces, albumin pre‐adsorbed sample surfaces, and fibrinogen pre‐adsorbed sample surfaces.

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The total number of adherent monocytes (nonactivated and activated) on the bare sample surfaces, albumin pre‐adsorbed sample surfaces, and fibrinogen pre‐adsorbed sample surfaces.
Branched Azobenzene Side‐Chain Liquid‐Crystalline Copolymers Obtained by Self‐Condensing ATR Copolymerization
Authors: He Xiaohua , Yan Deyue
Published: April 2004

Summary: The one step synthesis of a series of branched azobenzene side‐chain liquid‐crystalline copolymers by the self‐condensing vinyl copolymerization (SCVCP) of a methyl acrylic AB* inimer, 2‐(2‐bromoisobutyryloxy)ethyl methacrylate (BIEM), with the monomer 6‐(4‐methoxy‐azobenzene‐4′‐oxy)hexyl methacrylate (M), by atom transfer radical polymerization (ATRP) in the presence of CuBr/N,N,N′,N′,N″‐pentamethyldiethylenetriamine as a catalyst system, and in chlorobenzene solvent, is reported. The degree of branching (DB), and the molecular weights and polydispersities of the resultant polymers were determined by NMR spectroscopy and size exclusion chromatography, respectively. The phase behaviors of the branched copolymers were characterized by differential scanning calorimetry (DSC) and thermal polarized optical microscopy (POM). The degree of branching of the branched copolymers could be controlled by the comonomer ratio in the feed and influenced their liquid‐crystal properties. Liquid‐crystal properties were not exhibited when the comonomer ratio was low. Comonomer ratios greater than 8 gave polymers with a lower number of branches, which exhibited both a smectic and a nematic phase.

A polarized optical micrograph of the smectic phase texture of a polymer synthesized here with a higher comonomer feed ratio (magnification × 400).

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A polarized optical micrograph of the smectic phase texture of a polymer synthesized here with a higher comonomer feed ratio (magnification × 400).
Pathway‐Dependent Melting in a Low‐Molecular‐Weight Polyethylene‐block‐Poly(ethylene oxide) Diblock Copolymer
Authors: Sun Lu , Liu Yuxiu , Zhu Lei , Hsiao Benjamin S. , Avila‐Orta Carlos A.
Published: April 2004

Summary: In a low‐molecular‐weight polyethylene‐block‐poly(ethylene oxide) (PE‐b‐PEO) diblock copolymer, two pathway‐dependent melting processes were observed: Upon slow heating, the PE lamellar crystals melted at ≈97 °C into a disordered state. However, when the temperature rapidly jumped to above the melting point (e.g., 100 °C), the PE lamellar crystals transformed directly into an ordered lamellar melt, followed by an isothermal conversion into a disordered melt. This isothermal order‐to‐disorder transition was explained by superheating of the PE crystals using a G‐T diagram.

A schematic G‐T diagram explaining the pathway‐dependent double melting for a crystalline polyethylene‐block‐poly(ethylene oxide) copolymer.

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A schematic G‐T diagram explaining the pathway‐dependent double melting for a crystalline polyethylene‐block‐poly(ethylene oxide) copolymer.
Profile of families with parkinsonism‐predominant spinocerebellar ataxia type 2 (SCA2)
Authors: Furtado Sarah , Payami Haydeh , Lockhart Paul J. , Hanson Melissa , Nutt John G. , Singleton Andrew A. , Singleton Amanda , Bower Jamel , Utti Ryan J. , Bird Thomas D. , de la Fuente‐Fernandez Raul , Tsuboi Yoshio , Klimek Mary L. , Suchowersky Oksana , Hardy John , Calne Donald B. , Wszolek Zbigniew K. , Farrer Matthew , Gwinn‐Hardy Katrina , Stoessl A. Jon
Published: April 2004

Spinocerebellar ataxia type 2 (SCA2) has been recognized recently as an uncommon cause of parkinsonism, an alternate presentation to the typical cerebellar disorder. This research review summarizes the existing literature on parkinsonism‐predominant presentation SCA2 and presents new clinical cases of patients with this condition. Various phenotypes are noted in this subtype of SCA2, including parkinsonism indistinguishable from idiopathic Parkinson's disease (PD), parkinsonism plus ataxia, motor neuron disease, and postural tremor. In several kindreds with multiple affected family members, the SCA2 expansion segregated with disease; in addition, several single cases of parkinsonism with and without a family history are also described. The number of repeats in symptomatic patients ranged from 33 to 43. Interruption of the CAG repeat with CAA, CGG, or CCG was found in some individuals, possibly stabilizing the repeat structure and accounting for the relative stability of the repeat size across generations in some families; allele length is not necessarily indicative of trinucleotide repeat architecture. Positron emission tomography scanning in one family showed reduced fluorodopa uptake and normal to increased raclopride binding with a rostrocaudal gradient similar to that found in idiopathic PD. This review emphasizes the importance of testing for SCA2 in patients with parkinsonism and a family history of neurodegenerative disorders. Testing for SCA2 is also important in studies of inherited parkinsonism. © 2004 Movement Disorder Society
Unusual forehead tremor in a patient with essential tremor
Authors: Piboolnurak Panida , Pullman Seth L. , Louis Elan D.
Published: April 2004

Voice and head (neck) tremor commonly occur in patients with essential tremor (ET), but involvement of cranial musculature is generally limited to these specific cranial structures, and action tremor of the forehead has not been reported. We describe a patient with ET who had forehead tremor. The tremor seemed to be task‐specific, and neurophysiological features suggested that the forehead tremor was dystonic. The presence of forehead tremor in a patient with ET probably indicates an additional pathophysiologic process. The explanation for the specificity of involvement of cranial musculature in ET is not known, but this clinical observation might help guide investigators who are interested in the underlying pathophysiology of this condition. © 2004 Movement Disorder Society
Clinicopathological investigation of vascular parkinsonism, including clinical criteria for diagnosis
Authors: Zijlmans Jan C.M. , Daniel Susan E. , Hughes Andrew J. , Révész Tamas , Lees Andrew J.
Published: April 2004

Vascular parkinsonism (VP) is difficult to diagnose with any degree of clinical certainty. We investigated the importance of macroscopic cerebral infarcts and pathological findings associated with microscopic “small vessel disease” (SVD) in the aetiology of VP. The severity of microscopic SVD pathology (perivascular pallor, gliosis, hyaline thickening, and enlargement of perivascular spaces) and the presence of macroscopically visible infarcts were assessed in 17 patients with parkinsonism and no pathological evidence of either Parkinson's disease or any histopathological condition known to be associated with a parkinsonian syndrome, and compared with age‐matched controls. Microscopic SVD pathology was significantly more severe in the parkinsonian brains. Most patients presented with bilateral bradykinesia and rigidity together with a gait disorder characterised predominantly by a shuffling gait. Four patients presented acutely with hemiparesis and then progressed to develop a parkinsonian syndrome. They could be distinguished from the remaining VP patients by the presence at autopsy of macroscopically visible lacunar infarcts in regions where contralateral thalamocortical drive might be reduced. The clinical features at presentation varied according to the speed of onset and the underlying vascular pathological state. New clinical criteria for a diagnosis of VP are proposed based on the clinicopathological findings of this study. © 2004 Movement Disorder Society
Development of Parkinson's disease in patients with blepharospasm
Authors: Micheli Federico , Scorticati María Clara , Folgar Silvia , Gatto Emilia
Published: April 2004

The liability to develop parkinsonian symptoms was evaluated in 105 outpatients with idiopathic blepharospasm (IBS; 54 cases) or IBS associated to oromandibular dystonia (Meige's syndrome; 51 cases) mean age 70.3 ± 9.6 years, and compared with an age‐ and sex‐matched population. Eleven patients developed Parkinson's disease in the blepharospasm group, whereas only 2 of 105 patients were affected in the control group. Our results suggest that patients with IBS either isolated or associated with oromandibular dystonia are more prone to develop parkinsonian symptoms. © 2004 Movement Disorder Society
Spinocerebellar ataxia type 2 with levodopa‐responsive parkinsonism culminating in motor neuron disease
Authors: Infante Jon , Berciano José , Volpini Victor , Corral Jordi , Polo José Miguel , Pascual Julio , Combarros Onofre
Published: April 2004

We describe an exceptional spinocerebellar ataxia type 2 (SCA2) phenotype combining cerebellar ataxia, levodopa‐responsive parkinsonism, and motor neuron symptoms. We conclude that motor neuron symptoms and signs may be a striking manifestation in SCA2, masking pre‐existing cerebellar and extrapyramidal semeiology. © 2004 Movement Disorder Society