bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivo and in vitro antitumor activity of butyroyloxymethyl‐diethyl phosphate (AN‐7), a histone deacetylase inhibitor, in human prostate cancer
Authors: Rephaeli Ada , Blank‐Porat Diana , Tarasenko Nataly , Entin‐Meer Michal , Levovich Inesa , Cutts Suzanne M. , Phillips Don R. , Malik Zvi , Nudelman Abraham
Published: March 2005

AN‐7, a prodrug of butyric acid, induced histone hyperacetylation and differentiation and inhibited proliferation of human prostate 22Rv1 cancer cells in vitro and in vivo. In nude mice implanted with these cells, 50 mg/kg AN‐7 given orally thrice a week led to inhibition of tumor growth and metastasis, tumor regression in >25% of animals and increased survival. Median time to the experimental end point (tumor volume 2 cm3 or death) in the untreated was 52 days, and average tumor volume was 0.8 ± 0.18 cm3. At the same time, 94.4% of AN‐7‐treated mice survived and had average tumor volumes of 0.37 ± 0.1 cm3. PSA expression was a useful marker for 22Rv1 lung metastasis detection. Sizeable metastases positively stained for PSA and limited air gaps were found in lungs of untreated mice. In animals treated with AN‐7, lung morphology appeared normal. Primary tumors of treated animals were highly positive for PSA and had an elevated level of p21 and the proapoptotic protein Bax. Sections taken from AN‐7‐treated animals, examined under an electron microscope, exhibited condensed chromatin and apoptotic bodies. PSA serum levels were higher in untreated compared to treated animals and correlated with tumor volume. Since prolonged oral administration with 50 mg/kg or a single oral dose of 1.2 g/kg AN‐7 did not cause adverse effects and the former exhibited significant anticancer activity, AN‐7 is likely to display a high therapeutic index and may be beneficial for prostate cancer patients. © 2005 Wiley‐Liss, Inc.
Expression patterns of mitotic and meiotic cell cycle regulators in testicular cancer and development
Authors: Diederichs Sven , Bäumer Nicole , Schultz Nikolaus , Hamra F. Kent , Schrader Mark G. , Sandstede Marie‐Luise , Berdel Wolfgang E. , Serve Hubert , Müller‐Tidow Carsten
Published: March 2005

Mitotic and meiotic cell cycle regulation is essential for normal development and tumor prevention. The underlying molecular mechanisms are not completely characterized. The aim of our analysis was to derive a global expression map of cell cycle regulators in mitosis and meiosis. First, the expression of cyclins, CDKs and CDK inhibitors was determined during postnatal testis maturation in mice using microarrays and quantitative RT‐PCR. The abundance of cyclins A1, B2, K, M4, CDK2, all CDKLs, CDKN2c, CDKN2d and INCA1 increased during testis maturation. In contrast, cyclins A2, B1, D2, G1, G2, CDK1, CDK4 and CDK2AP1 showed a maturation‐associated decrease. Gene expression profiles of isolated germ cells and testicular somatic cells confirmed these results. Second, we determined cyclin expression patterns in human normal and malignant testis samples (n = 36) modeling the reciprocal difference between meiosis and mitosis. Testicular tumors strictly expressed cell cycle regulators identified in mitotically dividing germ cells. Expression of several transcripts was histology‐specific in testicular tumors, providing novel molecular markers and potential therapeutic targets. Taken together, our data provide a comprehensive expression map of cell cycle regulators at the switch between mitosis and meiosis in testis development and in cancerogenesis. © 2005 Wiley‐Liss, Inc.
Parathyroid hormone–related protein (PTHrP) as a causative factor of cancer‐associated wasting: Possible involvement of PTHrP in the repression of locomotor activity in rats bearing human tumor xenografts
Authors: Onuma Etsuro , Tsunenari Toshiaki , Saito Hidemi , Sato Koh , Yamada‐Okabe Hisafumi , Ogata Etsuro
Published: March 2005

Nude rats bearing the LC‐6‐JCK human lung cancer xenograft displayed cancer‐associated wasting syndrome in addition to humoral hypercalcemia of malignancy. In these rats, not only PTHrP but also several other human proinflammatory cytokines, such as IL‐6, leukemia‐inducing factor, IL‐8, IL‐5 and IL‐11, were secreted to the bloodstream. Proinflammatory cytokines induce acute‐phase reactions, as evidenced by a decrease of serum albumin and an increase in α1‐acid glycoprotein. Tumor resection abolished the production of proinflammatory cytokines and improved acute‐phase reactions, whereas anti‐PTHrP antibody affected neither proinflammatory cytokine production nor acute‐phase reactions. Nevertheless, tumor resection and administration of anti‐PTHrP antibody similarly and markedly attenuated not only hypercalcemia but also loss of fat, muscle and body weight. Body weight gain by anti‐PTHrP antibody was associated with increased food consumption; increased body weight from anti‐PTHrP antibody was observed when animals were freely fed but not when they were given the same feeding as those that received only vehicle. Furthermore, nude rats bearing LC‐6‐JCK showed reduced locomotor activity, less eating and drinking and low blood phosphorus; and anti‐PTHrP antibody restored them. Although alendronate, a bisphosphonate drug, decreased blood calcium, it affected neither locomotor activity nor serum phosphorus level. These results indicate that PTHrP represses physical activity and energy metabolism independently of hypercalcemia and proinflammatory cytokine actions and that deregulation of such physiologic activities and functions by PTHrP is at least in part involved in PTHrP‐induced wasting syndrome. © 2005 Wiley‐Liss, Inc.
Combined subcarcinogenic benzo[a]pyrene and UVA synergistically caused high tumor incidence and mutations in H‐ras gene, but not p53, in SKH‐1 hairless mouse skin
Authors: Wang Yongyin , Gao Dayuan , Atencio David P. , Perez Evangeline , Saladi Rao , Moore Julian , Guevara Denise , Rosenstein Barry S. , Lebwohl Mark , Wei Huachen
Published: March 2005

Combined subcarcinogenic doses of benzo[a]pyrene (BaP) and UVA induced H‐ras, but not p53, gene mutations 8 weeks before tumor emergence in SKH‐1 mice. Neither UVA (40 kJ/m2) nor BaP (8 nmol) induced any tumors after mice were topically treated 3 times/week for 25 weeks. However, combined BaP‐UVA treatment synergistically increased tumor incidence and multiplicity. All tumors induced by BaP‐UVA were malignant. The epidermis was collected from mice treated for 2, 6 and 10 weeks. DNA from UVB‐ (0.3 kJ/m2) or BaP‐UVA‐(8 nmol and 40 kJ/m2‐induced tumors was isolated and screened for H‐ras and p53 mutations. Four types of point mutation, GGC→GAC, GCC, GTC and CGC, occurred in UVB‐induced tumors at H‐ras codon 13; and one type of point mutation, GGA→GAA, at codon 12. Treatment with either BaP alone or BaP‐UVA for 10 weeks caused GGA→GAA mutation at codon 12 or GGC→GAC mutation at codon 13 in nontumor skin, respectively, as well as in tumors induced by BaP‐UVA. All of the 10‐week samples treated with either BaP or BaP‐UVA showed detectable mutations at codons 12 and 13, but the genetic load was significantly higher in BaP‐UVA‐treated mice than in those exposed only to BaP. UVA alone induced mutations at codon 12 in only one‐third of samples. G→A mutations induced by BaP or BaP‐UVA at position 38 of codon 13 have not been reported previously. C→T transitions were detected in p53 hot spots of exon 8 in 2 of 19 BaP‐UVA‐induced tumors but were not found in nontumor skin. © 2005 Wiley‐Liss, Inc.
CDC91L1 (PIG‐U) mRNA expression in urothelial cell carcinomas
Authors: Schultz Iman J. , Kiemeney Lambertus A. , Witjes J. Alfred , Schalken Jack A. , Willems Johannes L. , Swinkels Dorine W. , de Kok Jacques B.
Published: March 2005

CDC91L1 (PIG‐U) was recently discovered as a new oncogene in human bladder cancer and showed mRNA overexpression in 36% of primary bladder tumor tissues compared to normal urothelium. We further investigated CDC91L1 mRNA expression in 8 bladder cancer cell lines, 14 normal bladder tissues and 42 urothelial cell carcinomas by real‐time quantitative PCR. The prognostic value of CDC91L1 mRNA expression was also investigated. Surprisingly, only one (2.4%) tumor tissue showed overexpression compared to normal urothelium. No significant relationship of CDC91L1 mRNA expression with increasing pathologic stage (p = 0.962) or grade (p = 0.557) was observed. Median normalized CDC91L1 mRNA expression values were 0.19 for superficial tumors (n = 21) and 0.18 for invasive tumors (n = 21). Grade I, grade II and grade III tumors had median normalized expression values of 0.26, 0.18 and 0.33, respectively. CDC91L1 mRNA expression level was not indicative of early tumor recurrence (log rank p = 0.1629), tumor progression (log rank p = 0.9307) or overall and disease‐specific survival (log rank p = 0.9193 and 0.4710, respectively). Our results suggest, in contrast to those of Guo et al. (Nat Med 2004;10:374–81), that the oncogene CDC91L1 is not overexpressed at the mRNA level in urothelial cell carcinomas and cannot be used to predict the course of the disease. © 2005 Wiley‐Liss, Inc.
CYP19 (aromatase) haplotypes and endometrial cancer risk
Authors: Paynter Randi A. , Hankinson Susan E. , Colditz Graham A. , Kraft Peter , Hunter David J. , De Vivo Immaculata
Published: March 2005

Endogenous estrogen exposure is an important determinant of endometrial cancer risk. Aromatase, encoded by CYP19, catalyzes the aromatization of androstenedione and testosterone to estrone and estradiol, respectively. Several common genetic polymorphisms in CYP19 have been identified, including a TCT insertion/deletion and a (TTTA)n repeat polymorphism in intron IV as well as a 3′UTR C/T polymorphism. We evaluated these 3 polymorphisms plus an additional 9 noncoding polymorphisms as individual genotypes and predicted haplotypes as risk factors for endometrial cancer using a nested case‐control study design. Invasive endometrial cancer cases (n = 222) and matched controls (n = 666) were identified among participants in the Nurses' Health Study who had provided a blood sample in 1989–1990 (n = 32,826). We estimated haplotypes from unphased genotype data spanning >123 kb of CYP19. Six haplotypes constructed from 10 SNPs were estimated with a frequency ≥5%. The highest prevalence haplotype (33% among cases, 28% among controls) was significantly associated with endometrial cancer risk (p = 0.03). Loci with variant alleles that comprise the risk haplotype were independently associated with endometrial cancer, with relative risk estimates ranging from 1.68 (95% CI 1.13–2.48) to 2.07 (95% CI 1.33–3.23), comparing variant allele carriers to wild‐type homozygotes. We observed significant interactions between menopausal status and 2 of the high‐risk loci (p = 0.03 and p < 0.01), with >2‐fold increased risk for variant allele carriers who were postmenopausal but no association between genotype and endometrial cancer among premenopausal women. We evaluated associations between CYP19 haplotypes and plasma steroid hormone levels. The haplotype associated with endometrial cancer risk is also significantly associated with the ratios of estrone to androstenedione and estradiol to testosterone, the products and substrates of the enzyme aromatase, encoded by CYP19. Our data suggest that there is a high‐frequency CYP19 haplotype related to higher estrogen to androgen ratios and increased risk of endometrial cancer and that this association may primarily pertain to postmenopausal women. (Supplementary material for this article can be found on the International Journal of Cancer website at http:www.interscience.wiley.com/jpages/0020‐7136/suppmat/index.html.) © 2005 Wiley‐Liss, Inc.
Sequential, randomized trial of a low‐fat, high‐fiber diet and soy supplementation: Effects on circulating IGF‐I and its binding proteins in premenopausal women
Authors: Gann Peter H. , Kazer Ralph , Chatterton Robert , Gapstur Susan , Thedford Kim , Helenowski Irene , Giovanazzi Sue , Van Horn Linda
Published: March 2005

Despite evidence supporting the involvement of the IGF system in the development of breast and other cancers, the major determinants of interindividual variability in circulatory IGF‐I levels are not well understood. Previous research has pointed to important genetic influences as well as dietary effects through marked calorie or protein restriction. We conducted a randomized trial to determine the effects of 2 dietary patterns on serum IGF‐1, IGFBP1 and IGFBP3 in free‐living premenopausal women: phase 1, an isocaloric low‐fat, high‐fiber (LFHF) vs. usual diet, and phase 2, a soy supplement either with or without isoflavones (soy+IF vs. soy–IF). Participants completed 12 menstrual cycles on phase 1 and then were randomly assigned to a soy supplement for 3 cycles while maintaining the phase 1 diet. Before and after each phase, 154 women provided serum. We found no difference in the change in IGF‐I, BP1 or BP3 in the LFHF group compared to the usual diet group. In phase 2, there were no differences in any IGF protein between the soy+IF and the soy–IF groups or any evidence of interaction between isoflavone exposure and the background diet. However, there was a small but statistically significant decrease (2.3%) in BP3 and an increase in the IGF‐I:BP3 molar ratio among all 153 subjects following either soy supplement. These changes were correlated with changes in intake of calcium, total vegetable protein and soy. The results are compatible with previous data suggesting that increases in dietary calcium, protein and soy, in particular, could increase circulating levels of bioavailable IGF‐I. © 2005 Wiley‐Liss, Inc.
Five‐year follow‐up of health‐related quality of life after primary treatment of localized prostate cancer
Authors: Korfage Ida J. , Essink‐Bot Marie‐Louise , Borsboom Gerard J.J.M. , Madalinska Joanna B. , Kirkels Wim J. , Habbema J. Dik F. , Schröder Fritz H. , de Koning Harry J.
Published: March 2005

Although with earlier detection of prostate cancer more men face the long‐term consequences of primary treatment, studies on the impact of treatment on long‐term health‐related quality of life (HRQoL) are scarce. We followed 314 men with newly diagnosed localized prostate cancer from 1 month before until 5 years after radical prostatectomy (n = 127) or external beam radiotherapy (n = 187; median follow‐up = 52 months). Questionnaires addressing disease‐specific (UCLA PCI) and generic (SF‐36, EQ‐5D) HRQoL were sent 1 month before and 6, 12 and 52 months after treatment. Repeated‐measures modeling was used to study HRQoL over time. Regular urinary leakage was reported by 12% of prostatectomy patients before treatment and by 31% at the 52‐month assessment. Erectile dysfunction before treatment was reported by 31% of prostatectomy patients and by 40% of radiotherapy patients; at the 52‐month assessment, these percentages were 88% and 64%, respectively. Erectile dysfunction present at 1 year posttreatment can be considered permanent. Prostatectomy patients reported better generic functioning both before and after treatment than radiotherapy patients, who were on average 5.9 years older and had more comorbid conditions. General physical functioning of prostatectomy patients slightly improved over time, but declined in radiotherapy patients. The relation between age and physical scores was found to be nonlinear. The long‐term physical decline in radiotherapy patients partly resulted from aging and its nonlinear impact on health, although treatment effects cannot be excluded. Scores of both patient groups remained above those of norm populations. Innovative graphs describing disease‐specific and generic functions after treatment can help patients and physicians in their treatment choices. © 2005 Wiley‐Liss, Inc.
Is there an association between maternal weight and the risk of testicular cancer? An epidemiologic study of Norwegian data with emphasis on World War II
Authors: Aschim Elin L. , Grotmol Tom , Tretli Steinar , Haugen Trine B.
Published: March 2005

Since registration started in the 1950s, the incidence of testicular cancer (TC) in the Western world has increased, which is also the case in Norway. Men born in Norway during World War II (WWII), however, have a lower TC incidence than men born in the years before or after WWII. Increased fetal exposure to estrogen during the first trimester of pregnancy has been proposed as a risk factor for the development of TC later in life. Increased maternal weight is associated with higher insulin levels, leading to lower sex hormone‐binding globulin levels and thereby increased levels of bioavailable estrogens for transplacental transfer from mother to fetus. The aim of the present study was therefore to examine whether there was an association between maternal weight and the incidence of TC among those who were born in a time period where the nutritional conditions changed, i.e., around the time of WWII. We compared data for a random sample of women giving birth in Oslo, Norway, in the years 1931 to 1955 with the TC incidence among men born in the whole country in the same time period. Maternal weight at delivery was used as a proxy for first‐trimester weight. We found a correlation (Spearman's rho = 1.00, p < 0.01; Pearson's r = 0.95, p = 0.02) between the TC incidence and maternal weight adjusted for birth weight and maternal age. Although one cannot draw firm conclusions from ecologic correlations, these findings suggest that the increase in TC incidence over the past decades could be at least partly attributed to the increased maternal body weight observed in most populations in the relevant time period since TC is thought to be associated with in utero conditions. © 2005 Wiley‐Liss, Inc.
Dendritic cells delivered inside human carcinomas are sequestered by interleukin‐8
Authors: Feijoó Esperanza , Alfaro Carlos , Mazzolini Guillermo , Serra Patricia , Peñuelas Iván , Arina Ainhoa , Huarte Eduardo , Tirapu Iñigo , Palencia Belén , Murillo Oihana , Ruiz Juan , Sangro Bruno , Richter José A. , Prieto Jesús , Melero Ignacio
Published: March 2005

In the course of a clinical trial consisting of intratumoral injections of dendritic cells (DCs) transfected to produce interleukin‐12, the use of 111In‐labeled tracing doses of DCs showed that most DCs remained inside tumor tissue, instead of migrating out. In search for factors that could explain this retention, it was found that tumors from patients suffering hepatocellular carcinoma, colorectal or pancreatic cancer were producing IL‐8 and that this chemokine attracted monocyte‐derived dendritic cells that uniformly express both IL‐8 receptors CXCR1 and CXCR2. Accordingly, neutralizing antihuman IL‐8 monoclonal antibodies blocked the chemotactic attraction of DCs by recombinant IL‐8, as well as by the serum of the patients or culture supernatants of human colorectal carcinomas. In addition, tissue culture supernatants of colon carcinoma cells inhibited DC migration induced by MIP‐3β in an IL‐8‐dependent fashion. IL‐8 production in malignant tissue and the responsiveness of DCs to IL‐8 are a likely explanation of the clinical images, which suggest retention of DCs inside human malignant lesions. Impairment of DC migration toward lymphoid tissue could be involved in cancer immune evasion. © 2005 Wiley‐Liss, Inc.
Migration‐stimulating factor displays HEXXH‐dependent catalytic activity important for promoting tumor cell migration
Authors: Houard Xavier , Germain Stéphane , Gervais Marianne , Michaud Annie , van den Brûle Frédéric , Foidart Jean‐Michel , Noël Agnès , Monnot Catherine , Corvol Pierre
Published: March 2005

Like most extracellular matrix (ECM) components, fibronectin (Fn) is proteolyzed generating specific activities. Fibronectin proteinase (Fn‐proteinase) represents such a cryptic activity located in the gelatin‐binding domain (GBD) of Fn and displays a zinc metalloproteinase activity. The migration‐stimulating factor (MSF) is a truncated Fn isoform generated by alternative mRNA splicing and corresponds to the N‐terminal part of Fn that comprises the GBD. We show that several human mammary epithelial cells express MSF and constitutively produce Fn‐proteinase activity. Furthermore, recombinant MSF produced by HEK‐293 and MCF‐7 cells possesses a constitutive Fn‐proteinase activity. Mutating the putative zinc‐binding motif, HEXXH, of the protein abolishes its activity thereby demonstrating its specificity. Using PCR, we showed that MSF is barely expressed in normal breast tissues, whereas its expression is significantly increased in tumors. Furthermore, an association between MSF expression and invasive capacity is observed in various breast adenocarcinoma cell lines. Indeed, when stably transfected in non‐invasive MCF‐7 cells, MSF promotes cell migration in a mechanism mostly dependent on its Fn‐proteinase activity. In summary, our study shows that: (i) MSF displays constitutive Fn‐proteinase activity; (ii) MSF expression is induced in human breast cancer; and (iii) MSF confers pro‐migratory activity that depends mostly on its Fn‐proteinase activity. These results suggest that MSF may be involved in tumor progression. © 2005 Wiley‐Liss, Inc.
Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial
Authors: Meyer François , Galan Pilar , Douville Pierre , Bairati Isabelle , Kegle Pastelle , Bertrais Sandrine , Estaquio Carla , Hercberg Serge
Published: March 2005

Randomized trials have shown, unexpectedly, that supplementation with selenium or vitamin E is associated with a reduction of prostate cancer risk. We assess whether a supplementation with low doses of antioxidant vitamins and minerals could reduce the occurrence of prostate cancer and influence biochemical markers. The SU.VI.MAX trial comprised 5,141 men randomized to take either a placebo or a supplementation with nutritional doses of vitamin C, vitamin E, β‐carotene, selenium and zinc daily for 8 years. Biochemical markers of prostate cancer risk such as prostate‐specific antigen (PSA) and insulin‐like growth factors (IGFs) were measured on plasma samples collected at enrollment and at the end of follow‐up from 3,616 men. Cox regression models were used to estimate the hazard ratio and related 95% confidence interval of prostate cancer associated with the supplementation and to examine whether the effect differed among predetermined susceptible subgroups. During the follow‐up, 103 cases of prostate cancer were diagnosed. Overall, there was a moderate nonsignificant reduction in prostate cancer rate associated with the supplementation (hazard ratio = 0.88; 95% CI = 0.60–1.29). However, the effect differed significantly between men with normal baseline PSA (< 3 μg/L) and those with elevated PSA (p = 0.009). Among men with normal PSA, there was a marked statistically significant reduction in the rate of prostate cancer for men receiving the supplements (hazard ratio = 0.52; 95% CI = 0.29–0.92). In men with elevated PSA at baseline, the supplementation was associated with an increased incidence of prostate cancer of borderline statistical significance (hazard ratio = 1.54; 95% CI = 0.87–2.72). The supplementation had no effect on PSA or IGF levels. Our findings support the hypothesis that chemoprevention of prostate cancer can be achieved with nutritional doses of antioxidant vitamins and minerals. © 2005 Wiley‐Liss, Inc.
Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor‐bearing DA rats
Authors: Gibson Rachel J. , Bowen Joanne M. , Keefe Dorothy M.K.
Published: March 2005

Mucositis is a common side effect of cancer chemotherapy for which there is currently no treatment. Irinotecan is a commonly used effective chemotherapeutic agent, causing severe gastrointestinal mucositis and diarrhea. Previous research suggests that palifermin is potentially antimucotoxic. The primary aim of this study was to determine whether palifermin was effective in ameliorating irinotecan‐induced gastrointestinal mucositis. We also determined the protective effects of single large and multiple small doses of palifermin. Tumor‐bearing DA rats were treated with a single large (10 mg/kg) dose of palifermin 3 days prior to, or multiple small (3 mg/kg day for 3 days) doses of palifermin or vehicle control prior to, receiving 2 doses of 150 mg/kg irinotecan. Animals were killed at 6, 24, 48, 72, 96, 120, or 144 hr after treatment. The primary endpoints were diarrhea and mortality. Gastrointestinal morphometry, histopathology and apoptosis were assessed. Tumor weights and mitoses were measured to ensure palifermin did not promote tumor growth. Data were analyzed using Peritz' F‐test, Student's t‐test and Tukey‐Kramer multiple comparison test. Animals pretreated with palifermin tolerated irinotecan treatment better than control animals with less severe diarrhea (5% in animals receiving 10 mg/kg palifermin, 11% in animals receiving 3 × 3 mg/kg palifermin and 28% in animals receiving irinotecan only) and reduced mortality (2% in animals receiving 10 mg/kg palifermin, 11% in animals receiving 3 × 3 mg/kg palifermin and 28% in animals receiving irinotecan only). Small and large intestinal weights were maintained. Intestinal morphometry was not maintained in palifermin‐pretreated rats despite being increased prior to irinotecan treatment. Palifermin pretreatment did not prevent apoptosis that peaked at 6 hr in the jejunum or colon, but prevented apoptosis at 96 hr in the small intestine. Palifermin pretreatment in both treatment regimens significantly reduces diarrhea and mortality following irinotecan administration without adversely affecting tumor growth. This positive response warrants further investigation, particularly in humans. © 2005 Wiley‐Liss, Inc.
Physical activity and risk for lung cancer in a Danish cohort
Authors: Bak Helle , Christensen Jane , Thomsen Birthe Lykke , Tjønneland Anne , Overvad Kim , Loft Steffen , Raaschou‐Nielsen Ole
Published: March 2005

Physical activity might reduce the risk for lung cancer by various mechanisms, but the evidence is inconclusive. We therefore examined the relationship between physical activity and risk for lung cancer in a large population‐based Danish cohort with detailed information about number of hours per week spent on specific physical activities as well as lifetime smoking patterns. Between 1993 and 1997, a total of 57,053 persons aged 50–64 years agreed to participate in the cohort. After exclusions of persons with cancer diagnosis before invitation and persons for whom data regarding study variables were missing, 26,070 men and 28,352 women remained for study. By 31 December 2002, lung cancer had been diagnosed in 194 men and 175 women. A questionnaire registered average number of hours per week spent on each of 6 types of leisure time physical activity. Level of occupational physical activity was registered in 5 categories. Cox's proportional hazard model stratified according to age at entry (1‐year intervals) was adjusted for smoking, school education, possible occupational exposure to lung carcinogens and intake of fruit and vegetables. No significant association was found between number of hours per week spent on 6 types of physical activity during leisure time and the incidence rate ratio (IRR) for lung cancer. For each type of activity, the IRR of lung cancer was lower for active compared to nonactive women, whereas for men lower IRRs were only observed for sports and gardening. Higher levels of occupational physical activity had no protective effect; the lowest IRR was found for sitting work. Our study shows no convincing protective effect of physical activity on lung cancer risk. © 2005 Wiley‐Liss, Inc.
The effects of the gender of children on expenditure patterns in rural China: a semiparametric analysis
Authors: Gong Xiaodong , van Soest Arthur , Zhang Ping
Published: March 2005

We analyse expenditure patterns for rural China, focusing on differences between families with boys and girls. The sample includes more than 5000 nuclear families from 19 Chinese provinces. Following the existing literature, we estimate Engel curves for food and for alcohol, a typical adult good. We use a flexible, partially linear specification and allow for endogeneity of total expenditures. The results are similar to those of other studies, not providing much evidence of gender differentials. We then focus on the decision to send a child to school and on the budget share spent on educational goods. Using both parametric and semiparametric estimates, we find evidence that boys are more often sent to school and that expenditures on a boy that goes to school are larger than for a school‐going girl of the same age. Copyright © 2005 John Wiley & Sons, Ltd.
Modelling and forecasting stock returns: exploiting the futures market, regime shifts and international spillovers
Authors: Sarno Lucio , Valente Giorgio
Published: March 2005

This paper proposes a vector equilibrium correction model of stock returns that exploits the information in the futures market, while allowing for both regime‐switching behaviour and international spillovers across stock market indices. Using data for three major stock market indices since 1989, we find that: (i) in sample, our model outperforms several alternative models on the basis of standard statistical criteria; (ii) in out‐of‐sample forecasting, our model does not produce significant gains in terms of point forecasts relative to more parsimonious alternative specifications, but it does so both in terms of market timing ability and in density forecasting performance. The economic value of the density forecasts is illustrated with an application to a simple risk management exercise. Copyright © 2005 John Wiley & Sons, Ltd.
Walk or wait? An empirical analysis of street crossing decisions
Authors: Das Sanghamitra , Manski Charles F. , Manuszak Mark D.
Published: March 2005

We examine the behaviour of pedestrians wishing to cross a stream of traffic at signalized intersections. We model each pedestrian as making a discrete crossing choice by comparing the gaps between vehicles in traffic to an individual‐specific ‘critical gap’ that characterizes the individual's minimal acceptable gap. We propose both parametric and nonparametric approaches to estimate the distribution of critical gaps in the population of pedestrians. To estimate the model, we gather field data on crossing decisions and vehicle flows at three intersections in New Delhi. The estimates provide information about heterogeneity in critical gaps across pedestrians and intersections, and permit simulation of the effect of changes in traffic light sequences on pedestrian crossing behaviour and waiting times. Copyright © 2005 John Wiley & Sons, Ltd.
Semiparametric three‐step estimation methods for simultaneous equation systems
Authors: Rodríguez‐Póo Juan M. , Sperlich Stefan , Fernández Ana I.
Published: March 2005

This paper proposes a new method for estimating a structural model of labour supply in which hours of work depend on (log) wages and the wage rate is considered endogenous. The main innovation with respect to other related estimation procedures is that a nonparametric additive structure in the hours of work equation is permitted. Though the focus of the paper is on this particular application, a three‐step methodology for estimating models in the presence of the above econometric problems is described. In the first step the reduced form parameters of the participation equation are estimated by a maximum likelihood procedure adapted for estimation of an additive nonparametric function. In the second step the structural parameters of the wage equation are estimated after obtaining the selection‐corrected conditional mean function. Finally, in the third step the structural parameters of the labour supply equation are estimated using local maximum likelihood estimation techniques. The paper concludes with an application to illustrate the feasibility, performance and possible gain of using this method. Copyright © 2005 John Wiley & Sons, Ltd.
Discrete choice modelling in airline network management
Authors: Grammig Joachim , Hujer Reinhard , Scheidler Michael
Published: March 2005

The task of airline network management is to develop new flight schedule variants and evaluate them in terms of expected passenger demand and revenue. Given the industry's trend towards global cooperation, this is especially important when evaluating the potential synergies with alliance partners. From the econometric point of view, this task represents a discrete choice modelling problem in which one has to account for a large number of dependent alternatives. In this paper we discuss the applicability of recently proposed approaches and introduce a new multinomial probit specification designed for the airline network management task. The superior performance of the new model is demonstrated in a real‐world application using airline bookings data. Copyright © 2005 John Wiley & Sons, Ltd.
Changes in serum α2u‐globulin levels in castrated male rats treated with testosterone propionate in a Hershberger assay
Authors: Takeyoshi Masahiro , Mitoma Hideo , Yamasaki Kanji
Published: March 2005

The Hershberger assay has been proposed as a candidate screening test method for the detection of androgenic and anti‐androgenic chemicals and is being validated presently under the test guideline programme of the Organization for Economic Cooperation and Development (OECD). Rat α2u‐globulin is male rat‐specic protein appearing in their serum and urine, and the protein is known to be induced by androgens. We investigated the usefulness of measuring serum α2u‐globulin levels as a parameter for the androgenic activity of chemicals tested in the Hershberger assay. The serum α2u‐globulin level was measured after the administration of testosterone propionate at dosages of 0, 20, 100 or 500 µg kg−1 day−1 for ten consecutive days in the castrated male rats. The ventral prostate, balbocavernosus[sol ]levator ani muscles, glans penis and Cowper's gland were collected and weighed. Although all the androgen‐responsive organ weights were increased signicantly at dosages of 100 and 500 µg kg−1 day−1, the serum α2u‐globulin level was increased signicantly only at a dosage of 500 µg kg−1 day−1. These results show that the serum α2u‐globulin level may be a useful biomarker for detecting androgenic activity caused by test chemicals, but it is less sensitive than the organ weights of androgen‐responsive tissues in the Hershberger assay. Copyright © 2005 John Wiley & Sons, Ltd.
Efficiency of magnetic liposomal transforming growth factor‐beta 1 in the repair of articular cartilage defects in a rabbit model
Authors: Tanaka Haruyuki , Sugita Takashi , Yasunaga Yuji , Shimose Shouji , Deie Masataka , Kubo Tadahiko , Murakami Teruo , Ochi Mitsuo
Published: March 2005

We evaluated the efficacy of a magnetic liposomal delivery system of transforming growth factor (TGF)‐β1 in the treatment of articular cartilage defects in a rabbit model. Articular cartilage defects were created in the patellar groove of rabbits, and a permanent magnet or a nonmagnetic alloy was implanted in the defect site. Magnetic liposomal drugs, prepared by the conventional film method and sonication, were injected into the defect site 1 week after surgery. First, the efficacy of the magnetic liposomal delivery system was evaluated by using a model compound fluorescence‐labeled dextran 40,000 (FD‐40). Then, the therapeutic efficiency of magnetic liposomal TGF‐β1 was evaluated by cartilage histological scoring at 4, 8, and 12 weeks after surgery. The injected magnetic liposomal FD‐40 accumulated at the target site where a permanent magnet had been implanted. The histological score showed that the injection of magnetic liposomal TGF‐β1 under magnetic force was significantly effective in the repair of the defect site over 12 weeks after surgery. Injection of TGF‐β1 into the cartilage defect was effective as a magnetic liposomal preparation under magnetic force, resulting in acceleration of the cartilage repair, probably because of the desirable accumulation of TGF‐β1 at the target site. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res 73A: 255–263, 2005
Osteocalcin enhances bone remodeling around hydroxyapatite/collagen composites
Authors: Rammelt Stefan , Neumann Mirjam , Hanisch Uwe , Reinstorf Antje , Pompe Wolfgang , Zwipp Hans , Biewener Achim
Published: March 2005

The effect of osteocalcin (OC), an extracellular bone matrix protein, on bone healing around hydroxyapatite/collagen composites was investigated. Cylindrical nanocrystalline hydroxyapatite implants of 2.5‐mm diameter containing 2.5% biomimetically mineralized collagen type I were inserted press‐fit into the tibial head of adult Wistar rats. To one implant group, 10 μg/g OC was added. Six specimens per group were analyzed at 2, 7, 14, 28, and 56 days. After 14 days, newly formed woven bone had reached the implant surface of the OC implants whereas a broad fibrous interface could still be observed around controls. Woven bone was formed directly around both implant groups after 28 days and had been replaced partially by lamellar bone around the OC implants only. No significant differences in total bone contact were seen between both groups after 56 days. The higher number of phagocytosing cells and osteoclasts characterized immunohistochemically with ED1, cathepsin D, and tartate‐resistant alkaline phosphatase around the OC implants at the early stages of bone healing suggests an earlier onset of bone remodeling. The earlier and increased expression of bone‐specific matrix proteins and multifunctional adhesion proteins (osteopontin, bone sialoprotein, CD44) at the interface around the OC implants indicates that OC may accelerate bone formation and regeneration. This study supports the observations from in vitro studies that OC activates both osteoclasts and osteoblasts during early bone formation. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res 73A: 284–294, 2005
Electrostatic energies and forces computed without explicit interparticle interactions: A linear time complexity formulation
Authors: Petrella Robert J. , Karplus Martin
Published: March 2005

A rapid method for the calculation of the electrostatic energy of a system without a cutoff is described in which the computational time grows linearly with the number of particles or charges. The inverse of the distance is approximated as a polynomial, which is then transformed into a function whose terms involve individual particles, instead of particle pairs, by a partitioning of the double sum. In this way, the electrostatic energy that is determined by the interparticle interactions is obtained without explicit calculation of these interactions. For systems of positive charges positioned on a face‐centered cubic lattice, the calculation of the energy by the new method is shown to be faster than the calculation of the exact energy, in many cases by an order of magnitude, and to be accurate to within 1–2%. The application of this method to increase the accuracy of conventional truncation‐based calculations in condensed‐phase systems is also demonstrated by combining the approximated long‐range electrostatic interactions with the exact short‐range interactions in a “hybrid” calculation. For a 20‐Å sphere of water molecules, the forces are shown to be six times as accurate using this hybrid method as those calculated with conventional truncation of the electrostatic energy function at 12 Å. This is accomplished with a slight increase in speed, and with a sevenfold increase in speed relative to the exact all‐pair calculation. Structures minimized with the hybrid function are shown to be closer to structures minimized with an exact all‐pair electrostatic energy function than are those minimized with a conventional 13‐Å cutoff‐based electrostatic energy function. Comparison of the energies and forces calculated with the exact method illustrate that the absolute errors obtained with standard truncation can be very large. The extension of the current method to other pairwise functions as well as to multibody functions, is described. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 755–787, 2005
Interactions between the Greenland Ice Sheet and the Liverpool Land coastal ice cap during the last two glaciation cycles
Authors: Adrielsson Lena , Alexanderson Helena
Published: March 2005

The sedimentary record from the Ugleelv Valley on central Jameson Land, East Greenland, adds new information about terrestrial palaeoenvironments and glaciations to the glacial history of the Scoresby Sund fjord area. A western extension of a coastal ice cap on Liverpool Land reached eastern Jameson Land during the early Scoresby Sund glaciation (≈the Saalian). During the following glacial maximum the Greenland Ice Sheet inundated the Jameson Land plateau from the west. The Weichselian also starts with an early phase of glacial advance from the Liverpool Land ice cap, while polar desert and ice‐free conditions characterised the subsequent part of the Weichselian on the Jameson Land plateau. The two glaciation cycles show a repeated pattern of interaction between the Greenland Ice Sheet in the west and an ice cap on Liverpool Land in the east. Each cycle starts with extensive glacier growth in the coastal mountains followed by a decline of the coastal glaciation, a change to cold and arid climate and a late stage of maximum extent of the Greenland Ice Sheet. Copyright © 2005 John Wiley & Sons, Ltd.
Impacts of rapid sea‐level rise on mangrove deposit erosion: application of taraxerol and Rhizophora records
Authors: Kim Jung‐Hyun , Dupont Lydie , Behling Hermann , Versteegh Gerard J. M.
Published: March 2005

We investigated a well‐dated marine sediment core from the tropical SE Atlantic covering the last 25 kyr, applying taraxerol and Rhizophora pollen as organic geochemical and palynological proxies for mangrove, respectively. Taraxerol records are positively correlated with Rhizophora pollen records, showing an enhanced supply of mangrove materials into deep‐sea environments during the last deglaciation (Termination I). Sedimentation rates peaked during Meltwater Pulses 1A and 1B, which were associated with the maxima of taraxerol and Rhizophora pollen. This study supports the view that mangrove input was dominantly controlled by erosion of mangrove‐rich shelf sediments during the transgressions. Whether reworked materials were penecontemporaneous or from much older deposits formed during previous sea‐level cycles is discussed. Copyright © 2005 John Wiley & Sons, Ltd.
Hydrologic variability and the onset of modern El Niño–Southern Oscillation: a 19 250‐year record from Lake Elsinore, southern California
Authors: Kirby Matthew E. , Lund Steve P. , Poulsen Christopher J.
Published: March 2005

There are very few terrestrial palaeoclimate archives spanning the Last Glacial Maximum through the Holocene from coastal southern California. Yet, knowledge of past climate dynamics is critical for assessing present and future constraints on the region's dwindling freshwater resources. We present initial results from two drill cores extracted from the present‐day edge of Lake Elsinore, southern California's largest natural lake. Using a multiproxy approach including lithologic description, mass magnetic susceptibility, LOI 550°C (total organic matter), and LOI 950°C (total carbonate), we infer first‐order, long‐term climate change over the past 19 250 calendar years. Furthermore, we suggest possible first‐order forcing mechanisms that drive this change, which include presence/absence of continental ice sheets, insolation, and complex ocean–atmosphere interactions. Our results indicate four distinct millennial‐scale climate modes over the past 19 250 calendar years. These modes include a wet Last Glacial Maximum (19 250–17 120 cal. yr BP), a relatively dry late‐Glacial/Holocene transition (17 120–9450 cal. yr BP), a wet early Holocene (9450–7670 cal. yr BP), and a highly variable mid‐to‐late Holocene climate (i.e., alternating wet/dry cycles; 7670 cal. yr BP–present). We attribute the mid‐to‐late Holocene climate interval to the onset of El Niño–Southern Oscillation ca. 7000 cal. yr BP and a more vigorous hydrologic system. These results are supported by a variety of regional terrestrial and marine palaeoclimate archives. Copyright © 2005 John Wiley & Sons, Ltd.
A new early Holocene cryptotephra from northwest Scotland
Authors: Ranner Patricia H. , Allen Judy R. M. , Huntley Brian
Published: March 2005

Clarification of the temporal relationships amongst records of environmental change is dependent on accurate timescales. Event markers such as tephra layers are extremely important for constraining chronologies and providing tie points. In this report we present evidence of a previously unknown early Holocene Icelandic cryptotephra from a lake in northern Scotland—the ‘An Druim Tephra’. The calibrated radiocarbon age of 9560 cal. yr BP for this new cryptotephra makes it an important addition to the suite of cryptotephras now recorded from the last glacial termination and early Holocene in northwest Europe. In addition we report evidence in support of a ‘Younger Borrobol Tephra’ from Lateglacial sediments of Allerød age. Copyright © 2005 John Wiley & Sons, Ltd.
Thermo‐ and pH‐Responsive Micelles of Poly(acrylic acid)‐block‐Poly(N,N‐diethylacrylamide)
Authors: André Xavier , Zhang Mingfu , Müller Axel H. E.
Published: March 2005

Summary: The bis‐hydrophilic block copolymer, poly(acrylic acid)45‐block‐poly(N,N‐diethylacrylamide)360, was obtained after hydrolysis of poly(tert‐butyl acrylate)45‐block‐poly(N,N‐diethylacrylamide)360, synthesized by sequential anionic polymerization of tert‐butyl acrylate (tBA) and N,N‐diethylacrylamide (DEAAm) in the presence of Et3Al. The polymer is stimuli‐sensitive with respect to both pH and temperature in aqueous solution, reversibly forming spherical crew‐cut micelles with PDEAAm‐core (〈Rh〉z = 21.5 nm) under alkaline conditions for T > 35 °C as well as inverse star‐like micelles with an expanded PAA‐core (〈Rh〉z = 43.8 nm) under acidic conditions for T < 35 °C, as indicated by dynamic light scattering.

Modes of micelle formation for poly(acrylic acid)45‐block‐poly(N,N‐diethylacrylamide)360 in aqueous solution depending on the pH and temperature.

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Modes of micelle formation for poly(acrylic acid)45‐block‐poly(N,N‐diethylacrylamide)360 in aqueous solution depending on the pH and temperature.
Effect of Polydispersity on the Phase Behavior of Polymer Blends
Authors: Lo Chieh‐Tsung , Seifert Soenke , Thiyagarajan Pappannan , Narasimhan Balaji
Published: March 2005

Summary: The effect of polydispersity on polymer blend phase behavior is studied by in situ small‐angle X‐ray scattering. In a polydisperse polyethylene (PE)/isotactic poly(propylene) (iPP) blend, the enthalpic portion of the interaction parameter is greater than that of a corresponding blend with lower polydispersity. This is attributed to the presence of long chains, which provide a higher interaction energy and packing constraint, reducing the system miscibility. As expected, the radius of gyration is higher in the system with higher polydispersity.

Comparison of phase diagrams of the iPP/PE system used in this study (thin lines) with that obtained from the literature (thick lines). The solid lines represent binodals and the dashed lines are spinodals.

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Comparison of phase diagrams of the iPP/PE system used in this study (thin lines) with that obtained from the literature (thick lines). The solid lines represent binodals and the dashed lines are spinodals.