bluuebunny/crossref_metadata_2025 huggingface dataset:
THE RELATIONSHIPS BETWEEN FOREIGN COMPETITION, ABSORPTIVE CAPACITY AND PIONEERING INNOVATION: AN EMPIRICAL INVESTIGATION IN CANADA
Authors: LI YING , VANHAVERBEKE WIM
Published: April 2009

The relationship between competition and innovation has drawn great attention from economists and strategic management researchers. However, the empirical evidence for this relationship remains inconsistent. On the one hand, the Schumpeterian viewpoint credits that the large firms with substantial monopoly market power have resources and incentives to innovate. On the other hand, it is also possible for a monopolist to have incentives to suppress subsequent innovations. It is suggested by Baldwin and Scott (1987) and Tang (2006) that the relationship between competition and innovation is dependent on the competition context and specific type of innovation activities. In this study, we investigate the relationship between foreign competition and pioneering innovation and consider the moderating role of absorptive capacity for this relationship, using the Canadian Innovation Data. We find a U-shaped relationship between foreign competition and pioneering innovation: when foreign competition increases from a low to a moderate level, the likelihood of pioneering innovation decreases. However, the likelihood of pioneering innovation increases when foreign competition continues to increase from a moderate to a high level. We also found evidence that absorptive capacity may positively moderate the relationship between foreign competition and pioneering innovation.
THE CONCEPT OFINTERESSEMENT: THE STORY OF A POWER-SPLIT TECHNOLOGY FOR HYBRID ELECTRIC VEHICLES
Authors: POHL HANS , STYHRE ALEXANDER , ELMQUIST MARIA
Published: April 2009

Innovation processes are out of necessity and by definition always open-ended and embedded in social interests and beliefs. This paper reports a study of how a power-split technology for hybrid vehicles needed and found support and interest from a variety of social actors to reach the market. One of the principal challenges of innovators is to mobilise support and attract interest among relevant social groups; innovations are always, to some extent, dependent on their ability to conform to pre-existing practices and beliefs. Based on a study of a hybrid electric vehicle (HEV) project at Volvo Cars, this paper investigates how the concept of interessement can contribute to a better understanding of the innovation processes (Akrich et al., 2002a,b). It concludes that this concept contributes to interesting perspectives on the dual technological and social nature of the innovation process but that the idea of one central innovator driving the process all the way may not always be applicable.
SELF-ASSEMBLY OF THREE-DIMENSIONAL NANOPOROUS CONTAINERS
Authors: WANG JAIHAI , PATEL MIRA , GRACIAS DAVID H.
Published: April 2009

We describe a strategy to construct three-dimensional (3D) containers with nanoporous walls by the self-assembly of lithographically patterned two-dimensional cruciforms with solder hinges. The first step involves fabricating two-dimensional (2D) cruciforms composed of six unlinked patterns: each pattern has an open window. The second step entails photolithographic patterning of solder hinges that connect the cruciform. The third step involves the deposition of polystyrene particles within the windows and the subsequent electrodeposition of metal in the voids between the polystyrene particles. Following the dissolution of the particles, the cruciforms are released from the substrate and heated above the melting point of the solder causing the cruciforms to spontaneously fold up into 3D cubic containers with nanoporous walls. We believe these 3D containers with nanoporous side walls are promising for molecular separations and cell-based therapies.
STUDY OF DOMAIN WALL MOTION OF ROUND MARKS IN AN EXCHANGE-COUPLED CoNi/Pt FILM
Authors: ZHANG LI , PENG JIE-GANG , ZHONG ZHI-YONG , ZU XIAO-TAO
Published: April 2009

We study the motion of domain wall in round marks formed in an exchange-coupled CoNi/Pt film, suitable for perpendicular magnetic recording. Marks were written by probe-based magnetic recording, with an average size of 180 nm. By applying external magnetic field on those marks, they begin to shrink. The minimum field required to move the domain wall of marks, i.e., domain wall coercivity, is 60% the nucleation coercivity of the medium. A model of dynamic domain motion was executed to study the stability of magnetic domains in exchange-coupled perpendicular media. It shows that the domain wall coercivity is a better fit than the nucleation coercivity to calculate the minimum stable domain size of the medium.
Visfatin activates eNOS via Akt and MAP kinases and improves endothelial cell function and angiogenesis in vitro and in vivo: translational implications for atherosclerosis
Authors: Lovren Fina , Pan Yi , Shukla Praphulla C. , Quan Adrian , Teoh Hwee , Szmitko Paul E. , Peterson Mark D. , Gupta Milan , Al-Omran Mohammed , Verma Subodh
Published: April 2009

Improving endothelial nitric oxide synthase (eNOS) bioactivity and endothelial function is important to limit native, vein graft, and transplant atherosclerosis. Visfatin, a NAD biosynthetic enzyme, regulates the activity of the cellular survival factor, Sirt1. We hypothesized that visfatin may improve eNOS expression, endothelial function, and postnatal angiogenesis. In human umbilical vein (HUVEC) and coronary artery endothelial cells, we evaluated the effects of recombinant human visfatin on eNOS protein and transcript expression and mRNA stability, in the presence and absence of visfatin RNA silencing. We also assessed visfatin-induced protein kinase B (Akt) activation and its association with src-tyrosine kinases, phosphorylation of Ser1177within eNOS in the presence and absence of phosphatidylinositol 3-kinase (PI 3-kinase) inhibition with LY-294002, and evaluated the contributory role of extracellular signal-regulated kinase 1/2. Finally, we determined the impact of visfatin on HUVEC migration, proliferation, inflammation-induced permeability, and in vivo angiogenesis. Visfatin (100 ng/ml) upregulated and stabilized eNOS mRNA and increased the production of nitric oxide and cGMP. Visfatin-treated HUVEC demonstrated greater proliferation, migration, and capillary-like tube formation but less tumor necrosis factor-α-induced permeability; these effects were decreased in visfatin gene-silenced cells. Visfatin increased total Akt and Ser473-phospho-Akt expression with concomitant rises in eNOS phosphorylation at Ser1177; these effects were blocked by LY-2940002. Studies with PP2 showed that the nonreceptor tyrosine kinase, src, is an upstream stimulator of the PI 3-kinase-Akt pathway. Visfatin also activated mitogen-activated protein (MAP) kinase through PI 3-kinase, and mitogen/extracellular signal-regulated kinase inhibition attenuated visfatin-elicited Akt and eNOS phosphorylation. Visfatin-filled Matrigel implants showed an elevated number of infiltrating vessels, and visfatin treatment produced significant recovery of limb perfusion following hindlimb ischemia. These results indicate a novel effect of visfatin to stimulate eNOS expression and function in endothelial cells, via a common upstream, src-mediated signaling cascade, which leads to activation of Akt and MAP kinases. Visfatin represents a translational target to limit endothelial dysfunction, native, vein graft and transplant atherosclerosis, and improve postnatal angiogenesis.
Hypothalamic AMP-activated protein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of type 1 diabetes
Authors: Fan X. , Ding Y. , Brown S. , Zhou L. , Shaw M. , Vella M. C. , Cheng H. , McNay E. C. , Sherwin R. S. , McCrimmon R. J.
Published: April 2009

In nondiabetic rodents, AMP-activated protein kinase (AMPK) plays a role in the glucose-sensing mechanism used by the ventromedial hypothalamus (VMH), a key brain region involved in the detection of hypoglycemia. However, AMPK is regulated by both hyper- and hypoglycemia, so whether AMPK plays a similar role in type 1 diabetes (T1DM) is unknown. To address this issue, we used four groups of chronically catheterized male diabetic BB rats, a rodent model of autoimmune T1DM with established insulin—requiring diabetes (40 ± 4 pmol/l basal c-peptide). Two groups were subjected to 3 days of recurrent hypoglycemia (RH), while the other two groups were kept hyperglycemic [chronic hyperglycemia (CH)]. All groups subsequently underwent hyperinsulinemic hypoglycemic clamp studies on day 4 in conjunction with VMH microinjection with either saline (control) or AICAR (5-aminoimidazole-4-carboxamide) to activate AMPK. Compared with controls, local VMH application of AICAR during hypoglycemia amplified both glucagon [means ± SE, area under the curve over time (AUC/ t) 144 ± 43 vs. 50 ± 11 ng·l−1·min−1; P < 0.05] and epinephrine [4.27 ± 0.96 vs. 1.06 ± 0.26 nmol·l−1·min−1; P < 0.05] responses in RH-BB rats, and amplified the glucagon [151 ± 22 vs. 85 ± 22 ng·l−1·min−1; P < 0.05] response in CH-BB rats. We conclude that VMH AMPK also plays a role in glucose-sensing during hypoglycemia in a rodent model of T1DM. Moreover, our data suggest that it may be possible to partially restore the hypoglycemia-specific glucagon secretory defect characteristic of T1DM through manipulation of VMH AMPK.
Predicting Tinnitus Pitch From Patients' Audiograms With a Computational Model for the Development of Neuronal Hyperactivity
Authors: Schaette Roland , Kempter Richard
Published: April 2009

Tinnitus is often related to hearing loss, but how hearing loss could lead to tinnitus has remained unclear. Animal studies show that the occurrence of tinnitus is correlated to increased spontaneous firing rates of central auditory neurons, but mechanisms that give rise to such hyperactivity have not been identified yet. Here we present a computational model that reproduces tinnitus-related hyperactivity and predicts tinnitus pitch from the audiograms of tinnitus patients with noise-induced hearing loss and tone-like tinnitus. Our key assumption is that the mean firing rates of central auditory neurons are controlled by homeostatic plasticity. Decreased auditory nerve activity after hearing loss is counteracted through an increase of the neuronal response gain, which restores the mean rate but can also lead to hyperactivity. Hyperactivity patterns calculated from patients' audiograms exhibit distinct peaks at frequencies close to the perceived tinnitus pitch, corroborating hyperactivity through homeostatic plasticity as a mechanism for the development of tinnitus after hearing loss. The model suggests that such hyperactivity, and thus also tinnitus caused by cochlear damage, could be alleviated through additional stimulation.
Estrogens and Human Papilloma Virus Oncogenes Regulate Human Ether-à-go-go-1 Potassium Channel Expression
Authors: Díaz Lorenza , Ceja-Ochoa Irais , Restrepo-Angulo Iván , Larrea Fernando , Avila-Chávez Euclides , García-Becerra Rocío , Borja-Cacho Elizabeth , Barrera David , Ahumada Elías , Gariglio Patricio , Alvarez-Rios Elizabeth , Ocadiz-Delgado Rodolfo , Garcia-Villa Enrique , Hernández-Gallegos Elizabeth , Camacho-Arroyo Ignacio , Morales Angélica , Ordaz-Rosado David , García-Latorre Ethel , Escamilla Juan , Sánchez-Peña Luz Carmen , Saqui-Salces Milena , Gamboa-Dominguez Armando , Vera Eunice , Uribe-Ramírez Marisela , Murbartián Janet , Ortiz Cindy Sharon , Rivera-Guevara Claudia , De Vizcaya-Ruiz Andrea , Camacho Javier
Published: April 2009

Ether-à-go-go-1 (Eag1) potassium channels are potential tools for detection and therapy of numerous cancers. Here, we show human Eag1 (hEag1) regulation by cancer-associated factors. We studied hEag1 gene expression and its regulation by estradiol, antiestrogens, and human papillomavirus (HPV) oncogenes (E6/E7). Primary cultures from normal placentas and cervical cancer tissues; tumor cell lines from cervix, choriocarcinoma, keratinocytes, and lung; and normal cell lines from vascular endothelium, keratinocytes, and lung were used. Reverse transcription-PCR (RT-PCR) experiments and Southern blot analysis showed Eag1 expression in all of the cancer cell types, normal trophoblasts, and vascular endothelium, in contrast to normal keratinocytes and lung cells. Estradiol and antiestrogens regulated Eag1 in a cell type–dependent manner. Real-time RT-PCR experiments in HeLa cells showed that Eag1 estrogenic regulation was strongly associated with the expression of estrogen receptor-α. Eag1 protein was detected by monoclonal antibodies in normal placenta and placental blood vessels. Patch-clamp recordings in normal trophoblasts treated with estradiol exhibited potassium currents resembling Eag1 channel activity. Eag1 gene expression in keratinocytes depended either on cellular immortalization or the presence of HPV oncogenes. Eag1 protein was found in keratinocytes transfected with E6/E7 HPV oncogenes. Cell proliferation of E6/E7 keratinocytes was decreased by Eag1 antibodies inhibiting channel activity and by the nonspecific Eag1 inhibitors imipramine and astemizole; the latter also increased apoptosis. Our results propose novel oncogenic mechanisms of estrogen/antiestrogen use and HPV infection. We also suggest Eag1 as an early indicator of cell proliferation leading to malignancies and a therapeutic target at early stages of cellular hyperproliferation. [Cancer Res 2009;69(8):3300–7]
Identification of a Biphasic Role for Genistein in the Regulation of Prostate Cancer Growth and Metastasis
Authors: El Touny Lara H. , Banerjee Partha P.
Published: April 2009

Considered a chemopreventive agent, the ability of genistein to modulate the progression of existing prostate cancer (CaP) is not clear. We show here that the consumption of genistein (250 mg/kg diet) by 12-week-old transgenic adenocarcinoma mouse prostate (TRAMP-FVB) mice harboring prostatic intraepithelial neoplasia lesions until 20 weeks of age induces an aggressive progression of CaP, as evidenced by a 16% increase in the number of well-differentiated and poorly differentiated prostates, coinciding with a 70% incidence of pelvic lymph node (LN) metastases as opposed to 0% and 10% in 0 and 1,000 mg/kg groups, concomitant with elevated osteopontin (OPN) expression in prostates and LNs. Equivalent nanomolar (500 nmol/L) concentrations of genistein recapitulated these effects in human PC3 CaP cells as evidenced by increased proliferation, invasion, and matrix metalloproteinase-9 (MMP-9) activity (∼2-fold), accompanied by an up-regulation of OPN expression and secretion, compared with vehicle-treated cells. A pharmacologic dose (50 μmol/L) decreased proliferation, invasion, and MMP-9 activity (>2.0-fold) concomitant with OPN reduction. Upon OPN knockdown by short hairpin RNA, genistein was no longer effective in up-regulating PC3 cell proliferation, invasion, and MMP-9 activation, which were significantly reduced in the absence of OPN, highlighting the requirement for OPN in mediating the effects of genistein. Proliferation, invasion, and OPN levels were also nonsignificantly induced by genistein in the presence of ICI 182,780 or wortmannin, indicating a dependence on phosphatidylinositol 3-kinase and estrogen signaling. Our results suggest the presence of a biphasic regulation of CaP growth and metastasis by genistein, warranting careful examination of the effects of genistein on hormone-dependent cancers in a chemotherapeutic setting. [Cancer Res 2009;69(8):3695–703]
Tripeptidyl Peptidase II Plays a Role in the Radiation Response of Selected Primary Cell Types but not Based on Nuclear Translocation and p53 Stabilization
Authors: Firat Elke , Tsurumi Chizuko , Gaedicke Simone , Huai Jisen , Niedermann Gabriele
Published: April 2009

The giant cytosolic protease tripeptidyl peptidase II (TPPII) was recently proposed to play a role in the DNA damage response. Shown were nuclear translocation of TPPII after γ-irradiation, lack of radiation-induced p53 stabilization in TPPII-siRNA–treated cells, and complete tumor regression in mice after γ-irradiation when combined with TPPII-siRNA silencing or a protease inhibitor reported to inhibit TPPII. This suggested that TPPII could be a novel target for tumor radiosensitization and prompted us to study radiation responses using TPPII-knockout mice. Neither the sensitivity to total body irradiation nor the radiosensitivity of resting lymphoid cells, which both strongly depend on p53, was altered in the absence of TPPII. Functional integrity of p53 in TPPII-knockout cells is further shown by a proper G1 arrest and by the accumulation of p53 and its transcriptional targets, p21, Bax, and Fas, on γ-irradiation. Furthermore, we could not confirm radiation-induced nuclear translocation of TPPII. Nevertheless, after γ-irradiation, we found slightly increased mitotic catastrophe of TPPII-deficient primary fibroblasts and increased apoptosis of TPPII-deficient activated CD8+ T cells. The latter was accompanied by delayed resolution of the DNA double-strand break marker γH2AX. This could, however, be due to increased apoptotic DNA damage rather than reduced DNA damage repair. Our data do not confirm a role for TPPII in the DNA damage response based on nuclear TPPII translocation and p53 stabilization but nevertheless do show increased radiation-induced cell death of selected nontransformed cell types in the absence of the TPPII protease. [Cancer Res 2009;69(8):3325–31]
K858, a Novel Inhibitor of Mitotic Kinesin Eg5 and Antitumor Agent, Induces Cell Death in Cancer Cells
Authors: Nakai Ryuichiro , Iida Shin-ichi , Takahashi Takeshi , Tsujita Tetsuya , Okamoto Seiho , Takada Chie , Akasaka Kazuhito , Ichikawa Shunji , Ishida Hiroyuki , Kusaka Hideaki , Akinaga Shiro , Murakata Chikara , Honda Shinobu , Nitta Masayuki , Saya Hideyuki , Yamashita Yoshinori
Published: April 2009

The aim of this study was to investigate the mechanism of inhibition of Eg5 (kinesin spindle protein), a mitotic kinesin that plays an essential role in establishing mitotic spindle bipolarity, by the novel small molecule inhibitor K858. K858 was selected in a phenotype-based forward chemical genetics screen as an antimitotic agent, and subsequently characterized as an inhibitor of Eg5. K858 blocked centrosome separation, activated the spindle checkpoint, and induced mitotic arrest in cells accompanied by the formation of monopolar spindles. Long-term continuous treatment of cancer cells with K858 resulted in antiproliferative effects through the induction of mitotic cell death, and polyploidization followed by senescence. In contrast, treatment of nontransformed cells with K858 resulted in mitotic slippage without cell death, and cell cycle arrest in G1 phase in a tetraploid state. In contrast to paclitaxel, K858 did not induce the formation of micronuclei in either cancer or nontransformed cells, suggesting that K858 has minimal effects on abnormalities in the number and structure of chromosomes. K858 exhibited potent antitumor activity in xenograft models of cancer, and induced the accumulation of mitotic cells with monopolar spindles in tumor tissues. Importantly, K858, unlike antimicrotubule agents, had no effect on microtubule polymerization in cell-free and cell-based assays, and was not neurotoxic in a motor coordination test in mice. Taken together, the Eg5 inhibitor K858 represents an important compound for further investigation as a novel anticancer therapeutic. [Cancer Res 2009;69(9):3901–9]
Oncogenic Kras Requires Simultaneous PI3K Signaling to Induce ERK Activation and Transform Thyroid Epithelial Cells In vivo
Authors: Miller Kelly A. , Yeager Nicole , Baker Kristen , Liao Xiao-Hui , Refetoff Samuel , Di Cristofano Antonio
Published: April 2009

Thyroid tumors arising from the follicular cells often harbor mutations leading to the constitutive activation of the PI3K and Ras signaling cascades. However, it is still unclear what their respective contribution to the neoplastic process is, as well as to what extent they interact. We have used mice harboring a Kras oncogenic mutation and a Pten deletion targeted to the thyroid epithelium to address in vivo these questions. Here, we show that although each of these two pathways, alone, is unable to transform thyroid follicular cells, their simultaneous activation is highly oncogenic, leading to invasive and metastatic follicular carcinomas. In particular, phosphatidylinositol-3-kinase (PI3K) activation suppressed Kras-initiated feedback signals that uncouple mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activation, thus stunting MAPK activity; in addition, PI3K and Kras cooperated to drastically up-regulate cyclin D1 mRNA levels. Finally, combined pharmacologic inhibition of PI3K and MAPK completely inhibited the growth of double-mutant cancer cell lines, providing a compelling rationale for the dual targeting of these pathways in thyroid cancer. [Cancer Res 2009;69(8):3689–94]
Race and Time from Diagnosis to Radical Prostatectomy: Does Equal Access Mean Equal Timely Access to the Operating Room?—Results from the SEARCH Database
Authors: Bañez Lionel L. , Terris Martha K. , Aronson William J. , Presti Joseph C. , Kane Christopher J. , Amling Christopher L. , Freedland Stephen J.
Published: April 2009

Background: African American men with prostate cancer are at higher risk for cancer-specific death than Caucasian men. We determine whether significant delays in management contribute to this disparity. We hypothesize that in an equal-access health care system, time interval from diagnosis to treatment would not differ by race.

Methods: We identified 1,532 African American and Caucasian men who underwent radical prostatectomy (RP) from 1988 to 2007 at one of four Veterans Affairs Medical Centers that comprise the Shared Equal-Access Regional Cancer Hospital (SEARCH) database with known biopsy date. We compared time from biopsy to RP between racial groups using linear regression adjusting for demographic and clinical variables. We analyzed risk of potential clinically relevant delays by determining odds of delays >90 and >180 days.

Results: Median time interval from diagnosis to RP was 76 and 68 days for African Americans and Caucasian men, respectively (P = 0.004). After controlling for demographic and clinical variables, race was not associated with the time interval between diagnosis and RP (P = 0.09). Furthermore, race was not associated with increased risk of delays >90 (P = 0.45) or >180 days (P = 0.31).

Conclusions: In a cohort of men undergoing RP in an equal-access setting, there was no significant difference between racial groups with regard to time interval from diagnosis to RP. Thus, equal-access includes equal timely access to the operating room. Given our previous finding of poorer outcomes among African Americans, treatment delays do not seem to explain these observations. Our findings need to be confirmed in patients electing other treatment modalities and in other practice settings. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1208–12)
Secondhand Smoking, 4-Aminobiphenyl, and Bladder Cancer: Two Meta-analyses
Authors: Van Hemelrijck Mieke J.J. , Michaud Dominique S. , Connolly Gregory N. , Kabir Zubair
Published: April 2009

Objective: To quantify the relation between secondhand smoking (SHS) and levels of 4-aminobiphenyl (4-ABP; in urine or blood) and SHS and bladder cancer risk in nonsmokers.

Methods: PubMed and Embase were searched (search terms to represent SHS, bladder cancer, and 4-ABP) to conduct two meta-analyses. Information about gender and age of participants, mean 4-ABP level for each SHS category, number of subjects, relative risk or odds ratio and 95% confidence intervals (95% CI) in each SHS category, and covariates for which adjustment was made was extracted based on predefined inclusion and exclusion criteria. Random-effects analyses were done using STATA (version 9).

Results: A 118 studies were reviewed for information on SHS and 4-ABP (31 studies) and SHS and bladder cancer risk (87 studies). Of those, seven case-control studies were included for analysis of SHS and 4-ABP and eight articles (three cohort and five case-control studies) for SHS and bladder cancer risk. A random-effects model found a pooled standardized mean difference of 1.47 (95% CI, 0.23-2.71), indicating higher levels of 4-ABP among nonsmokers exposed to SHS. A random-effects model showed no evidence for an association between SHS and bladder cancer risk (relative risk, 0.99; 95% CI, 0.86-1.14), comparing nonsmokers with and without SHS exposure.

Conclusion: Higher levels of 4-ABP were significantly associated with SHS exposure, which is consistent with earlier findings for 4-ABP levels in sidestream smoke. The current evidence indicates that there is no association between SHS and bladder cancer, but future studies that address methodologic limitations are needed to further clarify this important question. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1312–20)
Global DNA Hypomethylation (LINE-1) in the Normal Colon and Lifestyle Characteristics and Dietary and Genetic Factors
Authors: Figueiredo Jane C. , Grau Maria V. , Wallace Kristin , Levine A. Joan , Shen Lanlan , Hamdan Randala , Chen Xinli , Bresalier Robert S. , McKeown-Eyssen Gail , Haile Robert W. , Baron John A. , Issa Jean-Pierre J.
Published: April 2009

Background: Global loss of methylated cytosines in DNA, thought to predispose to chromosomal instability and aneuploidy, has been associated with an increased risk of colorectal neoplasia. Little is known about the relationships between global hypomethylation and lifestyle, demographics, dietary measures, and genetic factors.

Methods: Our data were collected as part of a randomized clinical trial testing the efficacy of aspirin and folic acid for the prevention of colorectal adenomas. At a surveillance colonoscopy ∼3 years after the qualifying exam, we obtained two biopsies of the normal-appearing mucosa from the right colon and two biopsies from the left colon. Specimens were assayed for global hypomethylation using a pyrosequencing assay for LINE-1 (long interspersed nucleotide elements) repeats.

Results: The analysis included data from 388 subjects. There was relatively little variability in LINE methylation overall. Mean LINE-1 methylation levels in normal mucosa from the right bowel were significantly lower than those on the left side (P < 0.0001). No significant associations were found between LINE-1 methylation and folate treatment, age, sex, body mass index, smoking status, alcohol use, dietary intake, or circulating levels of B vitamins, homocysteine, or selected genotypes. Race, dietary folic acid, and plasma B6 showed associations with global methylation that differed between the right and the left bowel. The effect of folic acid on risk of adenomas did not differ according to extent of LINE-1 methylation, and we found no association between LINE-1 methylation and risk of adenomas.

Conclusions: LINE-1 methylation is not influenced by folic acid supplementation but differs by colon subsite. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1041–9)
Independent Effect of EBV and Cigarette Smoking on Nasopharyngeal Carcinoma: A 20-Year Follow-Up Study on 9,622 Males without Family History in Taiwan
Authors: Hsu Wan-Lun , Chen Jen-Yang , Chien Yin-Chu , Liu Mei-Ying , You San-Lin , Hsu Mow-Ming , Yang Czau-Siung , Chen Chien-Jen
Published: April 2009

This study aimed to assess independent effects of EBV and cigarette smoking on nasopharyngeal carcinoma, which have never been assessed in long-term follow-up studies. A cohort of 9,622 men was enrolled from 1984 to 1986. Blood samples collected at study entry were tested for antibodies against EBV antigens (anti-EBV) viral capsid antigen immunoglobulin A and DNase. The cigarette smoking habit was inquired through questionnaire interview. Newly developed nasopharyngeal carcinoma cases were ascertained through computerized linkage with national cancer registry profile. Cox's proportional hazard regression analysis was used to estimate multivariate-adjusted hazard ratio with its 95% confidence interval (95% CI). During the follow-up of 173,706 person-years, 32 pathologically confirmed nasopharyngeal carcinoma cases were identified >1 year after recruitment. Increasing serum levels of anti–EBV viral capsid antigen immunoglobulin A and DNase were significantly associated with nasopharyngeal carcinoma risk in a dose-response relationship. The multivariate-adjusted hazard ratio (95% CI) of developing nasopharyngeal carcinoma for low and high antibody levels compared with seronegatives was 9.5 (2.2-40.1) and 21.4 (2.8-161.7), respectively, for anti–EBV viral capsid antigen immunoglobulin A (P < 0.001 for trend), and 1.6 (0.5-4.6) and 16.0 (5.4-47.1), respectively, for anti–EBV DNase (P < 0.001 for trend). The shorter the time interval between study entry and nasopharyngeal carcinoma diagnosis, the higher was the proportion of anti–EBV viral capsid antigen immunoglobulin A among nasopharyngeal carcinoma patients. The multivariate-adjusted hazard ratio (95% CI) was 3.0 (1.3-7.2) for ≥30 pack-years of cumulative cigarette smoking compared with <30 pack-years as the reference. The longer and heavier the cigarette smoking habit, the higher was the nasopharyngeal carcinoma risk. Anti–EBV viral capsid antigen immunoglobulin A, anti–EBV DNase, and long-term heavy cigarette smoking are independent nasopharyngeal carcinoma risk predictors. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1218–26)
Cervical Carcinoma and Sexual Behavior: Collaborative Reanalysis of Individual Data on 15,461 Women with Cervical Carcinoma and 29,164 Women without Cervical Carcinoma from 21 Epidemiological Studies
Authors:   International Collaboration of Epidemiological Studies of Cervical Cancer
Published: April 2009

High-risk human papillomavirus (HPV) types cause most cervical carcinomas and are sexually transmitted. Sexual behavior therefore affects HPV exposure and its cancer sequelae. The International Collaboration of Epidemiological Studies of Cervical Cancer has combined data on lifetime number of sexual partners and age at first sexual intercourse from 21 studies, or groups of studies, including 10,773 women with invasive cervical carcinoma, 4,688 women with cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ, and 29,164 women without cervical carcinoma. Relative risks for invasive cancer and CIN3 were estimated by conditional logistic regression. Risk of invasive cervical carcinoma increased with lifetime number of sexual partners (P for linear trend <0.001). The relative risk for ≥6 versus 1 partner, conditioned on age, study, and age at first intercourse, was 2.27 [95% confidence interval (95% CI), 1.98-2.61] and increased to 2.78 (95% CI, 2.22-3.47) after additional conditioning on reproductive factors. The risk of invasive cervical carcinoma increased with earlier age at first intercourse (P for linear trend <0.001). The relative risk for age at first intercourse ≤14 versus ≥25 years, conditioned on age, study, and lifetime number of sexual partners was 3.52 (95% CI, 3.04-4.08), which decreased to 2.05 (95% CI, 1.54-2.73) after additional conditioning on reproductive factors. CIN3/carcinoma in situ showed a similar association with lifetime number of sexual partners; however, the association with age at first intercourse was weaker than for invasive carcinoma. Results should be interpreted with caution given the strong correlation between sexual and reproductive factors and the limited information on HPV status. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1060–9)
Absence of Deleterious Palladin Mutations in Patients with Familial Pancreatic Cancer
Authors: Klein Alison P. , Borges Michael , Griffith Margaret , Brune Kieran , Hong Seung-Mo , Omura Noriyuki , Hruban Ralph H. , Goggins Michael
Published: April 2009

It has been reported that germline mutations in the palladin gene (PALLD) cause the familial aggregation of pancreatic cancer, but the evidence is weak and controversial. We sequenced the coding regions of PALLD in 48 individuals with familial pancreatic cancer. We did not find any deleterious mutations and find no evidence to implicate mutations in PALLD as a cause of familial pancreatic cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1328–30)
Molecular Detection of Lymph Node Metastases in Breast Cancer Patients: Results of a Multicenter Trial Using the One-Step Nucleic Acid Amplification Assay
Authors: Tamaki Yasuhiro , Akiyama Futoshi , Iwase Takuji , Kaneko Tomoyo , Tsuda Hitoshi , Sato Kazuhiko , Ueda Shigeto , Mano Masayuki , Masuda Norikazu , Takeda Masashi , Tsujimoto Masahiko , Yoshidome Katsuhide , Inaji Hideo , Nakajima Hiromu , Komoike Yoshifumi , Kataoka Tatsuki R. , Nakamura Seigo , Suzuki Koyu , Tsugawa Koichiro , Wakasa Kenichi , Okino Tsuyoshi , Kato Yo , Noguchi Shinzaburo , Matsuura Nariaki
Published: April 2009

Purpose: Accurate assessment of metastasis in sentinel lymph nodes (SLN) of breast cancer is important but involves a heavy workload for the pathologist. We conducted a multicenter clinical trial in Japan to evaluate a new automated assay system for cytokeratin 19 mRNA, the one-step nucleic acid amplification (OSNA) assay (Sysmex), to detect lymph node metastasis of breast cancer.

Experimental Design: Surgically obtained axillary lymph nodes were sectioned into four pieces, two of which were examined with the OSNA assay. The other two adjacent pieces were examined with H&E and immunohistochemical staining for cytokeratin 19. Serial sections at 0.2-mm intervals were used in trial 1 to determine the specificity of the OSNA assay, and three pairs of sections cut from the sliced surfaces of the pieces were used in trial 2 to compare the accuracy of the OSNA assay with that of a routine pathologic examination for SLNs in Japan.

Results: In trial 1, the sensitivity and specificity were 95.0% [95% confidence interval (95% CI), 75.1-99.9%] and 97.1% (95% CI, 91.8-99.4%), respectively, for 124 axillary lymph nodes obtained from 34 patients. In trial 2, the agreement between findings of the assay and of the pathologic examination was 92.9% (95% CI, 90.1-95.1%) for 450 axillary lymph nodes obtained from 164 patients.

Conclusion: The OSNA assay can detect lymph node metastasis as accurately as can conventional pathology and thus can be an effective addition to or alternative for rapid intraoperative examination of SLNs.
Phase II Trial of Tipifarnib plus Neoadjuvant Doxorubicin-Cyclophosphamide in Patients with Clinical Stage IIB-IIIC Breast Cancer
Authors: Sparano Joseph A. , Moulder Stacy , Kazi Aslamuzzaman , Coppola Domenico , Negassa Abdissa , Vahdat Linda , Li Tianhong , Pellegrino Christine , Fineberg Susan , Munster Pam , Malafa Mokenge , Lee David , Hoschander Shira , Hopkins Una , Hershman Dawn , Wright John J. , Kleer Celina , Merajver Sofia , Sebti Said M.
Published: April 2009

Purpose: Tipifarnib is a farnesyl transferase (FTase) inhibitor that has activity in metastatic breast cancer and enhances the efficacy of cytotoxic agents in preclinical models. We evaluated the biological effects of tipifarnib in primary breast cancers in vivo, whether adding tipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified.

Experimental Design: Forty-four patients with stage IIB-IIIC breast cancer received up to four cycles of neoadjuvant doxorubicin-cyclophosphamide (AC) every 2 weeks plus tipifarnib and filgrastim followed by surgery. Enzymatic assays measuring FTase activity and Western blotting for phospho (p)-signal transducer and activator of transcription 3 (STAT3), phospho-extracellular signal-regulated kinase, p-AKT, and p27 were done in 11 patients who agreed to optional tissue biopsies before therapy and 2 hours after the final dose of tipifarnib during the first cycle, and predictive biomarkers were evaluated by immunohistochemistry in 33 patients. The trial was powered to detect an improvement in breast pCR rate of 10% or less expected for AC alone to 25% for AC-tipifarnib (α = 0.05, β = 0.10).

Results: Eleven patients had a breast pCR (25%; 95% confidence interval, 13-40%). FTase enzyme activity decreased in all patients (median, 91%; range, 24-100%) and p-STAT3 expression decreased in 7 of 9 (77%) patients. Low tumor Ki-67 expression (below the median of 60%) at baseline was significantly associated with resistance to therapy (P = 0.01).

Conclusion: Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation.
Antivascular Actions of Microtubule-Binding Drugs
Authors: Schwartz Edward L.
Published: April 2009

Microtubule-binding drugs (MBD) are widely used in cancer chemotherapy and also have clinically relevant antiangiogenic and vascular-disrupting properties. These antivascular actions are due in part to direct effects on endothelial cells, and all MBDs (both microtubule-stabilizing and microtubule-destabilizing) inhibit endothelial cell proliferation, migration, and tube formation in vitro, actions that are thought to correspond to therapeutic antiangiogenic actions. In addition, the microtubule-destabilizing agents cause prominent changes in endothelial cell morphology, an action associated with rapid vascular collapse in vivo. The effects on endothelial cells occur in vitro at low drug concentrations, which do not affect microtubule gross morphology, do not cause microtubule bundling or microtubule loss and do not induce cell cycle arrest, apoptosis, or cell death. Rather, it has been hypothesized that, at low concentrations, MBDs produce more subtle effects on microtubule dynamics, block critical cell signaling pathways, and prevent the microtubules from properly interacting with transient subcellular assemblies (focal adhesions and adherens junctions) whose subsequent stabilization and/or maturation are required for cell motility and cell-cell interactions. This review will focus on recent studies to define the molecular mechanisms for the antivascular actions of the MBDs, information that could be useful in the identification or design of agents whose actions more selectively target the tumor vasculature.
Protumorigenic Role of HAPLN1 and Its IgV Domain in Malignant Pleural Mesothelioma
Authors: Ivanova Alla V. , Goparaju Chandra M.V. , Ivanov Sergey V. , Nonaka Daisuke , Cruz Christina , Beck Amanda , Lonardo Fulvio , Wali Anil , Pass Harvey I.
Published: April 2009

Purpose: Tumor extracellular matrix (ECM) plays a crucial role in cancer progression mediating and transforming host-tumor interactions. Targeting the ECM is becoming an increasingly promising therapeutic approach in cancer treatment. We find that one of the ECM proteins, HAPLN1, is overexpressed in the majority of mesotheliomas. This study was designed to characterize the protumorigenic role of HAPLN1 in mesothelioma.

Experimental Design: Overexpression of HAPLN1 was assessed and validated on a large set of normal/mesothelioma specimens on the RNA and protein levels. We also analyzed DNA copy number alterations in the HAPLN1 genomic locus using the array-based comparative genomic hybridization representational oligonucleotide microarray analysis tool. Tumorigenic activities of the HAPLN1 domains were evaluated in vitro on mesothelioma cells transfected with HAPLN1-expressing constructs.

Results: We found that HAPLN1 is 23-fold overexpressed in stage I mesothelioma and confirmed it for 76% samples (n = 53) on RNA and 97% (n = 40) on protein levels. The majority of lung cancers showed no differential expression of HAPLN1. Analysis of DNA copy number alterations identified recurrent gain in the 5q14.3 HAPLN1 locus in ∼27% of tumors. Noteworthy, high expression of HAPLN1 negatively correlated with time to progression (P = 0.05, log-rank test) and overall survival (P = 0.006). Proliferation, motility, invasion, and soft-agar colony formation assays on mesothelioma cells overexpressing full-length HAPLN1 or its functional domains strongly supported the protumorigenic role of HAPLN1 and its SP-IgV domain.

Conclusion: Overexpression of HAPLN1 and its SP-IgV domain increases tumorigenic properties of mesothelioma. Thus, targeting the SP-IgV domain may be one of the therapeutic approaches in cancer treatment.
Comparison Studies of Tacrine and Bis(7)-Tacrine on the Suppression of Scopolamine-Induced Behavioral Changes and Inhibition of Acetylcholinesterase in Mice
Authors: Pan Si-Yuan , Yu Zhi-Ling , Xiang Chun-Jing , Dong Hang , Fang Hai-Yan , Ko Kam-Ming
Published: April 2009

Effects of the cholinesterase inhibitors tacrine and bis(7)- tacrine (0.25–20 μmol/kg, s.c.) on locomotor activity and passive-avoidance response were investigated in mice treated with scopolamine (SCP, 1 or 5 μmol/kg, i.p.), using an open-field test and step-through task with a 24-hour retention interval. Drugs were given 30 min prior to the first session. During the acquisition session, SCP treatment increased the locomotor activity (10–16%). Tacrine, but not bis(7)-tacrine, cotreatment significantly reduced the locomotor activity by 23 or 27%, when compared with the SCP-treated control mice. In the step-through task, tacrine or bis(7)-tacrine coadministration dose-dependently attenuated the increase in the number of footshocks (by 50 or 58%) in SCP-treated mice. The lowest dose of tacrine and bis(7)-tacrine for prolonging the retention latency (up to 500%) in SCP-treated mice was 5 and 1 μmol/kg, respectively. Tacrine and bis(7)-tacrine inhibited brain acetylcholinesterase (AChE) activity 15 min (but not 30 min) after the drug administration in mice. At the same dose of 20 μmol/kg, the bis(7)-tacrine-induced AChE inhibition in serum was 14-fold higher than that of tacrine. The results indicated that bis(7)-tacrine was less potent than tacrine in causing motor dysfunction. However, bis(7)-tacrine was more potent than tacrine in the cognitive enhancement of SCP-induced memory loss and in AChE inhibition.
Toll-Like Receptors in Innate Immunity: Role of Bacterial Endotoxin and Toll-Like Receptor 4 in Endometrium and Endometriosis
Authors: Khan Khaleque Newaz , Kitajima Michio , Hiraki Koichi , Fujishita Akira , Sekine Ichiro , Ishimaru Tadayuki , Masuzaki Hideaki
Published: April 2009

Macrophages, dendritic cells, and Toll-like receptors (TLRs) are integral components of the innate immune system. This rapidly reactive system responds immediately to infectious or other non-self agents, thereby inducing an inflammatory response to protect the host until the activation of the slower adaptive immune system. The fundamentals of the innate immune system, functional characteristics of TLRs, and signaling pathways of TLR4 are discussed for the easy understanding by readers. Studies showed that the growth and progression of endometriosis continue even in ovariectomized animals. This indicates that besides ovarian steroid hormones, the growth of endometriosis can be regulated by the innate immune system in the pelvic environment. As a component of the innate immune system, increased infiltration of macrophages has been described in the intact tissue and peritoneal fluid of women with endometriosis. In this review article, we discuss the role of bacterial endotoxin and TLR4 in endometrium and endometriosis and outline the involvement of endotoxin in causing adverse reproductive outcome.
The Rate of Living Theory Revisited
Authors: Lints F.A.
Published: April 2009

A rereading of The Rate of Living [Pearl, University of London Press, London 1928] shows that Pearl’s thoughts about the meaning of inheritance and heredity, about the relations of between and within populations measurements and about the ways in which life span should be measured are unclear. New ways in which the theory should, eventually, be tested are suggested and the genetic implications of these suggested experimental ways are given. A review is made, mainly in insects, accessorily in rodents, of the different manners in which the theory has been essayed, namely by relating life span with temperature, rate of energy expenditure, growth rate and activity. It is concluded that the theory rests on a weak theoretical basis and even on a series of highly nonplausible assumptions and that, furthermore, the evidence experimentally accumulated is, with a few odd exceptions, not in favor of the theory.
Socioeconomic Position and Graft Failure in Pediatric Heart Transplant Recipients
Authors: Singh Tajinder P. , Gauvreau Kimberlee , Bastardi Heather J. , Blume Elizabeth D. , Mayer John E.
Published: April 2009

Background—

Socioeconomic (SE) position may affect availability of resources, health-related behavior, and outcomes. We assessed whether patient SE position, determined for the block group of patient residence (average population 1000, smallest census unit with SE data), is associated with graft failure in pediatric heart transplant recipients.

Methods and Results—

We used the US Census 2000 database to derive a composite SE score for the block group of residence for all patients who underwent their first heart transplant at Children’s Hospital Boston between 1991 and 2005 (n=135). Cox proportional hazards models were used to determine the risk of graft failure (death or retransplant) in the lowest tertile SE group (low SE group) compared with the remaining 2 of 3 patients (controls). The 2 groups were similar with respect to age, gender, diagnosis, and year of transplant. White race was less frequent in low SE group (64% versus 90%,
P
=0.001). Graft failure occurred in 46 transplant recipients (40 deaths, 6 retransplant). Low SE group (hazard ratio 2.4, 95% CI 1.3 to 4.3) and nonwhite race (hazard ratio 2.7, 95% CI 1.4 to 5.2) were both associated with higher risk of graft failure. In a multivariable model controlling for diagnosis and pretransplant support, race, and low SE position (hazard ratio 2.0, 95% CI 1.0 to 3.7,
P
=0.04) remained associated with graft failure. Low SE position group had a higher incidence rate of graft rejection and was at a higher risk of late rejection.

Conclusion—

Low SE position may be an independent risk factor for graft failure in pediatric heart transplant recipients.
Old Wine in New Skins: The Sensitivity of Established Findings to New Methods
Authors: Foster E. Michael , Wiley-Exley Elizabeth , Bickman Leonard
Published: April 2009

Findings from an evaluation of a model system for delivering mental health services to youth were reassessed to determine the robustness of key findings to the use of methodologies unavailable to the original analysts. These analyses address a key concern about earlier findings—that the quasi-experimental design involved the comparison of two noncomparable groups. The authors employed propensity score methodology to reconsider between-group baseline differences in observed characteristics of participating families. The authors also considered the possible effect of unobserved between-group differences. The data support previous studies that show few differences in outcomes, but the findings are sensitive to unobserved heterogeneity.
Predicting Mathematical Achievement and Mathematical Learning Disability with a Simple Screening Tool
Authors: Geary David C. , Bailey Drew H. , Hoard Mary K.
Published: April 2009

The Number Sets Test was developed to assess the speed and accuracy with which children can identify and process quantities represented by Arabic numerals and object sets. The utility of this test for predicting mathematics achievement and risk for mathematical learning disability (MLD) was assessed for a sample of 223 children. A signal detection analysis of first grade Number Sets Test scores provided measures of children's sensitivity to number and their response bias. The sensitivity measure, d', but not the response bias measure was predictive of third grade mathematics achievement scores, above and beyond the influence of intelligence, working memory, and first grade achievement scores. Further analyses assessed the sensitivity and specificity of the test and revealed that first grade d' scores identified 2 out of 3 children diagnosed as MLD in third grade and correctly identified about 9 out of 10 children who were not at risk for MLD.