bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of self-assessment on test scores: student perceptions
Authors: Ramirez Beatriz U.
Published: September 2010

After a sudden increase in most of the individual grades in a multiple-choice test, students were asked to rank the three most relevant factors responsible for this outcome. Among eight others, the availability of a test for self-assessment before the final test was by far the most frequently mentioned (82.4% of the students). Questions applied during different course activities did not have the same effect on student scores as the “online” self-assessment test.
Teaching undergraduates the process of peer review: learning by doing
Authors: Rangachari P. K.
Published: September 2010

An active approach allowed undergraduates in Health Sciences to learn the dynamics of peer review at first hand. A four-stage process was used. In stage 1, students formed self-selected groups to explore specific issues. In stage 2, each group posted their interim reports online on a specific date. Each student read all the other reports and prepared detailed critiques. In stage 3, each report was discussed at sessions where the lead discussant was selected at random. All students participated in the peer review process. The written critiques were collated and returned to each group, who were asked to resubmit their revised reports within 2 wk. In stage 4, final submissions accompanied by rebuttals were graded. Student responses to a questionnaire were highly positive. They recognized the individual steps in the standard peer review, appreciated the complexities involved, and got a first-hand experience of some of the inherent variabilities involved. The absence of formal presentations and the opportunity to read each other's reports permitted them to study issues in greater depth.
IL-6 selectively stimulates fat metabolism in human skeletal muscle
Authors: Wolsk Emil , Mygind Helene , Grøndahl Thomas S. , Pedersen Bente K. , van Hall Gerrit
Published: September 2010

Interleukin (IL)-6 is chronically elevated in type 2 diabetes but also during exercise. However, the exact metabolic role, and hence the physiological significance, has not been elucidated. The objective of this study was to investigate the in vivo effect of recombinant human (rh) IL-6 on human fat and glucose metabolism and signaling of both adipose tissue and skeletal muscle. Eight healthy postabsorptive males were infused with either rhIL-6 or saline for 4 h, eliciting IL-6 levels of ∼40 and ∼1 pg/ml, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism was assessed before, during, and 2 h after cessation of the infusion. Glucose metabolism was unaffected by rhIL-6. In contrast, rhIL-6 increased systemic fatty acid oxidation approximately twofold after 60 min, and it remained elevated even 2 h after the infusion. The increase in oxidation was followed by an increase in systemic lipolysis. Adipose tissue lipolysis and fatty acid kinetics were unchanged with rhIL-6 compared with saline infusion. Conversely, rhIL-6 infusion caused an increase in skeletal muscle unidirectional fatty acid and glycerol release, indicative of an increase in lipolysis. The increased lipolysis in muscle could account for the systemic changes. Skeletal muscle signaling increased after 1 h of rhIL-6 infusion, indicated by a fourfold increase in the phosphorylated signal transducer and activator of transcription (STAT) 3-to-STAT3 ratio, whereas no changes in phosphorylated AMP-activated protein kinase or acetyl-CoA carboxylase levels could be observed. Our findings suggest that an acute increase in IL-6 at a normophysiological level selectively stimulates lipolysis in skeletal muscle, whereas adipose tissue is unaffected.
Chronic consumption of a high-fat/high-fructose diet renders the liver incapable of net hepatic glucose uptake
Authors: Coate Katie Colbert , Scott Melanie , Farmer Ben , Moore Mary Courtney , Smith Marta , Roop Joshua , Neal Doss W. , Williams Phil , Cherrington Alan D.
Published: September 2010

The objective of this study was to assess the response of a large animal model to high dietary fat and fructose (HFFD). Three different metabolic assessments were performed during 13 wk of feeding an HFFD ( n = 10) or chow control (CTR, n = 4) diet: oral glucose tolerance tests (OGTTs; baseline, 4 and 8 wk), hyperinsulinemic-euglycemic clamps (HIEGs; baseline and 10 wk) and hyperinsulinemic-hyperglycemic clamps (HIHGs, 13 wk). The ΔAUC for glucose during the OGTTs more than doubled after 4 and 8 wk of HFFD feeding, and the average glucose infusion rate required to maintain euglycemia during the HIEG clamps decreased by ≈30% after 10 wk of HFFD feeding. These changes did not occur in the CTR group. The HIHG clamps included experimental periods 1 (P1, 0–90 min) and 2 (P2, 90–180 min). During P1, somatostatin, basal intraportal glucagon, 4 × basal intraportal insulin, and peripheral glucose (to double the hepatic glucose load) were infused; during P2, glucose was also infused intraportally (4.0 mg·kg−1·min−1). Net hepatic glucose uptake during P1 and P2 was −0.4 ± 0.1 [output] and 0.2 ± 0.8 mg·kg−1·min−1in the HFFD group, respectively, and 1.8 ± 0.8 and 3.5 ± 1.0 mg·kg−1·min−1in the CTR group, respectively ( P < 0.05 vs. HFFD during P1 and P2). Glycogen synthesis through the direct pathway was 0.5 ± 0.2 and 1.5 ± 0.4 mg·kg−1·min−1in the HFFD and CTR groups, respectively ( P < 0.05 vs. HFFD). In conclusion, chronic consumption of an HFFD diminished the sensitivity of the liver to hormonal and glycemic cues and resulted in a marked impairment in NHGU and glycogen synthesis.
Optimal Erythrocyte Ribavirin Level to Reduce the Risk of Anemia and Obtain an Early Virological Response in Patients with Chronic Hepatitis C Caused by Genotype 1b Infection
Authors: Kubota Rie , Komiyama Takako , Kumagai Naoki , Kimijima Miyuki , Mitsuki Keiko , Uetake Junko , Kaneko Fumihiko , Tsunematsu Satoshi , Tsuchimoto Kanji
Published: September 2010

Aims. To determine whether the erythrocyte phosphorylated ribavirin (RBV) level might be a useful index of EVR and risk of anemia and to determine the optimal dose of RBV in 24 patients with hepatitis C with pegylated interferon and RBV. Methodology. The RBV level was measured by a high-performance liquid chromatography. Results and Conclusion. In patients aged 50 years or over, a negative correlation (, ) was observed between the RBV level at week 2 and rate of Hb reduction () at week 4. The at week 4 was significantly greater in patients with RBV levels of ≥800  ( %) than in patients with RBV levels <800  ( %). None of the patients with RBV levels <600  at week 2 achieved EVR and SVR. Thus the optimal levels of erythrocyte phosphorylated RBV at week 2 of therapy in order to achieve EVR without anemia seemed to be 600–800 .
Responses of Three Bromegrass (Bromus) Species to Defoliation under Different Growth Conditions
Authors: Biligetu B. , Coulman Bruce
Published: September 2010

Bromegrass species are important forage crops in temperate regions of world. This study compared responses of three bromegrass species to defoliation in the greenhouse and field to determine if the former could predict responses in the latter. Experiments were conducted in 2006 and 2007 in Saskatoon (52°07′N,106°38′W), Canada on meadow bromegrass (Bromus ripariusRehm.), smooth bromegrass (Bromus inermisLeyss.), and hybrid bromegrass (B. ripariusX B.inermis) following defoliation to 5 cm stubble height. When defoliated at the vegetative stage, above-ground biomass was similar among the three species in the field, but meadow bromegrass produced greater above-ground biomass than smooth bromegrass in the greenhouse. When defoliated at the stem elongation stage, meadow bromegrass produced greater above-ground biomass than smooth bromegrass in both environments. In the field, for all defoliation treatments, tiller number was greatest in meadow bromegrass, intermediate in hybrid bromegrass, and least in smooth bromegrass. In the greenhouse, however, the three species did not differ in tiller number. Similar results were found for below-ground biomass. Thus, testing the effect of defoliation in the greenhouse environment did not accurately predict the effect in the field environment.
Induction by TNF-αof IL-6 and IL-8 in Cystic Fibrosis Bronchial IB3-1 Epithelial Cells Encapsulated in Alginate Microbeads
Authors: Borgatti Monica , Mazzitelli Stefania , Breveglieri Giulia , Gambari Roberto , Nastruzzi Claudio
Published: September 2010

We have developed a microencapsulation procedure for the entrapment and manipulation of IB3-1 cystic fibrosis cells. The applied method is based on generation of monodisperse droplets by a vibrational nozzle. Different experimental parameters were analyzed, including frequency and amplitude of vibration, polymer pumping rate and distance between the nozzle and the gelling bath. We have found that the microencapsulation procedure does not alter the viability of the encapsulated IB3-1 cells. The encapsulated IB3-1 cells were characterized in term of secretomic profile, analyzing the culture medium by Bio-Plex strategy. The experiments demonstrated that most of the analyzed proteins, were secreted both by the free and encapsulated cells, even if in a different extent. In order to determine the biotechnological applications of this procedure, we determined whether encapsulated IB3-1 cells could be induced to pro-inflammatory responses, after treatment with TNF-α. In this experimental set-up, encapsulated and free IB3-1 cells were treated with TNF-α, thereafter the culture media from both cell populations were collected. As expected, TNF-αinduced a sharp increase in the secretion of interleukins, chemokines and growth factors. Of great interest was the evidence that induction of interleukin-6 and interleukin-8 occurs also by encapsulated IB3-1 cells.
Molecular Detection of PersistentFrancisella tularensisSubspeciesholarcticain Natural Waters
Authors: Broman T. , Thelaus J. , Andersson A.-C. , Bäckman S. , Wikström P. , Larsson E. , Granberg M. , Karlsson L. , Bäck E. , Eliasson H. , Mattsson R. , Sjöstedt A. , Forsman M.
Published: September 2010

Tularemia, caused by the bacteriumFrancisella tularensis, whereF. tularensissubspeciesholarcticahas long been the cause of endemic disease in parts of northern Sweden. Despite this, our understanding of the natural life-cycle of the organism is still limited. During three years, we collected surface water samples (n=341) and sediment samples (n=245) in two areas in Sweden with endemic tularemia. Real-time PCR screening demonstrated the presence ofF. tularenis lpnAsequences in 108 (32%) and 48 (20%) of the samples, respectively. The 16S rRNA sequences from those samples all grouped to the speciesF. tularensis. Analysis of the FtM19InDel region oflpnA-positive samples from selected sampling points confirmed the presence ofF. tularensissubspeciesholarctica-specific sequences. These sequences were detected in water sampled during both outbreak and nonoutbreak years. Our results indicate that diverseF. tularensis-like organisms, includingF. tularensissubsp.holarctica, persist in natural waters and sediments in the investigated areas with endemic tularemia.
Loss of Osteoclasts Contributes to Development of Osteosarcoma Pulmonary Metastases
Authors: Endo-Munoz Liliana , Cumming Andrew , Rickwood Danny , Wilson Danielle , Cueva Claudia , Ng Charlotte , Strutton Geoffrey , Cassady A. Ian , Evdokiou Andreas , Sommerville Scott , Dickinson Ian , Guminski Alexander , Saunders Nicholas A.
Published: September 2010

We conducted a transcriptomic screen of osteosarcoma (OS) biopsies and found that expression of osteoclast-specific tartrate-resistant acid phosphatase 5 (ACP5/TRAP) is significantly downregulated in OS compared with nonmalignant bone (P < 0.0001). Moreover, lesions from OS patients with pulmonary metastases had 2-fold less ACP5/TRAP expression (P < 0.018) than lesions from patients without metastases. In addition, we found a direct correlation (P = 0.0166) between ACP5/TRAP expression and time to metastasis. Therefore, we examined whether metastasis-competent (MC) OS cells could induce loss of ACP5+ osteoclasts and contribute to metastasis. We found that MC OS cell lines can inhibit osteoclastogenesis in vitro and in vivo. In addition, osteoclasts can inhibit the migration of MC OS cells in vitro. Finally, ablation of osteoclasts with zoledronic acid increases the number of metastatic lung lesions in an orthotopic OS model, whereas fulvestrant treatment increases osteoclast numbers and reduces metastatic lesions. These data indicate that the metastatic potential of OS is determined early in tumor development and that loss of osteoclasts in the primary lesion enhances OS metastasis. Cancer Res; 70(18); 7063–72. ©2010 AACR.
Modifying Akt Signaling in B-Cell Chronic Lymphocytic Leukemia Cells
Authors: Hofbauer Sebastian W. , Piñón Josefina D. , Brachtl Gabriele , Haginger Lucia , Wang Wei , Jöhrer Karin , Tinhofer Ingeborg , Hartmann Tanja Nicole , Greil Richard
Published: September 2010

Emerging evidence suggests that the survival of B-cell chronic lymphocytic leukemia (CLL) cells is dependent on microenvironmental influences such as antigenic stimulation and support by stromal cells. Akt, also known as protein kinase B, is a central component in prosurvival signaling downstream of these events. We investigated the role of Akt and its modulation by the protooncogene T-cell leukemia 1a (Tcl1a) in the survival pathways of primary CLL samples and CLL-derived prolymphocytic cell lines MEC-1 and MEC-2. Akt activation was increased by the protective presence of human bone marrow stromal cells and B-cell receptor mimicking signals but antagonized by direct Akt blockade with the novel specific inhibitor AiX, with preferential apoptosis induction in CLL cells with an unmutated immunoglobulin status, which predicts poor clinical outcome. In addition, we found a direct interaction of Akt with Tcl1a in an endogenous coimmunoprecipitation assay. Confirming the critical role of Tcl1a in modulating Akt signaling, Akt activation was enhanced by overexpressing Tcl1a in CLL. In contrast, decreasing Tcl1a levels by small interfering RNA reduced Akt activation in the fludarabine-insensitive CLL cell line MEC-2 and sensitized the malignant cells to fludarabine treatment. In summary, our data reveal a significant role for the Akt-Tcl1a axis in CLL survival and propose a further evaluation of this interplay for targeting chemoresistance phenomena. Cancer Res; 70(18); 7336–44. ©2010 AACR.
The Sympathetic Nervous System Induces a Metastatic Switch in Primary Breast Cancer
Authors: Sloan Erica K. , Priceman Saul J. , Cox Benjamin F. , Yu Stephanie , Pimentel Matthew A. , Tangkanangnukul Veera , Arevalo Jesusa M.G. , Morizono Kouki , Karanikolas Breanne D.W. , Wu Lily , Sood Anil K. , Cole Steven W.
Published: September 2010

Metastasis to distant tissues is the chief driver of breast cancer–related mortality, but little is known about the systemic physiologic dynamics that regulate this process. To investigate the role of neuroendocrine activation in cancer progression, we used in vivo bioluminescence imaging to track the development of metastasis in an orthotopic mouse model of breast cancer. Stress-induced neuroendocrine activation had a negligible effect on growth of the primary tumor but induced a 30-fold increase in metastasis to distant tissues including the lymph nodes and lung. These effects were mediated by β-adrenergic signaling, which increased the infiltration of CD11b+F4/80+ macrophages into primary tumor parenchyma and thereby induced a prometastatic gene expression signature accompanied by indications of M2 macrophage differentiation. Pharmacologic activation of β-adrenergic signaling induced similar effects, and treatment of stressed animals with the β-antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited tumor spread to distant tissues. The effects of stress on distant metastasis were also inhibited by in vivo macrophage suppression using the CSF-1 receptor kinase inhibitor GW2580. These findings identify activation of the sympathetic nervous system as a novel neural regulator of breast cancer metastasis and suggest new strategies for antimetastatic therapies that target the β-adrenergic induction of prometastatic gene expression in primary breast cancers. Cancer Res; 70(18); 7042–52. ©2010 AACR.
Chemotherapy-Induced Genotoxic Stress Promotes Sensitivity to Natural Killer Cell Cytotoxicity by Enabling Missing-Self Recognition
Authors: Fine Jason H. , Chen Peter , Mesci Aruz , Allan David S.J. , Gasser Stephan , Raulet David H. , Carlyle James R.
Published: September 2010

Natural killer (NK) cells can recognize and kill tumor cells lacking “self” markers, such as class I MHC, but the basis for this recognition is not completely understood. NKR-P1 receptors are members of the C-type lectin-related NK receptor superfamily that are conserved from rodents to humans. Identification of Clr ligands for the NKR-P1 receptors has facilitated functional analysis of MHC-independent target cell recognition by NK cells. One receptor-ligand pair, NKR-P1B:Clr-b, can mediate “missing-self” recognition of tumor and infected cells, but the role of this axis in sensing stressed cells remains unknown. Here, we show that Clr-b is rapidly downregulated in cells undergoing genotoxic and cellular stress at the level of both RNA and surface protein. Stress-mediated loss of Clr-b on leukemia cells enhanced cytotoxicity mediated by NKR-P1B+ NK cells. Notably, Clr-b downregulation was coordinated functionally with stress-mediated upregulation of NKG2D ligands (but not class I MHC). Our findings highlight a unique role for the MHC-independent NKR-P1B:Clr-b missing-self axis in recognition of stressed cells, and provide evidence of two independent levels of Clr-b regulation in stressed cells. Cancer Res; 70(18); 7102–13. ©2010 AACR.
Strategies for Increasing Mammography Screening in Primary Care in Chile: Results of a Randomized Clinical Trial
Authors: Püschel Klaus , Coronado Gloria , Soto Gabriela , Gonzalez Karla , Martinez Javiera , Holte Sarah , Thompson Beti
Published: September 2010

Background: Breast cancer is the cancer with the highest incidence among women in Chile and in many Latin American countries. Breast cancer screening has very low compliance among Chilean women.

Methods: We compared the effects on mammography screening rates of standard care, of a low-intensity intervention based on mail contact, and of a high-intensity intervention based on mail plus telephone or personal contact. A random sample of 500 women with the age of 50 to 70 years registered at a community clinic in Santiago who had not had a mammogram in the past 2 years were randomly assigned to one of the three intervention groups. Six months after randomization, participants were re-evaluated for their compliance with mammography screening. The outcome was measured by self-report and by electronic clinical records. An intention to treat model was used to analyze the results.

Results: Between 92% and 93% of participants completed the study. Based on electronic records, mammography screening rates increased significantly from 6% in the control group to 51.8% in the low-intensity group and 70.1% in the high-intensity group. About 14% of participants in each group received opportunistic advice, 100% of participants in the low- and high-intensity groups received the mail contact, and 50% in the high-intensity group received a telephone or personal contact.

Conclusion: A primary care intervention based on mail or brief personal contact could significantly improve mammogram screening rates.

Impact: A relatively simple intervention could have a strong impact in breast cancer prevention in underserved communities. Cancer Epidemiol Biomarkers Prev; 19(9); 2254–61. ©2010 AACR.
Communication of BRCA Results and Family Testing in 1,103 High-Risk Women
Authors: Cheung Eleanor L. , Olson Ashley D. , Yu Tina M. , Han Pamela Z. , Beattie Mary S.
Published: September 2010

Background: Genetic testing for hereditary cancer risk has implications for individuals and families. This study of women at risk of hereditary breast and ovarian cancer examines communication of BRCA results and subsequent genetic testing in the family.

Methods: We surveyed 1,103 female BRCA testers at two hospitals, querying for communication of results and testing in relatives.

Results: Ninety-seven percent of participants communicated BRCA results with at least one relative. Communication was negatively associated with older age [odds ratio (OR), 0.66 per decade; 95% confidence interval, (95% CI), 0.4–0.9], Asian race (OR, 0.18; 95% CI, 0.06–0.5), and testing at the public hospital versus the cancer center (OR, 0.19; 95% CI, 0.07–0.5). Communication was positively associated with increased knowledge of hereditary breast and ovarian cancer screening and risk reduction recommendations (OR, 1.9; 95% CI, 1.1–3.4) and increased satisfaction with the decision to BRCA test (OR, 2.6; 95% CI, 1.6–4.0). Seventy-five percent of BRCA-positive participants reported that at least one relative pursued genetic testing. Family testing was negatively associated with Asian race (OR, 0.15; 95% CI, 0.02–0.8) and positively associated with increased socioeconomic status (OR, 1.4; 95% CI, 1.1–1.7) and increased satisfaction with decision (OR, 2.1; 95% CI, 1.1–4.1).

Conclusion: Despite high overall rates of communicating BRCA results, underserved and some minority women seem less likely to inform relatives of their BRCA status or have relatives test for a known family mutation. Satisfaction with the decision to BRCA test is positively associated with both outcomes.

Impact: This study identified several novel predictors of family communication and family genetic testing in a large population of high-risk women. This work can inform clinicians interested in improving family communication regarding cancer predisposition testing. Cancer Epidemiol Biomarkers Prev; 19(9); 2211–9. ©2010 AACR.
Seroprevalence of Antibodies against Human Papillomavirus (HPV) Types 16 and 18 in Four Continents: the International Agency for Research on Cancer HPV Prevalence Surveys
Authors: Vaccarella Salvatore , Franceschi Silvia , Clifford Gary M. , Touzé Antoine , Hsu Charles C. , de Sanjosé Silvia , Anh Pham Thi Hoang , Hieu Nguyen Trong , Matos Elena , Shin Hai Rim , Sukvirach Sukhon , Thomas Jaiye O. , Boursaghin Latifa , Gaitan Julien , Snijders Peter J.F. , Meijer Chris J.L.M. , Muñoz Nubia , Herrero Rolando , Coursaget Pierre ,   for the IARC HPV Prevalence Surveys Study Group
Published: September 2010

Background: Few human papillomavirus (HPV) seroprevalence studies have been carried out in women from low-resource countries.

Methods: Seroprevalence of antibodies against HPV16 and HPV18 was assessed in 7,074 women ≥15 years of age (median 44 years) from eight world areas. Serum antibodies against HPV16 and HPV18 were tested for using enzyme-linked immunosorbent assay. HPV DNA was assessed using a general primer GP5+/6+–mediated PCR.

Results: HPV16 and HPV18 seroprevalence both ranged from <1% (Hanoi, Vietnam) to ≥25% (Nigeria). Of women who were HPV16 or HPV18 DNA-positive, seropositivity for the same type was 39.8% and 23.2%, respectively. Seropositivity for either type was directly associated with markers of sexual behavior. HPV16 and/or 18 (HPV16/18)–seropositive women had an increased risk of having cytologic abnormalities only if they were also HPV DNA-positive. A high international correlation was found between HPV16/18 seroprevalence and overall HPV DNA prevalence (r = 0.81; P = 0.022). However, HPV16/18 seroprevalence was substantially higher than the corresponding DNA prevalence in all study areas (although to different extents) and, contrary to DNA, tended to increase from young to middle age, and then decline or remain fairly constant. In all study areas, the vast majority of the information on the burden of exposure to HPV16/18 derived from serology.

Conclusions: The correlation between HPV DNA and HPV serology was not very good at an individual woman level, but high at a population level.

Impact: HPV serology is a poor marker of current infection or related lesions, but it can contribute, together with DNA, in evaluating the variations in the burden of HPV infection worldwide. Cancer Epidemiol Biomarkers Prev; 19(9); 2379–88. ©2010 AACR.
Asthma, Asthma Medications, and Prostate Cancer Risk
Authors: Severi Gianluca , Baglietto Laura , Muller David C. , English Dallas R. , Jenkins Mark A. , Abramson Michael J. , Douglass Jo A. , Hopper John L. , Giles Graham G.
Published: September 2010

Background: The aim of this study was to assess whether a history of asthma or the use of asthma medications is associated with prostate cancer risk.

Methods: Of 16,934 men participating in the Melbourne Collaborative Cohort Study, 1,179 were diagnosed with prostate cancer during an average follow-up of 13.4 years to the end of December 2007. Information on asthma history was obtained at baseline interview. Participants were asked to bring their current medications to the study center. The names of the drugs were entered into a form and coded. Asthma medications were categorized into four groups and corresponding hazard ratios (HR) were estimated from Cox regression models adjusted for country of birth.

Results: Asthma was associated with a small increase in prostate cancer risk [HR 1.25; 95% confidence interval (95% CI), 1.05-1.49]. The HRs for use of medications were 1.39 (95% CI, 1.03-1.88) for inhaled glucocorticoids, 1.71 (95% CI, 1.08-2.69) for systemic glucocorticoids, 1.36 (95% CI, 1.05-1.76) for bronchodilators, and 0.78 (95% CI, 0.45-1.35) for antihistamines. The HRs for asthma and asthma medication use changed only slightly after mutual adjustment.

Conclusions: A history of asthma and the use of asthma medications, particularly systemic glucocorticoids, are associated with an increased risk of prostate cancer, although it is difficult to disentangle the effects of asthma medications from those of asthma per se.

Impact: These findings, if confirmed in independent studies, might lead to the identification of new risk factors for prostate cancer. Cancer Epidemiol Biomarkers Prev; 19(9); 2318–24. ©2010 AACR.
ST14Gene Variant and Decreased Matriptase Protein Expression Predict Poor Breast Cancer Survival
Authors: Kauppinen Jaana M. , Kosma Veli-Matti , Soini Ylermi , Sironen Reijo , Nissinen Minna , Nykopp Timo K. , Kärjä Vesa , Eskelinen Matti , Kataja Vesa , Mannermaa Arto
Published: September 2010

Background: Matriptase plays a role in carcinogenesis, but the role of its genetic variation or that of the hepatocyte growth factor activator inhibitor-1 (HAI-1) has not been evaluated. This study aimed to examine the genetic variation of matriptase (ST14 gene) and HAI-1 (SPINT1 gene) in breast cancer risk and prognosis, to assess matriptase and HAI-1 gene and protein expression in breast tumors, and to identify their clinicopathologic correlations and prognostic significance.

Methods: Five single nucleotide polymorphisms in ST14 and three in SPINT1 were genotyped in 470 invasive breast cancer cases and 446 healthy controls. Gene expression analysis was done for 40 breast cancer samples. Protein expression was assessed by immunohistochemical analyses in 377 invasive breast tumors. The statistical significance of the associations among genotypes, clinicopathologic variables, and prognosis was assessed.

Results: The ST14 single nucleotide polymorphism rs704624 independently predicted breast cancer survival, a poor outcome associated with the minor allele (P = 0.001; risk ratio, 2.221; 95% confidence interval, 1.382-3.568). Moreover, ST14 gene expression levels were lower among the minor allele carriers (P = 0.009), and negative/low matriptase protein expression was independently predictive of poorer survival (P = 0.046; risk ratio, 1.554; 95% confidence interval, 1.008-2.396).

Conclusions: The ST14 variant rs704624 and protein expression of matriptase have prognostic significance in breast cancer. This study adds to the evidence for the role of matriptase in breast cancer and has found new evidence for the genotypes having an impact in breast cancer.

Impact: This is the first study showing that genetic variation in matriptase has clinical importance. The results encourage further study on the genetic variation affecting protein levels and function in type II transmembrane serine proteases. Cancer Epidemiol Biomarkers Prev; 19(9); 2133–42. ©2010 AACR.
Blood Vitamin D Levels in Relation to Genetic Estimation of African Ancestry
Authors: Signorello Lisa B. , Williams Scott M. , Zheng Wei , Smith Jeffrey R. , Long Jirong , Cai Qiuyin , Hargreaves Margaret K. , Hollis Bruce W. , Blot William J.
Published: September 2010

Background: African-Americans generally have lower circulating levels of 25 hydroxyvitamin D [25(OH)D] than Whites, attributed to skin pigmentation and dietary habits. Little is known about the genetic determinants of 25(OH)D levels nor whether the degree of African ancestry associates with circulating 25(OH)D.

Methods: With the use of a panel of 276 ancestry informative genetic markers, we estimated African and European admixture for a sample of 758 African-American and non-Hispanic White Southern Community Cohort Study participants. For African-Americans, cut points of <85%, 85% to 95%, and ≥95% defined low, medium, and high African ancestry, respectively. We estimated the association between African ancestry and 25(OH)D and also explored whether vitamin D exposure (sunlight, diet) had varying effects on 25(OH)D levels dependent on ancestry level.

Results: The mean serum 25(OH)D levels among Whites and among African-Americans of low, medium, and high African ancestry were 27.2, 19.5, 18.3, and 16.5 ng/mL, respectively. Serum 25(OH)D was estimated to decrease by 1.0 to 1.1 ng/mL per 10% increase in African ancestry. The effect of high vitamin D exposure from sunlight and diet was 46% lower among African-Americans with high African ancestry than among those with low/medium ancestry.

Conclusions: We found novel evidence that the level of African ancestry may play a role in clinical vitamin D status.

Impact: This is the first study to describe how 25(OH)D levels vary in relation to genetic estimation of African ancestry. Further study is warranted to replicate these findings and uncover the potential pathways involved. Cancer Epidemiol Biomarkers Prev; 19(9); 2325–31. ©2010 AACR.
Variety in Fruit and Vegetable Consumption and the Risk of Lung Cancer in the European Prospective Investigation into Cancer and Nutrition
Authors: Büchner Frederike L. , Bueno-de-Mesquita H. Bas , Ros Martine M. , Overvad Kim , Dahm Christina C. , Hansen Louise , Tjønneland Anne , Clavel-Chapelon Françoise , Boutron-Ruault Marie-Christine , Touillaud Marina , Kaaks Rudolf , Rohrmann Sabine , Boeing Heiner , Nöthlings Ute , Trichopoulou Antonia , Zylis Dimosthenis , Dilis Vardis , Palli Domenico , Sieri Sabina , Vineis Paolo , Tumino Rosario , Panico Salvatore , Peeters Petra H.M. , van Gils Carla H. , Lund Eiliv , Gram Inger T. , Braaten Tonje , Sánchez María-José , Agudo Antonio , Larrañaga Nerea , Ardanaz Eva , Navarro Carmen , Argüelles Marcial V. , Manjer Jonas , Wirfält Elisabet , Hallmans Göran , Rasmuson Torgny , Key Tim J. , Khaw Kay-Tee , Wareham Nick , Slimani Nadia , Vergnaud Anne-Claire , Xun Wei W. , Kiemeney Lambertus A.L.M. , Riboli Elio
Published: September 2010

Background: We investigated whether a varied consumption of vegetables and fruits is associated with lower lung cancer risk in the European Prospective Investigation into Cancer and Nutrition study.

Methods: After a mean follow-up of 8.7 years, 1,613 of 452,187 participants with complete information were diagnosed with lung cancer. Diet diversity scores (DDS) were used to quantify the variety in fruit and vegetable consumption. Multivariable proportional hazards models were used to assess the associations between DDS and lung cancer risk. All models were adjusted for smoking behavior and the total consumption of fruit and vegetables.

Results: With increasing variety in vegetable subgroups, risk of lung cancer decreases [hazard ratios (HR), 0.77; 95% confidence interval (CI), 0.64-0.94 highest versus lowest quartile; P trend = 0.02]. This inverse association is restricted to current smokers (HR, 0.73; 95% CI, 0.57-0.93 highest versus lowest quartile; P trend = 0.03). In continuous analyses, in current smokers, lower risks were observed for squamous cell carcinomas with more variety in fruit and vegetable products combined (HR/two products, 0.88; 95% CI, 0.82-0.95), vegetable subgroups (HR/subgroup, 0.88; 95% CI, 0.79-0.97), vegetable products (HR/two products, 0.87; 95% CI, 0.79-0.96), and fruit products (HR/two products, 0.84; 95% CI, 0.72-0.97).

Conclusion: Variety in vegetable consumption was inversely associated with lung cancer risk among current smokers. Risk of squamous cell carcinomas was reduced with increasing variety in fruit and/or vegetable consumption, which was mainly driven by the effect in current smokers.

Impact: Independent from quantity of consumption, variety in fruit and vegetable consumption may decrease lung cancer risk. Cancer Epidemiol Biomarkers Prev; 19(9); 2278–86. ©2010 AACR.
Rising Melanoma Incidence Rates of the Trunk among Younger Women in the United States
Authors: Bradford Porcia T. , Anderson William F. , Purdue Mark P. , Goldstein Alisa M. , Tucker Margaret A.
Published: September 2010

Background: Melanoma rates are rising among young women, possibly due to increasing UV radiation to previously protected body sites. Therefore, we examined melanoma incidence trends by age, gender, and body site. Descriptive methods were complemented with the age-period-cohort parameters net drift and longitudinal age trend.

Methods: Case and population data were obtained from the Surveillance, Epidemiology, and End Results (SEER) 9 Registries Database (1975-2006). Net drift summarized the average annual percentage change in log-linear rates per year of calendar-time (or year of diagnosis). Longitudinal age trend summarized the average annual percentage change by attained age at diagnosis. Early- and late-onset melanomas have low and high longitudinal age trends, respectively.

Results: There were 105,829 melanomas diagnosed in the SEER 9 Registries. The overall age-adjusted incidence rate (IR) for melanoma was 17.7/100,000 person-years. Age-specific IRs were greater among women than men prior to age 40 years. Among women, IRs decreased for all anatomic sites relative to the trunk. The highest net drift occurred in truncal lesions among women (net drift, 3.8%/year of calendar time; 95% confidence interval, 3.5-4.0%). The lowest longitudinal age trends also were observed for truncal lesions among women (longitudinal age trend, 5.4%/year of attained age; 95% confidence interval, 5.1-5.7).

Conclusions: Although melanoma IRs overall have risen for decades, the combination of high net drift and low longitudinal age trend show that melanomas are rising preferentially on the trunk among young women.

Impact: Future surveillance and analytic studies should consider melanoma effect modification by age, gender, and body site. Cancer Epidemiol Biomarkers Prev; 19(9); 2401–6. ©2010 AACR.
Histone γH2AX and Poly(ADP-Ribose) as Clinical Pharmacodynamic Biomarkers
Authors: Redon Christophe E. , Nakamura Asako J. , Zhang Yong-Wei , Ji Jiuping (Jay) , Bonner William M. , Kinders Robert J. , Parchment Ralph E. , Doroshow James H. , Pommier Yves
Published: September 2010

Tumor cells are often deficient in DNA damage response (DDR) pathways, and anticancer therapies are commonly based on genotoxic treatments using radiation and/or drugs that damage DNA directly or interfere with DNA metabolism, leading to the formation of DNA double-strand breaks (DSB), and ultimately to cell death. Because DSBs induce the phosphorylation of histone H2AX (γH2AX) in the chromatin flanking the break site, an antibody directed against γH2AX can be employed to measure DNA damage levels before and after patient treatment. Poly(ADP-ribose) polymerases (PARP1 and PARP2) are also activated by DNA damage, and PARP inhibitors show promising activity in cancers with defective homologous recombination (HR) pathways for DSB repair. Ongoing clinical trials are testing combinations of PARP inhibitors with DNA damaging agents. Poly(ADP-ribosylation), abbreviated as PAR, can be measured in clinical samples and used to determine the efficiency of PARP inhibitors. This review summarizes the roles of γH2AX and PAR in the DDR, and their use as biomarkers to monitor drug response and guide clinical trials, especially phase 0 clinical trials. We also discuss the choices of relevant samples for γH2AX and PAR analyses. Clin Cancer Res; 16(18); 4532–42. ©2010 AACR.
Poly (ADP-Ribose) Polymerase as a Novel Therapeutic Target in Cancer
Authors: Annunziata Christina M. , O'Shaughnessy Joyce
Published: September 2010

Cancer chemotherapy exploits limitations in repairing DNA damage in order to kill proliferating malignant cells. Recent evidence suggests that cancers within and across tissue types have specific defects in DNA repair pathways, and that these defects may predispose for sensitivity and resistance to various classes of cytotoxic agents. Poly (ADP-ribose) polymerase (PARP) and BRCA proteins are central to the repair of DNA strand breaks and, when defective, lead to the accumulation of mutations introduced by error-prone DNA repair. Breast, ovarian, and other cancers develop in the setting of BRCA deficiency, and these cancers may be more sensitive to cytotoxic agents that induce DNA strand breaks, as well as inhibitors of PARP activity. A series of recent clinical trials has tested whether PARP inhibitors can achieve synthetic lethality in BRCA-pathway-deficient tumors. Future studies must seek to identify sporadic cancers that harbor genomic instability, rendering susceptibility to agents that induce additional and lethal DNA damage. Clin Cancer Res; 16(18); 4517–26. ©2010 AACR.
DNA Damage and Repair in Translational Oncology: An Overview
Authors: Reed Eddie
Published: September 2010

Unknown to early investigators, DNA damage and repair has been a major focus of anticancer therapy from the beginning of clinical oncology. From the early days of using x-irradiation, to the development of nitrogen mustard analogs, to today's more sophisticated approaches, DNA damage and repair has strongly impacted our ability to successfully treat human malignancy. This area of basic, translational, and clinical science is very broad. The traditional focus of DNA damage and repair has been on diseases such as Xeroderma pigmentosum, and attempting to understand the basic molecular mechanisms of DNA repair processes. It is only recently that we have begun to appreciate how we might modulate these processes to improve our ability to advance cancer care. No fewer than 10 separate DNA repair processes are operative in higher organisms, and the total number of separable processes could be substantially higher. Some of our most useful clinical agents depend on causing DNA damage that is repaired by nucleotide excision repair. X-irradiation induces damage that is mostly repaired by base excision repair and double-strand break repair. We are now learning how to modulate select DNA repair pathways to benefit patients with breast cancer and other malignancies. Clin Cancer Res; 16(18); 4511–6. ©2010 AACR.
Regulation of Excision Repair Cross-Complementation Group 1 by Snail Contributes to Cisplatin Resistance in Head and Neck Cancer
Authors: Hsu Dennis Shin-Shian , Lan Hsin-Yi , Huang Chi-Hung , Tai Shyh-Kuan , Chang Shyue-Yih , Tsai Tung-Lung , Chang Cheng-Chi , Tzeng Cheng-Hwai , Wu Kou-Juey , Kao Jung-Yie , Yang Muh-Hwa
Published: September 2010

Purpose: We investigated the mechanism and clinical significance of the epithelial-mesenchymal transition (EMT)-induced chemoresistance in head and neck squamous cell carcinoma (HNSCC).

Experimental Design: The correlation between the expression of different EMT regulators and chemoresistance genes, such as excision repair cross complementation group 1 (ERCC1), was evaluated in cancer cell lines from the NCI-60 database and four human HNSCC cell lines. Ectopic expression of Snail or short-interference RNA-mediated repression of Snail or ERCC1 was done in HNSCC cell lines. Cell viability was examined for cells after cisplatin treatment. A luciferase reporter assay and chromatin immunoprecipitation were used to identify the transcriptional regulation of ERCC1 by Snail. Immunohistochemical analysis of Snail, Twist1, ERCC1, hypoxia inducible factor-1 α (HIF-1α), and NBS1 were done in samples from 72 HNSCC patients receiving cisplatin-based chemotherapy.

Results: The correlation between the expression of Snail and ERCC1 was confirmed in different cell lines, including HNSCC cells. In HNSCC cell lines, overexpression of Snail in the low endogenous Snail/ERCC1 cell lines FaDu or CAL-27 increased ERCC1 expression, and hypoxia or overexpression of NBS1 also upregulated ERCC1. Knockdown of Snail in the high endogenous Snail/ERCC1 cell line OECM-1 downregulated ERCC1 expression and attenuated cisplatin resistance. Furthermore, suppression of ERCC1 in Snail- or NBS1-overexpressing HNSCC cells enhanced sensitivity to cisplatin. Snail directly regulated ERCC1 transcription. In patients with HNSCC, coexpression of Snail and ERCC1 correlated with cisplatin resistance and a poor prognosis.

Conclusions: Activation of ERCC1 by Snail is critical in the generation of cisplatin resistance of HNSCC cells. Clin Cancer Res; 16(18); 4561–71. ©2010 AACR.
Therapeutic Targeting of the DNA Mismatch Repair Pathway
Authors: Martin Sarah A. , Lord Christopher J. , Ashworth Alan
Published: September 2010

The mismatch repair (MMR) pathway is involved in the removal of DNA base mismatches that arise either during DNA replication or are caused by DNA damage. Mutations in four genes involved in MMR, MSH2, MLH1, PMS2 and MSH6, predispose to a range of tumorigenic conditions, including hereditary nonpolyposis colon cancer, also known as Lynch syndrome. Here we discuss the canonical MMR pathway and the burgeoning evidence for noncanonical roles for the MMR genes, and highlight the therapeutic implications of MMR. In particular, we discuss how the DNA repair defect in MMR-deficient cancers could be exploited by the development of novel therapeutic strategies based on synthetic lethal approaches. Clin Cancer Res; 16(21); 5107–13. ©2010 AACR.
Spectrum and Outcome of Reoperations After the Ross Procedure
Authors: Stulak John M. , Burkhart Harold M. , Sundt Thoralf M. , Connolly Heidi M. , Suri Rakesh M. , Schaff Hartzell V. , Dearani Joseph A.
Published: September 2010

Background—

Proposed advantages to the Ross procedure included presumed increased freedom from reoperation and simpler reoperation for pulmonary conduit replacement if needed. It is increasingly apparent, however, that reoperations are frequent after the Ross procedure and that when required, they may be more complex than previously thought.

Methods and Results—

Between September 1991 and August 2008, 56 patients underwent reoperation at our institution after a Ross procedure performed by ourselves (n=13) or elsewhere (n=43). Median age at first reoperation at our institution was 26 years (range 1 to 69 years). The 4 most common indications for reoperation were isolated autograft (neoaortic) regurgitation in 11 cases (20), isolated pulmonary conduit regurgitation/stenosis in 9 (16), combined autograft regurgitation/dilatation in 8 (14), and combined autograft regurgitation and pulmonary conduit regurgitation/stenosis in 6 (11). A total of 144 procedures were performed in these 56 patients during first reoperation at our institution. The autograft valve required replacement in 21 cases (38) and aortic root replacement in 21 (38), with ascending aortic/arch reconstruction in 13 (23) and mitral valve surgery in 5 (9). The pulmonary valve was replaced in 33 cases (59) and the tricuspid valve was repaired/replaced in 10 (18). Early mortality was 1.8 (1 of 56 patients), and morbidity included 6 patients with respiratory failure and 3 who required postcardiotomy extracorporeal membrane oxygenation. There were 4 late deaths during the median follow-up of 8 months (range 1 to 179 months).

Conclusions—

A broad spectrum of complex reoperations may be required after the Ross procedure. Patients and family members considering the procedure should be informed of the potential for associated morbidity should reoperation be necessary.
Association of Colony-Forming Units With Coronary Artery and Abdominal Aortic Calcification
Authors: Cheng Susan , Cohen Kenneth S. , Shaw Stanley Y. , Larson Martin G. , Hwang Shih-Jen , McCabe Elizabeth L. , Martin Roderick P. , Klein Rachael J. , Hashmi Basma , Hoffmann Udo , Fox Caroline S. , Vasan Ramachandran S. , O'Donnell Christopher J. , Wang Thomas J.
Published: September 2010

Background—

Certain bone marrow–derived cell populations, called endothelial progenitor cells, have been reported to possess angiogenic activity. Experimental data suggest that depletion of these angiogenic cell populations may promote atherogenesis, but limited data are available on their relation to subclinical atherosclerotic cardiovascular disease in humans.

Methods and Results—

We studied 889 participants of the Framingham Heart Study who were free of clinically apparent cardiovascular disease (mean age, 65 years; 55% women). Participants underwent endothelial progenitor cell phenotyping with an early-outgrowth colony-forming unit assay and cell surface markers. Participants also underwent noncontrast multidetector computed tomography to assess the presence of subclinical atherosclerosis, as reflected by the burden of coronary artery calcification and abdominal aortic calcification. Across decreasing tertiles of colony-forming units, there was a progressive increase in median coronary artery calcification and abdominal aortic calcification scores. In multivariable analyses adjusting for traditional cardiovascular risk factors, each 1-SD increase in colony-forming units was associated with a ≈16% decrease in coronary artery calcification (
P
=0.02) and 17% decrease in abdominal aortic calcification (
P
=0.03). In contrast, neither CD34
+
/KDR
+
nor CD34
+
variation was associated with significant differences in coronary or aortic calcification.

Conclusions—

In this large, community-based sample of men and women, lower colony-forming unit number was associated with a higher burden of subclinical atherosclerosis in the coronary arteries and aorta. Decreased angiogenic potential could contribute to the development of atherosclerosis in humans.