bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of multimodal, systematic non-surgical treatment of knee osteoarthritis for patients not eligible for a total knee replacement: a study protocol of a randomised controlled trial
Authors: Skou Soren Thorgaard , Roos Ewa M , Laursen Mogens Berg , Rathleff Michael Skovdal , Arendt-Nielsen Lars , Simonsen Ole , Rasmussen Sten
Published: November 2012

Introduction

It is recommended that non-operative treatment of knee osteoarthritis (KOA) should be individually tailored and include multiple treatment modalities. Despite these recommendations, no one has yet investigated the efficacy of combining several non-surgical treatment modalities in a randomised controlled study. The purpose of this randomised controlled study is to examine if an optimised, combined non-surgical treatment programme results in greater improvements in pain, function and quality of life in comparison with usual care in patients with KOA who are not eligible for total knee arthroplasty (TKA).

Methods and analysis

This study will include 100 consecutive patients from the North Denmark Region not eligible for TKA with radiographic KOA (K-L grade ≥1) and mean pain during the previous week of ≤60 mm (0–100). The participants will be randomised to receive either a 12-week non-surgical treatment programme consisting of patient education, exercise, diet, insoles, paracetamol and/or NSAIDs or usual care (two information leaflets containing information on KOA and advice regarding the above non-surgical treatment). The primary outcome will be the change from baseline to 12 months on the self-report questionnaire Knee Injury and Osteoarthritis Outcome Score (KOOS)4defined as the average score for the subscale scores for pain, symptoms, activities of daily living and quality of life. Secondary outcomes include the five individual KOOS subscale scores, pain on a 100 mm Visual Analogue Scale, EQ-5D, self-efficacy, pain pressure thresholds, postural control and isometric knee flexion and knee extension strength.

Ethics and dissemination

This study was approved by the local Ethics Committee of The North Denmark Region (N-20110085) and the protocol conforms to the principles of the Declaration of Helsinki. Data collection will be completed by April 2014. Publications will be ready for submission in the summer of 2014.

Trial registration number

This study is registered withhttp://clinicaltrials.gov(NCT01535001).
Responses of native and invasive fishes to carbon dioxide: potential for a nonphysical barrier to fish dispersal
Authors: Kates Dan , Dennis Clark , Noatch Matthew R. , Suski Cory D.
Published: November 2012

Upon arrival in a novel environment, invasive species have the potential to cause negative consequences at their new location. Rather than try to eliminate invasive species after introduction, preventing their spread is a more efficient strategy to mitigate impact. The current study used a laboratory setting to quantify the efficacy of elevated carbon dioxide (CO2) in water to act as a nonphysical barrier to deter fish movement. Our focus was on deterring the movements of silver carp (Hypophthalmichthys molitrix) and bighead carp (Hypophthalmichthys nobilis), but largemouth bass (Micropterus salmoides) and bluegill (Lepomis macrochirus) were also examined to quantify the impact of elevated CO2on native species. Exposure of all species to 30 mg·L−1dissolved CO2for 1 h, compared with ambient CO2concentrations of 10 mg·L−1, resulted in an elevated stress response, along with alterations to ionic–osmotic balance. Exposure of fish to 70 mg·L−1CO2caused a reduction in ventilation rates after 1 h, while both silver carp and bighead carp lost equilibrium. Silver carp, largemouth bass, and bluegill also showed avoidance of CO2at approximately 100 mg·L−1. Together, results suggest that zones of elevated CO2have potential to deter the movement of fishes.
Comment on “Does timber harvest influence the dynamics of marine-derived nutrients in Southeast Alaska streams?” 1Original article by Levi et al. appears in Can. J. Fish. Aquat. Sci. 68(8): 1316–1329 and is available at http://www.nrcresearchpress.com/doi/full/10.1139/f2011-067. Reply by Levi et al. appears in Can. J. Fish. Aquat. Sci. 69: this issue, and is available at http://www.nrcresearchpress.com/doi/full/10.1139/f2012-106.
Authors: Jackson C. Rhett , Martin Douglas J.
Published: November 2012

Levi et al. (2011, Can. J. Fish. Aquat. Sci. 68: 1316–1329) related nutrient concentrations before, during, and after spawning, as well as various measures of channel morphology, to levels of prior timber harvest in seven watersheds on Prince of Wales Island in Southeast Alaska, USA. They assumed that single reaches of seven streams were otherwise similar and that other controls on channel morphology and nutrient dynamics could be ignored relative to the effects of prior timber harvest. In this commentary we show that the seven watersheds were not similar and that the sample set was too small to address geomorphic variability unrelated to timber harvest. Levi et al. failed to consider adequately the natural drivers of spatial and temporal variability in channel morphology and to consider stronger alternate hypotheses for observed channel conditions.
Chromatin diminution in the copepod Mesocyclops edax: elimination of both highly repetitive and nonhighly repetitive DNA
Authors: McKinnon Christian , Drouin Guy
Published: November 2012

Chromatin diminution, a developmentally regulated process of DNA elimination, is found in numerous eukaryotic species. In the copepod Mesocyclops edax, some 90% of its genomic DNA is eliminated during the differentiation of embryonic cells into somatic cells. Previous studies have shown that the eliminated DNA contains highly repetitive sequences. Here, we sequenced DNA fragments from pre- and postdiminution cells to determine whether nonhighly repetitive sequences are also eliminated during the process of chromatin diminution. Comparative analyses of these sequences, as well as the sequences eliminated from the genome of the copepod Cyclops kolensis, show that they all share similar abundances of tandem repeats, dispersed repeats, transposable elements, and various coding and noncoding sequences. This suggests that, in the chromatin diminution observed in M. edax, both highly repetitive and nonhighly repetitive sequences are eliminated and that there is no bias in the type of nonhighly repetitive DNA being eliminated.
Estimating extreme avalanche runout for the Columbia Mountains and Fernie area Rocky Mountains of British Columbia, Canada
Authors: Johnston Katherine S. , Jamieson Bruce , Jones Alan
Published: November 2012

Extreme snow avalanche runout is typically estimated using a combination of historical and vegetation records as well as statistical and dynamic models. The two classes of statistical models (α–β and runout ratio) are based on estimating runout distance past the β-point, which is typically defined as the point where the avalanche slope incline first decreases to 10°. The parameters for these models vary from mountain range to mountain range. In Canada, α–β and runout ratio parameters have been published for the combined Rocky and Purcell Mountains and for the British Columbia Coast Mountains. Despite active development, no suitable tall avalanche path model parameters have been published for the Columbia Mountains or for the Lizard Range area around Fernie, B.C. Using a dataset of 65 avalanche paths, statistical model parameters have been derived for these regions.
Evaluating modified Cam clay parameters from undrained triaxial compression data using targeted optimization
Authors: Doherty James , Alguire Helen , Muir Wood David
Published: November 2012

The widely used modified Cam clay soil model requires five soil parameters. In simulations of standard triaxial tests these parameters appear in certain combinations. An efficient and practical strategy for deriving these parameters is presented in which visual and numerical optimization techniques are used to estimate the values of these combinations in sequence. Selecting parameters using triaxial tests with stress levels similar to those expected to be important in the ground helps to ensure that the values are appropriate for the application and reduces the extent of the extrapolation required from the region of stress space explored in these tests.
STERILE NEUTRINOS AND PULSAR VELOCITIES REVISITED
Authors: KISSLINGER LEONARD S. , JOHNSON MIKKEL B.
Published: November 2012

We calculate the momentum given to a proto-neutron star during the first 10 s after temperature equilibrium is reached, using recent evidence of sterile neutrinos and a measurement of the mixing angle. This is a continuation of an earlier estimate with a wide range of possible mixing angles. Using the new mixing angle we find that sterile neutrinos can account for the observed pulsar velocities.
Definitive evidence using enucleated cytoplasts for a nongenomic basis for the cystic change in endoplasmic reticulum structure caused by STAT5a/b siRNAs
Authors: Lee Jason E. , Yang Yang-Ming , Yuan Huijuan , Sehgal Pravin B.
Published: November 2012

STAT5a/b species are well known as transcription factors that regulate nuclear gene expression. In a novel line of research in human pulmonary arterial endothelial cells (HPAECs), we previously observed that STAT5a associated with the Golgi apparatus and that siRNA-mediated knockdown of STAT5a/b led to the rapid development of a dramatic cystic change in the endoplasmic reticulum (ER) characterized by deposition along cyst membranes and tubule-to-cyst boundaries of the proteins reticulon-4 (RTN4; also called Nogo-B) and the ER-resident GTPase atlastin-3 (ATL3) and Golgi fragmentation. We now report that STAT5a can be observed in ER sheets in digitonin-permeabilized HPAECs and that anti-STAT5a cross- immunopanned ATL3 but not RTN4. Moreover, there was marked accumulation of the 63-kDa cytoskeleton-linking membrane protein and ER-spacer CLIMP63 (also called cytoskeleton-associated protein 4, CKAP4) and KDEL-mCherry within the cysts. That the STAT5a/b-siRNA-induced cystic ER phenotype developed in the presence of the transcription inhibitor 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB) had suggested that the mechanism was independent of the transcription factor functions of STAT5a/b, i.e., was “nongenomic.” We have now definitively tested the requirement for the nucleus in eliciting the STAT5a/b-siRNA-induced cystic ER phenotype. Enucleated HPAEC cytoplasts were prepared using adherent 35-mm cultures using the cytochalasin B-centrifugation method (typically yielding 65–75% enucleation). STAT5a/b siRNAs readily elicited the cystic ER phenotype including the marked luminal accumulation of CLIMP63 and Golgi fragmentation in the recovered HPAEC cytoplasts demonstrably lacking a nucleus. These studies provide unequivocal evidence using enucleated cytoplasts for a nongenomic mechanism(s) underlying the cystic change in ER structure elicited by STAT5a/b knockdown.
Pirfenidone inhibits macrophage infiltration in 5/6 nephrectomized rats
Authors: Chen Jun-Feng , Ni Hai-Feng , Pan Ming-Ming , Liu Hong , Xu Min , Zhang Ming-Hui , Liu Bi-Cheng
Published: November 2012

Tubulointerstitial macrophage infiltration is a hallmark of chronic kidney disease involved in the progression of renal fibrosis. Pirfenidone is a newly identified antifibrotic drug, the potential mechanism of which remains unclear. The aim of this study was to investigate the effects of pirfenidone on M1/M2 macrophage infiltration in nephrectomized rats. Nephrectomized rats were treated with pirfenidone by gavage for 12 wk. Twenty-four hour urinary protein, N-acetyl-β-d-glycosaminidase (NAG) activity, systolic blood pressure, and C-reactive protein were determined. Paraffin-embedded sections were stained for CD68, CCR7, and CD163 macrophages. Monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), as well as M1 and M2 macrophages secretory markers, were evaluated by real-time RT-PCR and Western blotting analysis. Pirfenidone significantly improved the elevated proteinuria and NAG activity from week 2 onward after surgery. Pirfenidone attenuated interstitial fibrosis and decreased expression of fibrotic markers including transforming growth factor-β1, connective tissue growth factor, α-smooth muscle actin, fibronectin, and fibroblast-specific protein-1. Pirfenidone significantly decreased the infiltrating macrophages. The number of M1 and M2 macrophages was significantly lower after pirfenidone treatment. MCP-1 and MIP-1α were increased in nephrectomized rats at mRNA and protein levels. Pirfenidone treatment significantly inhibited their expression. The TNF-α, IL-6, and nitric oxide synthases-2 expressed by M1 macrophages were increased in nephrectomized rats, and pirfenidone significantly attenuated their expression. Pirfenidone treatment also significantly decreased arginase-1, dectin-1, CD206, and CD86 expressed by M2 macrophages. Thus pirfenidone inhibits M1 and M2 macrophage infiltration in 5/6 nephrectomized rats, which suggests its efficacy in the early and late periods of renal fibrosis.
Cardiac mechanics are impaired during fatiguing exercise and cold pressor test in healthy older adults
Authors: Muller Matthew D. , Mast Jessica L. , Patel Hardikkumar , Sinoway Lawrence I.
Published: November 2012

We sought to determine how the aging left ventricle (LV) responds to sympathetic nervous system (SNS) activation. Three separate echocardiographic experiments were conducted in 11 healthy young (26 ± 1 yr) and 11 healthy older (64 ± 1 yr) adults. Tissue Doppler imaging was used to measure systolic myocardial velocity (Sm), early diastolic myocardial velocity (Em), and late diastolic myocardial velocity (Am) during isometric fatiguing handgrip (IFHG), a 2-min cold pressor test (CPT), and 5 min of normobaric hypoxia. Heart rate (HR) and mean arterial pressure (MAP) were also monitored on a beat-by-beat basis; rate pressure product (RPP) was used as an index of myocardial oxygen demand. At peak IFHG, the groups had similar increases in RPP, but the ΔSm was significantly greater (i.e., larger impairment) in the older subjects (−0.82 ± 0.13 cm/s) compared with the young subjects (0.37 ± 0.30 cm/s). At peak IFHG, the ΔEm was similar between older (−1.59 ± 0.68 cm/s) and young subjects (−1.06 ± 0.76 cm/s). In response to the CPT, both Sm and Em were reduced in the older adults but did not change relative to baseline in the young subjects. Normobaric hypoxia elevated HR and RPP in both groups but did not alter Tissue Doppler parameters. These data indicate that Sm and Em are reduced in healthy older adults during IFHG and CPT. We speculate that suboptimal LV adaptations to SNS stress may partly explain why acute heavy exertion can trigger myocardial ischemia.
Cooling reduces the cutaneous afferent firing response to vibratory stimuli in glabrous skin of the human foot sole
Authors: Lowrey Catherine R. , Strzalkowski Nicholas D. J. , Bent Leah R.
Published: November 2012

Skin on the foot sole plays an important role in postural control. Cooling the skin of the foot is often used to induce anesthesia to determine the role of skin in motor and balance control. The effect of cooling on the four classes of mechanoreceptor in the skin is largely unknown, and thus the aim of the present study was to characterize the effects of cooling on individual skin receptors in the foot sole. Such insight will better isolate individual receptor contributions to balance control. Using microneurography, we recorded 39 single nerve afferents innervating mechanoreceptors in the skin of the foot sole in humans. Afferents were identified as fast-adapting (FA) or slowly adapting (SA) type I or II (FA I n = 16, FA II n = 7, SA I n = 6, SA II n = 11). Receptor response to vibration was compared before and after cooling of the receptive field (2–20 min). Overall, firing response was abolished in 30% of all receptors, and this was equally distributed across receptor type ( P = 0.69). Longer cooling times were more likely to reduce firing response below 50% of baseline; however, some afferent responses were abolished with shorter cooling times (2–5 min). Skin temperature was not a reliable indicator of the level of receptor activation and often became uncoupled from receptor response levels, suggesting caution in the use of this parameter as an indicator of anesthesia. When cooled, receptors preferentially coded lower frequencies in response to vibration. In response to a sustained indentation, SA receptors responded more like FA receptors, primarily coding “on-off” events.
Network interneurons underlying ciliary locomotion inHermissenda
Authors: Crow Terry , Jin Nan Ge , Tian Lian-Ming
Published: November 2012

In the nudibranch mollusk Hermissenda, ciliary locomotion contributes to the generation of two tactic behaviors. Light elicits a positive phototaxis, and graviceptive stimulation evokes a negative gravitaxis. Two classes of light-responsive premotor interneurons in the network contributing to ciliary locomotion have been recently identified in the cerebropleural ganglia. Aggregates of type I interneurons receive monosynaptic excitatory (Ie) or inhibitory (Ii) input from identified photoreceptors. Type II interneurons receive polysynaptic excitatory (IIe) or inhibitory (IIi) input from photoreceptors. The ciliary network also includes type III inhibitory (IIIi) interneurons, which form monosynaptic inhibitory connections with ciliary efferent neurons (CENs). Illumination of the eyes evokes a complex inhibitory postsynaptic potential, a decrease of Iispike activity, a complex excitatory postsynaptic potential, and an increase of Iespike activity. Here, we characterized the contribution of identified I, II, and IIIiinterneurons to the neural network supporting visually guided locomotion. In dark-adapted preparations, light elicited an increase in the tonic spike activity of IIeinterneurons and a decrease in the tonic spike activity of IIiinterneurons. Fluorescent dye-labeled type II interneurons exhibited diverse projections within the circumesophageal nervous system. However, a subclass of type II interneurons, IIe(cp)and IIi(cp)interneurons, were shown to terminate within the ipsilateral cerebropleural ganglia and indirectly modulate the activity of CENs. Type II interneurons form monosynaptic or polysynaptic connections with previously identified components of the ciliary network. The identification of a monosynaptic connection between Ieand IIIiinterneurons shown here suggest that they provide a major role in the light-dependent modulation of CEN spike activity underlying ciliary locomotion.
Hemispheric differences in the control of limb dynamics: a link between arm performance asymmetries and arm selection patterns
Authors: Coelho Chase J. , Przybyla Andrzej , Yadav Vivek , Sainburg Robert L.
Published: November 2012

Human handedness has been described and measured from two perspectives: handedness inventories rate hand preferences, whereas other tests examine motor performance asymmetries. These two measurement approaches reflect a major controversy in a literature that defines handedness as either a preference or an asymmetry in sensorimotor processing. Over the past decade, our laboratory has developed a model of handedness based on lateralization of neural processes. This model attributes distinct control processes to each hemisphere, which in turn lead to observable interlimb sensorimotor performance asymmetries. We now hypothesize that arm preference, or choice, may depend on the interaction between sensorimotor performance asymmetries and the given task. The purpose of this study is to examine whether arm selection is linked to interlimb performance asymmetries during reaching. Right-handed subjects made choice and nonchoice reaches to each of eight targets ( d = 3.5 cm) arranged radially ( r = 13 cm) around a midline starting position. We displaced each cursor (one associated with each hand) 30 cm to the midline start circle to ensure that there were no hemispace-related geometric, mechanical, or perceptual biases to use either arm for the two midline targets. The three targets on each side of the midline received mostly reaches from the ipsilateral arm, a tendency previously described as a “hemispace bias.” However, the midline targets, which were equidistant from each hand, received more dominant arm reaches. Dominant arm hand paths to these targets were straighter and more accurately directed. Inverse dynamics analyses revealed a more proficient dominant arm strategy that exploited intersegmental dynamics to a greater extent than did the nondominant arm. These findings suggest that sensorimotor asymmetries in dynamic coordination might explain limb choices. We discuss the implications of these results for theories of action selection, models of handedness, and models of neural lateralization.
A Preclinical Mouse Model of Invasive Lobular Breast Cancer Metastasis
Authors: Doornebal Chris W. , Klarenbeek Sjoerd , Braumuller Tanya M. , Klijn Christiaan N. , Ciampricotti Metamia , Hau Cheei-Sing , Hollmann Markus W. , Jonkers Jos , de Visser Karin E.
Published: November 2012

Metastatic disease accounts for more than 90% of cancer-related deaths, but the development of effective antimetastatic agents has been hampered by the paucity of clinically relevant preclinical models of human metastatic disease. Here, we report the development of a mouse model of spontaneous breast cancer metastasis, which recapitulates key events in its formation and clinical course. Specifically, using the conditional K14cre;Cdh1F/F;Trp53F/F model of de novo mammary tumor formation, we orthotopically transplanted invasive lobular carcinoma (mILC) fragments into mammary glands of wild-type syngeneic hosts. Once primary tumors were established in recipient mice, we mimicked the clinical course of treatment by conducting a mastectomy. After surgery, recipient mice succumbed to widespread overt metastatic disease in lymph nodes, lungs, and gastrointestinal tract. Genomic profiling of paired mammary tumors and distant metastases showed that our model provides a unique tool to further explore the biology of metastatic disease. Neoadjuvant and adjuvant intervention studies using standard-of-care chemotherapeutics showed the value of this model in determining therapeutic agents that can target early- and late-stage metastatic disease. In obtaining a more accurate preclinical model of metastatic lobular breast cancer, our work offers advances supporting the development of more effective treatment strategies for metastatic disease. Cancer Res; 73(1); 353–63. ©2012 AACR.
Targeting Truncated Retinoid X Receptor-α by CF31 Induces TNF-α–Dependent Apoptosis
Authors: Wang Guang-Hui , Jiang Fu-Quan , Duan Ying-Hui , Zeng Zhi-Ping , Chen Fan , Dai Yi , Chen Jie-Bo , Liu Jin-Xing , Liu Jie , Zhou Hu , Chen Hai-Feng , Zeng Jin-Zhang , Su Ying , Yao Xin-Sheng , Zhang Xiao-Kun
Published: November 2012

A truncated version of retinoid X receptor-α, tRXR-α, promotes cancer cell survival by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway. However, targeting the tRXR-α–mediated survival pathway for cancer treatment remains to be explored. We report here our identification of a new natural product molecule, CF31, a xanthone isolated from Cratoxylum formosum ssp. pruniflorum, and the biologic evaluation of its regulation of the tRXR-α–mediated PI3K/AKT pathway. CF31 binds RXR-α and its binding results in inhibition of RXR-α transactivation. Through RXR-α mutational analysis and computational studies, we show that Arg316 of RXR-α, known to form salt bridges with certain RXR-α ligands, such as 9-cis-retinoic acid (9-cis-RA), is not required for the antagonist effect of CF31, showing a distinct binding mode. Evaluation of several CF31 analogs suggests that the antagonist effect is mainly attributed to an interference with Leu451 of helix H12 in RXR-α. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNF-α, it suppresses TNF-α activation of AKT by inhibiting TNF-α–induced tRXR-α interaction with the p85α regulatory subunit of PI3K. CF31 inhibition of TNF-α activation of AKT also results in TNF-α–dependent activation of caspase-8 and apoptosis. Together, our results show that CF31 is an effective converter of TNF-α signaling from survival to death by targeting tRXR-α in a unique mode and suggest that identification of a natural product that targets an RXR-mediated cell survival pathway that regulates PI3K/AKT may offer a new therapeutic strategy to kill cancer cells. Cancer Res; 73(1); 307–18. ©2012 AACR.
Reduced Overall and Event-Free Survival among Colon Cancer Patients Using Dual System Care
Authors: Tarlov Elizabeth , Lee Todd A. , Weichle Thomas W. , Durazo-Arvizu Ramon , Zhang Qiuying , Perrin Ruth , Bentrem David , Hynes Denise M.
Published: November 2012

Background: Many veterans have dual Veterans Administration (VA) and Medicare healthcare coverage. We compared 3-year overall and cancer event-free survival (EFS) among patients with nonmetastatic colon cancer who obtained substantial portions of their care in both systems and those whose care was obtained predominantly in the VA or in the Medicare fee-for-service system.

Methods: We conducted a retrospective observational cohort study of patients older than 65 years with stages I to III colon cancer diagnosed from 1999 to 2001 in VA and non-VA facilities. Dual use of VA and non-VA colon cancer care was categorized as predominantly VA use, dual use, or predominantly non-VA use. Extended Cox regression models evaluated associations between survival and dual use.

Results: VA and non-VA users (all stages) had reduced hazard of dying compared with dual users [e.g., for stage I, VA HR 0.40, 95% confidence interval (CI): 0.28–0.56; non-VA HR 0.54, 95% CI: 0.38–0.78). For EFS, stage I findings were similar (VA HR 0.47, 95% CI: 0.35–0.62; non-VA HR 0.64, 95% CI: 0.47–0.86). Stage II and III VA users, but not non-VA users, had improved EFS (stage II: VA HR 0.74, 95% CI: 0.56–0.97; non-VA HR 0.92, 95% CI: 0.69–1.22; stage III: VA HR 0.73, 95% CI: 0.56–0.94; non-VA HR 0.81, 95% CI: 0.62–1.06).

Conclusions: Improved survival among VA and non-VA compared with dual users raises questions about coordination of care and unmet needs.

Impact: Additional study is needed to understand why these differences exist, why patients use both systems, and how systems may be improved to yield better outcomes in this population. Cancer Epidemiol Biomarkers Prev; 21(12); 2231–41. ©2012 AACR.
Common Obesity-Related Genetic Variants and Papillary Thyroid Cancer Risk
Authors: Kitahara Cari M. , Neta Gila , Pfeiffer Ruth M. , Kwon Deukwoo , Xu Li , Freedman Neal D. , Hutchinson Amy A. , Chanock Stephen J. , Sturgis Erich M. , Sigurdson Alice J. , Brenner Alina V.
Published: November 2012

Background: Epidemiologic studies have shown consistent associations between obesity and increased thyroid cancer risk, but, to date, no studies have investigated the relationship between thyroid cancer risk and obesity-related single-nucleotide polymorphisms (SNP).

Methods: We evaluated 575 tag SNPs in 23 obesity-related gene regions in a case–control study of 341 incident papillary thyroid cancer (PTC) cases and 444 controls of European ancestry. Logistic regression models, adjusted for attained age, year of birth, and sex were used to calculate ORs and 95% confidence intervals (CI) with SNP genotypes, coded as 0, 1, and 2 and modeled continuously to calculate Ptrend.

Results: Nine of 10 top-ranking SNPs (Ptrend < 0.01) were located in the FTO (fat mass and obesity associated) gene region, whereas the other was located in INSR (insulin receptor). None of the associations were significant after correcting for multiple testing.

Conclusions: Our data do not support an important role of obesity-related genetic polymorphisms in determining the risk of PTC.

Impact: Factors other than selected genetic polymorphisms may be responsible for the observed associations between obesity and increased PTC risk. Cancer Epidemiol Biomarkers Prev; 21(12); 2268–71. ©2012 AACR.
Gender Difference in Systemic Oxidative Stress and Antioxidant Capacity in Current and Former Heavy Smokers
Authors: Hakim Iman A. , Harris Robin , Garland Linda , Cordova Catherine A. , Mikhael Dalia M. , Sherry Chow H-H.
Published: November 2012

Background: Several studies suggested that women may be more susceptible to oxidative damage induced by cigarette smoking, but the role of smoking status and antioxidant capacity in gender difference in susceptibility to oxidative damage has not been well studied.

Methods: We conducted a cross-sectional analysis of the baseline data from 146 current and former heavy smokers enrolled in a chemoprevention trial to determine the gender difference in oxidative damage and antioxidant capacity. Oxidative DNA and lipid damage were assessed by urinary 8-hydroxy-2′-deoxyguanosine (8OHdG) and 8-isoprostaglandin F2α (8-iso-PGF2α), respectively. The erythrocyte antioxidant enzymes and serum fat-soluble antioxidants were measured to assess antioxidant capacity.

Results: Female smokers had significantly greater levels of 8OHdG and 8-iso-PGF2α than males but the gender difference was only significant in current smokers. No gender difference was noted in erythrocyte antioxidant enzymes, although female current smokers had significantly lower or a trend for lower antioxidant enzymes. Female smokers had higher serum β-carotene than males. Biomarkers of oxidative damage did not correlate significantly with the antioxidant enzymes. Urinary 8OHdG did not correlate significantly with fat-soluble antioxidants. Inverse correlations were observed between urinary 8-iso-PGF2α and several serum carotenoids.

Conclusion: Female current smokers have a greater extent of oxidative damage despite having higher serum levels of fat-soluble antioxidants. Lower erythrocyte antioxidant enzymes in female current smokers may contribute to the greater extent of oxidative damage.

Impact: The study may help identify appropriate high-risk populations for interventions that attenuate oxidative damage and appropriate biomarkers for clinical studies in smokers. Cancer Epidemiol Biomarkers Prev; 21(12); 2193–200. ©2012 AACR.
HPV Vaccination among Adolescent Females from Appalachia: Implications for Cervical Cancer Disparities
Authors: Reiter Paul L. , Katz Mira L. , Paskett Electra D.
Published: November 2012

Background: Appalachia is a geographic region with high cervical cancer incidence and mortality rates, yet little is known about human papillomavirus (HPV) vaccination in this region. We determined HPV vaccine coverage among adolescent females from Appalachia, made comparisons to non-Appalachian females, and examined how coverage differs across subregions within Appalachia.

Methods: We analyzed data from the National Immunization Survey-Teen 2008–2010 for adolescent females ages 13–17 (n = 1,951, Appalachian females and n = 25,468, non-Appalachian females). We examined HPV vaccine initiation (receipt of at least one dose), completion (receipt of at least three doses), and follow-through (completion among initiators). Analyses used weighted logistic regression.

Results: HPV vaccine initiation [Appalachian = 40.8% vs. non-Appalachian = 43.6%; OR, 0.92; 95% confidence interval (CI), 0.79–1.07] and completion (Appalachian = 27.7% vs. non-Appalachian = 25.3%; OR, 1.12; 95% CI, 0.95–1.32) were similar between Appalachian and non-Appalachian females. HPV vaccine follow-through was higher among Appalachian females than non-Appalachian females (67.8% vs. 58.1%; OR, 1.36; 95% CI, 1.07–1.72). Vaccination outcomes tended to be higher in the Northern (completion and follow-through) and South Central (follow-through) subregions of Appalachia compared with non-Appalachian United States. Conversely, vaccination outcomes tended to be lower in the Central (initiation and completion) and Southern (initiation and completion) subregions.

Conclusions: In general, HPV vaccination in Appalachia is mostly similar to the rest of the United States. However, vaccination is lagging in regions of Appalachia where cervical cancer incidence and mortality rates are highest.

Impact: Current cervical cancer disparities could potentially worsen if HPV vaccine coverage is not improved in regions of Appalachia with low HPV vaccine coverage. Cancer Epidemiol Biomarkers Prev; 21(12); 2220–30. ©2012 AACR.
Age-Dependent Associations between Androgenetic Alopecia and Prostate Cancer Risk
Authors: Muller David C. , Giles Graham G. , Sinclair Rod , Hopper John L. , English Dallas R. , Severi Gianluca
Published: November 2012

Background: Both prostate cancer and androgenetic alopecia are strongly age-related conditions that are considered to be androgen dependent, but studies of the relationship between them have yielded inconsistent results. We aimed to assess whether androgenetic alopecia at ages 20 and 40 years are associated with risk of prostate cancer.

Methods: At a follow-up of the Melbourne Collaborative Cohort Study, men were asked to assess their hair pattern at ages 20 and 40 years relative to eight categories in showcards. Cases were men notified to the Victorian Cancer Registry with prostate cancer diagnosed between cohort enrollment (1990–1994) and follow-up attendance (2003–2009). Flexible parametric survival models were used to estimate age-varying HRs and predicted cumulative probabilities of prostate cancer by androgenetic alopecia categories.

Results: Of 9,448 men that attended follow-up and provided data on androgenetic alopecia, we identified 476 prostate cancer cases during a median follow-up of 11 years four months. Cumulative probability of prostate cancer was greater at all ages up to 76 years, for men with vertex versus no androgenetic alopecia at age of 40 years. At age of 76 years, the estimated probabilities converged to 0.15. Vertex androgenetic alopecia at 40 years was also associated with younger age of diagnosis for prostate cancer cases.

Conclusions: Vertex androgenetic alopecia at age of 40 years might be a marker of increased risk of early-onset prostate cancer.

Impact: If confirmed, these results suggest that the apparently conflicting findings of previous studies might be explained by failure to adequately model the age-varying nature of the association between androgenetic alopecia and prostate cancer. Cancer Epidemiol Biomarkers Prev; 22(2); 209–15. ©2012 AACR.
Protective Effects of Low Calcium Intake and Low Calcium Absorption Vitamin D Receptor Genotype in the California Collaborative Prostate Cancer Study
Authors: Rowland Glovioell W. , Schwartz Gary G. , John Esther M. , Ingles Sue Ann
Published: November 2012

Background: High calcium intake is consistently associated with increased prostate cancer risk in epidemiologic studies. We previously reported that the positive association between calcium intake and risk of aggressive prostate cancer was modified by the single-nucleotide polymorphism (SNP) in the CDX-2 binding site of the vitamin D receptor (VDR) gene, among African American men.

Methods: We expanded our previous study to include White men, a population with a higher calcium intake and a higher prevalence of the low absorption allele. We also examined VDR polymorphisms at other loci unrelated to calcium absorption. The study included 1,857 prostate cancer cases (1,140 with advanced stage at diagnosis, 717 with localized stage) and 1,096 controls. OR were estimated using conditional logistic regression.

Results: Among both Blacks and Whites, we observed a threshold for calcium intake (604 mg/d) below which prostate cancer risk declined sharply. Low calcium intake was most strongly associated with decreased risk among men with the VDR Cdx2 low calcium absorption genotype (P for interaction = 0.001 and P = 0.06 for Whites and African Americans, respectively). Among all men with this genotype, those in the lowest quartile of calcium intake (≤604 mg/d) had a 50% reduction in risk as compared with those in the upper three quartiles [OR = 0.49; 95% confidence interval (CI), 0.36–0.67]. The association between calcium intake and prostate cancer risk was not modified by genotype at other VDR loci.

Conclusions: Our findings support the hypothesis that genetic determinants of calcium absorption influence prostate cancer risk.

Impact: The differences between African Americans and Whites in calcium absorption and dietary calcium intake may contribute to racial disparities in prostate cancer incidence and mortality rates. Cancer Epidemiol Biomarkers Prev; 22(1); 16–24. ©2012 AACR.
False Positives in Cancer Epidemiology
Authors: McLaughlin Joseph K. , Tarone Robert E.
Published: November 2012

Background: A recent attempt to estimate the false-positive rate for cancer epidemiology studies is based on agents in International Agency for Research on Cancer (IARC) category 3 (agent not classifiable as to its carcinogenicity to humans) in the IARC Monographs Program.

Methods: The estimation method is critiqued regarding biases caused by its reliance on the IARC classification criteria for assessing carcinogenic potential.

Results: The privileged position given to epidemiologic studies by the IARC criteria ensures that the percentage of positive epidemiologic studies for an agent will depend strongly on the IARC category to which the agent is assigned. Because IARC category 3 is composed of agents with the lowest-assessed carcinogenic potential to which the estimation approach in question could be applied, a spuriously low estimated false-positive rate was necessarily the outcome of this approach.

Conclusions: Tendentious estimation approaches like that employed will by necessity produce spuriously low and misleading false positive rates.

Impact: The recently reported estimates of the false-positive rate in cancer epidemiology are seriously biased and contribute nothing substantive to the literature on the very real problems related to false-positive findings in epidemiology. Cancer Epidemiol Biomarkers Prev; 22(1); 11–15. ©2012 AACR.
Knowledge Integration in Cancer: Current Landscape and Future Prospects
Authors: Ioannidis John P.A. , Schully Sheri D. , Lam Tram Kim , Khoury Muin J.
Published: November 2012

Knowledge integration includes knowledge management, synthesis, and translation processes. It aims to maximize the use of collected scientific information and accelerate translation of discoveries into individual and population health benefits. Accumulated evidence in cancer epidemiology constitutes a large share of the 2.7 million articles on cancer in PubMed. We examine the landscape of knowledge integration in cancer epidemiology. Past approaches have mostly used retrospective efforts of knowledge management and traditional systematic reviews and meta-analyses. Systematic searches identify 2,332 meta-analyses, about half of which are on genetics and epigenetics. Meta-analyses represent 1:89-1:1162 of published articles in various cancer subfields. Recently, there are more collaborative meta-analyses with individual-level data, including those with prospective collection of measurements [e.g., genotypes in genome-wide association studies (GWAS)]; this may help increase the reliability of inferences in the field. However, most meta-analyses are still done retrospectively with published information. There is also a flurry of candidate gene meta-analyses with spuriously prevalent “positive” results. Prospective design of large research agendas, registration of datasets, and public availability of data and analyses may improve our ability to identify knowledge gaps, maximize and accelerate translational progress or—at a minimum—recognize dead ends in a more timely fashion. Cancer Epidemiol Biomarkers Prev; 22(1); 3–10. ©2012 AACR.
Molecular Pathways: Regulation of Metabolism by RB
Authors: Clem Brian F. , Chesney Jason
Published: November 2012

The discovery of the retinoblastoma (RB-1) gene as a tumor suppressor that is disrupted in a majority of human cancers either via direct or indirect genetic alterations has resulted in increased interest in its functions and downstream effectors. Although the canonical pathway that links this tumor suppressor to human cancers details its interaction with the E2F transcription factors and cell-cycle progression, recent studies have shown an essential role for RB-1 in the suppression of glycolytic and glutaminolytic metabolism. Characterization of the precise metabolic transporters and enzymes suppressed by the RB-E2F axis should enable the identification of small molecule antagonists that have selective and potent antitumor properties. Clin Cancer Res; 18(22); 6096–100. ©2012 AACR.
Predictors of Mortality in 6975 Patients With Chronic Heart Failure in the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico-Heart Failure Trial
Authors: Barlera Simona , Tavazzi Luigi , Franzosi Maria Grazia , Marchioli Roberto , Raimondi Elena , Masson Serge , Urso Renato , Lucci Donata , Nicolosi Gian Luigi , Maggioni Aldo P. , Tognoni Gianni
Published: November 2012

Background—

We developed a prognostic model to assess the risk of all-cause mortality in patients with chronic heart failure.

Methods and Results—

We examined 6975 patients with chronic heart failure enrolled in the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico-Heart Failure (GISSI-HF) trial (3.9 years follow-up). Multivariable Cox regression models were developed to predict mortality (1969 deaths). By stepwise selection, the full final model included 25 predictors. A reduced model, considering the most significant variables ranked according to the Wald χ
2
(
P
<0.0001) accounted for most of the prognostic information. Internal validation of the model was performed with bootstrap techniques. The discrimination ability of the reduced model constituted by 12 factors (concordance probability estimate, 0.693) was as good as the full final model (concordance probability estimate, 0.70). Among the first 12 independent risk factors emerging in the reduced model, the 3 most powerful predictors were older age, higher New York Heart Association class, and lower estimated glomerular filtration rate. Other independent predictors that increased risk included lower left ventricular ejection fraction, chronic obstructive pulmonary disease, lower systolic blood pressure, diabetes mellitus, male sex, higher uricemia, lower body mass index, lower hemoglobin, and aortic stenosis. The reduced model was used to build a nomogram to estimate the risk of death in individual patients. In a subgroup of patients, the 2 well-known biomarkers (high-sensitivity cardiac troponin T and N-terminal pro-brain natriuretic peptide) emerged as the most powerful predictors of outcome.

Conclusions—

In a large contemporary population with chronic heart failure, this model offers good ability to assess the risk of death, confirming most of the risk factors that have emerged in recent trials.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00336336.
Hemodynamic Determinants of Dyspnea Improvement in Acute Decompensated Heart Failure
Authors: Solomonica Amir , Burger Andrew J. , Aronson Doron
Published: November 2012

Background—

Dyspnea relief constitutes a major treatment goal and a key measure of treatment efficacy in decompensated heart failure. However, there are no data with regard to the relationship between hemodynamic measurements during treatment and dyspnea improvement.

Methods and Results—

We studied 233 patients assigned to right heart catheterization in the Vasodilation in the Management of Acute Congestive Heart Failure trial. Dyspnea (assessed using a 7-point Likert scale) and hemodynamic parameters were measured simultaneously at 15 and 30 minutes and 1, 2, 3, 6, and 24 hours. Dyspnea relief was defined as moderate or marked improvement. There was a time-dependent association between the reductions in pulmonary capillary wedge pressure (PCWP; 25.4, 24.6, 24.0, 23.5, 23.4, 21.5, and 19.9 mm Hg) and the percentage of patients achieving dyspnea relief (17.7%, 24.6%, 32.2%, 36.2%, 37.8%, 47.4%, and 66.1%, in the respective time points). Multivariable logistic generalized estimating equations modeling demonstrated that reductions of both PCWP and mean pulmonary artery pressure were independently associated with dyspnea relief. Compared with the highest PCWP quartile, the adjusted odds ratios for dyspnea relief were 0.92 (95% confidence interval [CI], 0.67–1.29), 1.07 (95% CI, 0.75–1.55), and 1.80 (95% CI, 1.22–2.65) in the third, second, and first PCWP quartiles, respectively (
P

trend

=0.003). Compared with the highest mean pulmonary artery pressure quartile, the adjusted odds ratios for dyspnea relief were 2.0 (95% CI, 1.41–2.82), 2.23 (95% CI, 1.52–3.27), and 2.98 (95% CI, 1.91–4.66) in the third, second, and first mean pulmonary artery pressure quartiles, respectively (
P
trend
<0.0001).

Conclusions—

A clinically significant improvement in dyspnea is associated with a reduction in both PCWP and mean pulmonary artery pressure.
The Lake of Black Swans—Attractors as a Source of Emergent Meaning
Authors: Tresilian Nicholas
Published: November 2012

Abstract

The conventional Western understanding of communication is profoundly asymmetric, biased towards a formal concept of communication as a one-way distribution of meaning from a Sender to a Receiver—the view enshrined in the Information Theory of Claude Shannon and implicit in Dawkins’ theory of the meme as a semantic replicator. Rational communication in the form of science has been singularly successful in identifying the probable and predictable, and thus in revealing nature’s laws. For the same reason rationality is fundamentally inadequate as the basis for a discourse with our chaotic planetary environment, where the probable and predictable are always in conflict with the improbable and unpredictable . . . a veritable lake of black swans (Taleb 2008).

The paper suggests that for our species to survive in that increasingly turbid lake we will need a more inclusive understanding of communication, taking into account both rational and relational communication, both the analytic and syncretic forms of meaning. The paper argues that the emergent forms of relational meaning have the potential to offer a more effective engagement with global risk than the predictive forms of the rational.
Evolution and Emergence: A Re-Evaluation of the “New Synthesis”
Authors: Crawford Michael James
Published: November 2012

Abstract

The modern obsession with methodological reductionism in some areas of biology is arguably a product of the exquisitely precise tools now available to dissect problems. Reductionist approaches assume that an understanding of atomized parts will be sufficient to approximate an understanding of the whole. Ironically, the sheer success of this approach and the consequent volume of data generated, particularly as a result of the genome projects, has made comprehension of the larger picture problematic. Consequently, historical patterns of more phenomenologically oriented analyses are re-emerging. This impulse is not new: Gould and Lewontin (1979) argued for a less reductionist view of evolution. They argue that an intense focus upon individual traits risks confusing evolutionary selection with the indirect consequences of other architectural decisions. They also argued that the “baggage” of ancestral traits constrains future possibilities for profound change. The “New Synthesis”, a more recent convergence of paleontology, evolutionary biology, genome science, and embryology provides fertile ground for their critique. New approaches to genome analysis and gene categorization have shown that profound inter-species similarities underlie a generic and robust body plan upon which variant morphologies are built. Moreover, phenomenologically oriented approaches have recently revealed functional and organizational similarities among diverse genomes that are indicative of large and preserved gene regulatory behaviours: genomes appear to be organized into similar regulatory blocks irrespective of species. The implications of these recent discoveries suggest that emergent organizational and functional properties of genomes could impose big constraints upon morphological innovation. They might also explain some of the curious and profound examples of convergent evolution that puzzled Darwin.