bluuebunny/crossref_metadata_2025_split huggingface dataset:
META-MONOIDS, META-BICROSSED PRODUCTS, AND THE ALEXANDER POLYNOMIAL
Authors: BAR-NATAN DROR , SELMANI SAM 
Published: September 2013

We introduce a new invariant of tangles along with an algebraic framework in which it is to be interpreted. We claim that the invariant contains the classical Alexander polynomial of knots and its multivariable extension to links. We argue that of the computationally efficient members of the family of Alexander invariants, it is the most meaningful. These are lecture notes for talks given by the first author, written and completed by the second. The talks, with handouts and videos, are available at http://www.math.toronto.edu/drorbn/Talks/Regina-1206/ . See also further comments at http://www.math.toronto.edu/drorbn/Talks/Caen-1206/#June8 .
Bispecific Antibody to ErbB2 Overcomes Trastuzumab Resistance through Comprehensive Blockade of ErbB2 Heterodimerization
Authors: Li Bohua , Meng Yanchun , Zheng Lei , Zhang Xunmin , Tong Qing , Tan Wenlong , Hu Shi , Li Hui , Chen Yang , Song Jinjing , Zhang Ge , Zhao Lei , Zhang Dapeng , Hou Sheng , Qian Weizhu , Guo Yajun 
Published: September 2013

Abstract
The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. However, resistance to trastuzumab is common. Heterodimerization between ErbB2 and other ErbBs may redundantly trigger cell proliferation signals and confer trastuzumab resistance. Here, we developed a bispecific anti-ErbB2 antibody using trastuzumab and pertuzumab, another ErbB2-specific humanized antibody that binds to a distinct epitope from trastuzumab. This bispecific antibody, denoted as TPL, retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule. Unexpectedly, TPL showed superior ErbB2 heterodimerization-blocking activity over the combination of both parental monoclonal antibodies, possibly through steric hindrance and/or inducing ErbB2 conformational change. Further data indicated that TPL potently abrogated ErbB2 signaling in trastuzumab-resistant breast cancer cell lines. In addition, we showed that TPL was far more effective than trastuzumab plus pertuzumab in inhibiting the growth of trastuzumab-resistant breast cancer cell lines, both in vitro and in vivo. Importantly, TPL treatment eradicated established trastuzumab-resistant tumors in tumor-bearing nude mice. Our results suggest that trastuzumab-resistant breast tumors remain dependent on ErbB2 signaling and that comprehensive blockade of ErbB2 heterodimerization may be an effective therapeutic avenue. The unique potential of TPL to overcome trastuzumab resistance warrants its consideration as a promising treatment in the clinic. Cancer Res; 73(21); 6471–83. ©2013 AACR.
Impact of Cardiovascular Comorbidity on Ovarian Cancer Mortality
Authors: Shinn Eileen H. , Lenihan Daniel J. , Urbauer Diana L. , Basen-Engquist Karen M. , Valentine Alan , Palmero Laura , Woods Myrshia L. , Patel Pooja , Nick Alpa M. , Shahzad Mian M.K. , Stone Rebecca L. , Golden Antoinette , Atkinson Emma , Lutgendorf Susan K. , Sood Anil K. 
Published: September 2013

Abstract
Background: A retrospective cohort study utilizing prospectively collected data was conducted from August 2003 until March 2008 at M.D. Anderson Cancer Center. It is unknown whether cardiovascular comorbidity and chronic stress impact ovarian cancer outcome, which remains poor despite advances in therapy. The purpose of this study was to determine whether cardiovascular disease and markers that may be associated with stress are also associated with survival in patients with ovarian cancer.
Methods: Participants with newly diagnosed epithelial ovarian cancer were followed until time of death or truncation of study period (median follow-up = 4.2 years; n = 271). Tumor characteristics (stage, tumor grade, histology, debulking status), demographic variables, and cardiovascular comorbidity were documented and compared to overall survival.
Results: Of the nine cardiovascular events tracked during follow-up, venous thromboembolism [VTE; HR, 3.2; 95% confidence interval (CI), 1.8–5.5] and pulmonary hypertension (HR, 8.5; 95% CI, 3.9–18.7) were associated with shorter survival in multivariate analysis. In addition, high tumor grade, suboptimal cytoreduction, and baseline heart rate (HR, 1.02; 95% CI, 1.01–1.04) were related to decreased survival.
Conclusion: Careful management of certain cardiovascular comorbidities may extend survival in patients with ovarian cancer. Our findings suggest that increased baseline heart rate and the development of VTE and pulmonary hypertension after cancer diagnosis may be significant predictors of survival in women with ovarian cancer.
Impact: Our study emphasizes the importance of identifying and optimally treating tachycardia, VTE, and pulmonary hypertension in conjunction with cancer therapy. Cancer Epidemiol Biomarkers Prev; 22(11); 2102–9. ©2013 AACR.
Genetic Variation in the Inflammation and Innate Immunity Pathways and Colorectal Cancer Risk
Authors: Wang Hansong , Taverna Darin , Stram Daniel O. , Fortini Barbara K. , Cheng Iona , Wilkens Lynne R. , Burnett Terrilea , Makar Karen W. , Lindor Noralane M. , Hopper John L. , Gallinger Steve , Baron John A. , Haile Robert , Kolonel Laurence N. , Henderson Brian E. , Newcomb Polly A. , Casey Graham , Duggan David , Ulrich Cornelia M. , Le Marchand Loïc 
Published: September 2013

AbstractBackground: It is widely accepted that chronic inflammation plays a role in the etiology of colorectal cancer. Using a two-stage design, we examined the associations between colorectal cancer and common variation in 37 key genes in the inflammation and innate immunity pathways.Methods: In the discovery stage, 2,322 discordant sibships (2,535 cases, 3,915 sibling controls) from the Colorectal Cancer Family Registry were genotyped for more than 600 tagSNPs and 99 single-nucleotide polymorphisms (SNP) were selected for further examination based on strength of association. In the second stage, 351 SNPs tagging gene regions covered by the 99 SNPs were tested in 4,783 Multiethnic Cohort subjects (2,153 cases, 2,630 controls).Results: The association between rs9858822 in the PPARG gene and colorectal cancer was statistically significant at the end of the second stage (OR per allele = 1.36, Bonferroni-adjusted P = 0.045), based on the “effective” number of markers in stage II (n = 306). The risk allele C was common (frequency 0.3) in African Americans but rare (frequency &lt; 0.03) in whites, Japanese Americans, Latinos, and Native Hawaiians. No statistically significant heterogeneity of effects across race/ethnicity, body mass index (BMI) levels, regular aspirin use, or pack-years of smoking was detected for this SNP. Suggestive associations were also observed for several SNPs in close vicinity to rs9858822.Conclusions: Our results provide new evidence of association between PPARG variants and colorectal cancer risk.Impact: Further replication in independent samples is warranted. Cancer Epidemiol Biomarkers Prev; 22(11); 2094–101. ©2013 AACR.
Hypoxic Activation of the PERK/eIF2α Arm of the Unfolded Protein Response Promotes Metastasis through Induction of LAMP3
Authors: Mujcic Hilda , Nagelkerke Anika , Rouschop Kasper M.A. , Chung Stephen , Chaudary Naz , Span Paul N. , Clarke Blaise , Milosevic Michael , Sykes Jenna , Hill Richard P. , Koritzinsky Marianne , Wouters Bradly G. 
Published: September 2013

Abstract
Purpose: Conditions of poor oxygenation (hypoxia) are present in many human tumors, including cervix cancer, and are associated with increased risk of metastasis and poor prognosis. Hypoxia is a potent activator of the PERK/eIF2α signaling pathway, a component of the unfolded protein response (UPR) and an important mediator of hypoxia tolerance and tumor growth. Here, the importance of this pathway in the metastasis of human cervix carcinoma was investigated.
Experimental Design: Amplification and expression of LAMP3, a UPR metastasis-associated gene, was examined using FISH and immunofluorescence in a cohort of human cervix tumors from patients who had received oxygen needle electrode tumor oxygenation measurements. To evaluate the importance of this pathway in metastasis in vivo, we constructed a series of inducible cell lines to interfere with PERK signaling during hypoxia and used these in an orthotopic cervix cancer model of hypoxia-driven metastasis.
Results: We show that LAMP3 expression in human cervix tumors is augmented both by gene copy number alterations and by hypoxia. Induced disruption of PERK signaling in established orthotopic xenografts resulted in complete inhibition of hypoxia-induced metastasis to the lymph nodes. This is due, in part, to a direct influence of the UPR pathway on hypoxia tolerance. However, we also find that LAMP3 is a key mediator of hypoxia-driven nodal metastasis, through its ability to promote metastatic properties including cell migration.
Conclusion: These data suggest that the association between hypoxia, metastasis, and poor prognosis is due, in part, to hypoxic activation of the UPR and expression of LAMP3. Clin Cancer Res; 19(22); 6126–37. ©2013 AACR.
miR-106a Represses the Rb Tumor Suppressor p130 to Regulate Cellular Proliferation and Differentiation in High-Grade Serous Ovarian Carcinoma
Authors: Liu Zhaojian , Gersbach Elizabeth , Zhang Xiyu , Xu Xiaofei , Dong Ruifen , Lee Peng , Liu Jinsong , Kong Beihua , Shao Changshun , Wei Jian-Jun 
Published: September 2013

Abstract
The degree of differentiation in human cancers generally reflects the degree of malignancy, with the most undifferentiated cancer being also the highest grade and the most aggressive. High-grade serous ovarian carcinomas (HGSOC) are poorly differentiated and fast-growing malignancies. The molecular mechanisms underlying the poor differentiation of HGSOC has not been completely characterized. Evidence suggests that miRNA, miR are dysregulated in HGSOC. Therefore, we focused on those miRNAs that are relevant to tumor differentiation. Expression profiling of miRNAs in HGSOC, indicated miR-106a and its family members were significantly upregulated. Upregulation of miR-106a was further validated by real-time reverse transcriptase PCR (qRT-PCR) and miRNA in situ hybridization in a large cohort of HGSOC specimens. Overexpression of miR-106a in benign and malignant ovarian cells significantly increased the cellular proliferation rate and expanded the side-population fraction. In particular, SKOV3 cells with miR-106a overexpression had significantly higher tumor initial/stem cell population (CD24- and CD133-positive cells) than control SKOV3 cells. Among many miR-106a predicated target genes, p130 (RBL2), an retinoblastoma (Rb) tumor suppressor family member, was not only confirmed as a specific target of miR-106a but also related to tumor growth and differentiation. The importance of mir-106a and RBL2 was further demonstrated in vivo, in which, SKOV3 cells overexpressing miR-106a formed poorly differentiated carcinomas and had reduced RBL2 levels. To our knowledge, this is the first study of miR-106a mediating proliferation and tumor differentiation in HGSOC.
Implications: The current study suggests that the RB tumor suppressor pathway is a critical regulator of growth and differentiation in HGSOC. Mol Cancer Res; 11(11); 1314–25. ©2013 AACR.
Ionic Mechanisms Underlying the Effects of Vasoactive Intestinal Polypeptide on Canine Atrial Myocardium
Authors: Xi Yutao , Wu Geru , Ai Tomohiko , Cheng Nancy , Kalisnik Jurij Matija , Sun Junping , Abbasi Shahrzad , Yang Donghui , Fan Christopher , Yuan Xiaojing , Wang Suwei , Elayda MacArthur , Gregoric Igor D. , Kantharia Bharat K. , Lin Shien-Fong , Cheng Jie 
Published: September 2013

Background—
Vasoactive intestinal polypeptide (VIP) is released from intracardiac neurons during vagal stimulation, ischemia, and heart failure, which are associated with increased vulnerability to atrial fibrillation. VIP shortens atrial effective refractory periods in dogs. Endogenous VIP contributes to vagally mediated acceleration of atrial electric remodeling. VIP is also shown to prolong the duration of acetylcholine-induced atrial fibrillation. However, the ionic mechanisms underlying VIP effects are largely unknown.

Methods and Results—

The effects of VIP on transmembrane ion channels were studied in canine atrial cardiomyocytes using patch-clamp techniques. VIP increased delayed rectifier K
+
current and L-type calcium current but decreased the transient outward K
+
current and sodium current. Optical mapping technique was used to assess effects of VIP on action potential durations (APDs) in isolated canine left atria. VIP shortened APD and slowed conduction velocity in a dose-dependent manner. Furthermore, VIP increased spatial heterogeneity of APD and conduction velocity, as assessed by the SDs of APD and conduction velocity, and atrial fibrillation inducibility.

Conclusions—
Through its diverse effects on ion channels, VIP shortens APD with increased APD spatial heterogeneity and decreases intra-atrial conduction velocity, which may play an important role in the pathogenesis of atrial arrhythmias in scenarios where VIP release is increased.
A Variant in
LDLR
Is Associated With Abdominal Aortic Aneurysm
Authors: Bradley Declan T. , Hughes Anne E. , Badger Stephen A. , Jones Gregory T. , Harrison Seamus C. , Wright Benjamin J. , Bumpstead Suzannah , Baas Annette F. , Grétarsdóttir Sólveig , Burnand Kevin , Child Anne H. , Clough Rachel E. , Cockerill Gillian , Hafez Hany , Scott D. Julian A. , Ariëns Robert A.S. , Johnson Anne , Sohrabi Soroush , Smith Alberto , Thompson Matthew M. , van Bockxmeer Frank M. , Waltham Matthew , Matthíasson Stefán E. , Thorleifsson Gudmar , Thorsteinsdottir Unnur , Blankensteijn Jan D. , Teijink Joep A.W. , Wijmenga Cisca , de Graaf Jacqueline , Kiemeney Lambertus A. , Wild John B. , Edkins Sarah , Gwilliam Rhian , Hunt Sarah E. , Potter Simon , Lindholt Jes S. , Golledge Jonathan , Norman Paul E. , van Rij Andre , Powell Janet T. , Eriksson Per , Stefánsson Kári , Thompson John R. , Humphries Steve E. , Sayers Robert D. , Deloukas Panos , Samani Nilesh J. , Bown Matthew J. 
Published: September 2013

Background—
Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance.

Methods and Results—

A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter ≥30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with
P
<1×10
−4
were carried through to in silico replication in 1292 AAA cases and 30 503 controls. One single-nucleotide polymorphism associated with
P
<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (
LDLR
) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio, 0.76; 95% confidence interval, 0.70–0.83;
P
=2.08×10
−10
).

Conclusions—
LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.
Temporal Differences in Out-of-Hospital Cardiac Arrest Incidence and Survival
Authors: Bagai Akshay , McNally Bryan F. , Al-Khatib Sana M. , Myers J. Brent , Kim Sunghee , Karlsson Lena , Torp-Pedersen Christian , Wissenberg Mads , van Diepen Sean , Fosbol Emil L. , Monk Lisa , Abella Benjamin S. , Granger Christopher B. , Jollis James G. 
Published: September 2013

Background—
Understanding temporal differences in the incidence and outcomes of out-of-hospital cardiac arrest (OHCA) has important implications for developing preventative strategies and optimizing systems for OHCA care.

Methods and Results—

We studied 18 588 OHCAs of presumed cardiac origin in patients aged ≥18 years who received resuscitative efforts by emergency medical services (EMS) and were enrolled in the Cardiac Arrest Registry to Enhance Survival (CARES) from October 1, 2005, to December 31, 2010. We evaluated temporal variability in OHCA incidence and survival to hospital discharge. There was significant variability in the frequency of OHCA by hour of the day (
P
<0.001), day of the week (
P
<0.001), and month of the year (
P
<0.001), with the highest incidence occurring during the daytime, from Friday to Monday, in December. Survival to hospital discharge was lowest for OHCA that occurred overnight (from 11:01
pm
to 7
am
; 7.1%) versus daytime (7:01
am
to 3
pm
; 10.8%) or evening (3:01
pm
to 11
pm
; 11.3%;
P
<0.001) and during the winter (8.8%) versus spring (11.1%), summer (11.0%), or fall (10.0%;
P
<0.001). There was no difference in survival to hospital discharge between OHCAs that occurred on weekends and weekdays (9.5% versus 10.4%,
P
=0.06). After multivariable adjustment for age, sex, race, witness status, layperson resuscitation, first monitored cardiac rhythm, and emergency medical services response time, compared with daytime and spring, survival to hospital discharge remained lowest for OHCA that occurred overnight (odds ratio, 0.81; 95% confidence interval, 0.70–0.95;
P
=0.008) and during the winter (odds ratio, 0.81; 95% confidence interval, 0.70–0.94;
P
=0.006), respectively.

Conclusions—
There is significant temporal variability in the incidence of and survival after OHCA. The relative contribution of patient pathophysiology, likelihood of the OHCA being observed, and prehospital and hospital-based resuscitative factors deserves further exploration.
Association of Geographical Factors With Administration of Tissue Plasminogen Activator for Acute Ischemic Stroke
Authors: Kunisawa Susumu , Morishima Toshitaka , Ukawa Naoto , Ikai Hiroshi , Otsubo Tetsuya , Ishikawa Koichi B. , Yokota Chiaki , Minematsu Kazuo , Fushimi Kiyohide , Imanaka Yuichi 
Published: September 2013

Background

Intravenous tissue plasminogen activator (
tPA
) is an effective treatment for acute ischemic stroke if administered within a few hours of stroke onset. Because of this time restriction,
tPA
administration remains infrequent. Ambulance use is an effective strategy for increasing
tPA
administration but may be influenced by geographical factors. The objectives of this study are to investigate the relationship between
tPA
administration and ambulance use and to examine how patient travel distance and population density affect
tPA
utilization.

Methods and Results

We analyzed administrative claims data from 114 194 acute ischemic stroke cases admitted to 603 hospitals between July 2010 and March 2012. Mixed‐effects logistic regression models of patients nested within hospitals with a random intercept were generated to analyze possible predictive factors (including patient characteristics, ambulance use, and driving time from home to hospital) of
tPA
administration for different population density categories to investigate differences in these factors in various regional backgrounds. Approximately 5.1% (5797/114 194) of patients received
tPA
. The composition of baseline characteristics varied among the population density categories, but adjustment for covariates resulted in all factors having similar associations with
tPA
administration in every category. The administration of
tPA
was associated with patient age and severity of stroke symptoms, but driving time showed no association. Ambulance use was significantly associated with
tPA
administration even after adjustment for covariates.

Conclusion

The association between ambulance use and
tPA
administration suggests the importance of calling an ambulance for suspected stroke. Promoting ambulance use for acute ischemic stroke patients may increase
tPA
use.
Isolating the Neural Mechanisms of Interference during Continuous Multisensory Dual-task Performance
Authors: Kasper Ryan W. , Cecotti Hubert , Touryan Jon , Eckstein Miguel P. , Giesbrecht Barry 
Published: September 2013

AbstractThe need to engage in multiple tasks simultaneously is often encountered in everyday experience, but coordinating between two or more tasks can lead to impaired performance. Typical investigations of multitasking impairments have focused on the performance of two tasks presented in close temporal proximity on discrete trials; however, such paradigms do not match well with the continuous performance situations more typically encountered outside the laboratory. As a result, the stages of information processing that are affected during multisensory continuous dual tasks and how these changes in processing relate to behavior remain unclear. To address these issues, participants were presented simultaneous rapid visual and auditory stimulus sequences under three conditions: attend visual only, attend auditory only, and dual attention (attend both visual and auditory). Performance, measured in terms of response time and perceptual sensitivity (d′), revealed dual-task impairments only in the auditory task. Neural activity, measured by the ERP technique, revealed that both early stage sensory processing and later cognitive processing of the auditory task were affected by dual-task performance, but similar stages of processing of the visual task were not. Critically, individual differences in neural activity at both early and late stages of information processing accurately rank-ordered individuals based on the observed difference in behavioral performance between the single and dual attention conditions. These results reveal relationships between behavioral performance and the neural correlates of both early and late stage information processing that provide key insights into the complex interplay between the brain and behavior when multiple tasks are performed continuously.