bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased running speed and pre-race muscle damage as risk factors for exercise-associated muscle cramps in a 56 km ultra-marathon: a prospective cohort study
Authors: Schwellnus Martin P , Allie Siddieq , Derman Wayne , Collins Malcolm 
Published: March 2011

BackgroundDespite the high prevalence of exercise-associated muscle cramping (EAMC) in endurance runners, the aetiology and risk factors for this condition are not fully understood.PurposeThe purpose of this prospective cohort study was to identify risk factors associated with the development of EAMC in ultra-distance runners.Methods49 runners participating in a 56 km race completed a validated pre-race questionnaire. Pre-race muscle pain in the calves, hamstrings and quadriceps muscles was recorded (visual analogue scale) and pre-race serum creatine kinase (CK) activity was measured. 20 runners reported EAMC (EAMC group) during or within 6 h after the event, while 29 runners reported no cramping (CON group).ResultsEAMC was not associated with age, body mass index, sex, recent and past personal best running times, pre-race muscle pain and pre-race training (duration and frequency). Runners in the EAMC group tended to report on average longer training sessions during the 3 days before the race (EAMC 1.2 (1.1), CON 0.6 (1.0); p=0.077). Significant risk factors for EAMC were a past history of EAMC (EAMC 100%, CON 48%; p<0.001) and a faster running time (min) for the first 28 km split time of the race (EAMC 144 (20), CON 157 (14); p=0.029) despite being matched for recent (<15 weeks before race) personal best times in the 42.2 km race. Pre-race CK activity tended to be higher in the EAMC group (EAMC 89 (80), CON 58 (35); p=0.066).ConclusionsNovel risk factors for EAMC in distance runners are a past history of EAMC, faster running pace at the early stage of a race and possibly pre-race muscle damage.
LR(1) parser generation system
Authors: Sorkin Arthur , Donovan Peter 
Published: March 2011

The LR(1) Parser Generation System generates full LR(1) parsers that are comparable in speed and size to those generated by LALR(1) parser generators, such as yacc [5]. In addition to the inherent advantages of full LR(1) parsing, it contains a number of novel features. This paper discusses three of them in detail: an LR(1) grammar specified automatic error recovery algorithm, oracles, and generic tokens.
The error recovery algorithm depends on the fact that full LR(1) parse tables preserve context. Oracles are pieces of code that are defined in a grammar and that are executed between the scanner and parser. They are used to resolve token ambiguities, including semantic ones. Generic tokens are used to replace syntactically identical tokens with a single token, which is, in effect, a variable representing a set of tokens.
Histone Methyltransferase EZH2 Induces Akt-Dependent Genomic Instability and BRCA1 Inhibition in Breast Cancer
Authors: Gonzalez Maria E. , DuPrie Matthew L. , Krueger Heather , Merajver Sofia D. , Ventura Alejandra C. , Toy Kathy A. , Kleer Celina G. 
Published: March 2011

Abstract
Increased levels of EZH2, a critical regulator of cellular memory, signal the presence of metastasis and poor outcome in breast cancer patients. High levels of EZH2 are associated with nuclear pleomorphism, lack of estrogen receptor expression, and decreased nuclear levels of BRCA1 tumor suppressor protein in invasive breast carcinomas. The mechanism by which EZH2 overexpression promotes the growth of poorly differentiated invasive carcinomas remains to be defined. Here, we show that EZH2 controls the intracellular localization of BRCA1 protein. Conditional doxycycline-induced upregulation of EZH2 in benign mammary epithelial cells results in nuclear export of BRCA1 protein, aberrant mitoses with extra centrosomes, and genomic instability. EZH2 inhibition in CAL51 breast cancer cells induces BRCA1 nuclear localization and rescues defects in ploidy and mitosis. Mechanistically, EZH2 overexpression is sufficient for activation of the phosphoinositide 3-kinase/Akt (PI3K/Akt) pathway specifically through activation of Akt isoform 1. EZH2-induced BRCA1 nuclear export, aneuploidy, and mitotic defects were prevented by treatment with the PI3K inhibitors LY294002 or wortmannin. Targeted inhibition of Akt-1, Akt-2, and Akt-3 isoforms revealed that the EZH2-induced phenotype requires specific activation of Akt-1. The relevance of our studies to human breast cancer is highlighted by the finding that high EZH2 protein levels are associated with upregulated expression of phospho-Akt-1 (Ser473) and decreased nuclear expression of phospho-BRCA1 (Ser1423) in 39% of invasive breast carcinomas. These results enable us to pinpoint one mechanism by which EZH2 regulates BRCA1 expression and genomic stability mediated by the PI3K/Akt-1 pathway. Cancer Res; 71(6); 2360–70. ©2011 AACR.
Influence of Affinity and Antigen Internalization on the Uptake and Penetration of Anti-HER2 Antibodies in Solid Tumors
Authors: Rudnick Stephen I. , Lou Jianlong , Shaller Calvin C. , Tang Yong , Klein-Szanto Andres J.P. , Weiner Louis M. , Marks James D. , Adams Gregory P. 
Published: March 2011

Abstract
Antibody drugs are widely used in cancer therapy, but conditions to maximize tumor penetration and efficacy have yet to be fully elucidated. In this study, we investigated the impact of antibody binding affinity on tumor targeting and penetration with affinity variants that recognize the same epitope. Specifically, we compared four derivatives of the C6.5 monoclonal antibody (mAb), which recognizes the same HER2 epitope (monovalent KD values ranging from 270 to 0.56 nmol/L). Moderate affinity was associated with the highest tumor accumulation at 24 and 120 hours after intravenous injection, whereas high affinity was found to produce the lowest tumor accumulation. Highest affinity mAbs were confined to the perivascular space of tumors with an average penetration of 20.4 ± 7.5 μm from tumor blood vessels. Conversely, lowest affinity mAbs exhibited a broader distribution pattern with an average penetration of 84.8 ± 12.8 μm. In vitro internalization assays revealed that antibody internalization and catabolism generally increased with affinity, plateauing once the rate of HER2 internalization exceeded the rate of antibody dissociation. Effects of internalization and catabolism on tumor targeting were further examined using antibodies of moderate (C6.5) or high-affinity (trastuzumab), labeled with residualizing (111In-labeled) or nonresidualizing (125I-labeled) radioisotopes. Significant amounts of antibody of both affinities were degraded by tumors in vivo. Furthermore, moderate- to high-affinity mAbs targeting the same HER2 epitope with monovalent affinity above 23 nmol/L had equal tumor accumulation of residualizing radiolabel over 120 hours. Results indicated equal tumor exposure, suggesting that mAb penetration and retention in tumors reflected affinity-based differences in tumor catabolism. Together, these results suggest that high-density, rapidly internalizing antigens subject high-affinity antibodies to greater internalization and degradation, thereby limiting their penetration of tumors. In contrast, lower-affinity antibodies penetrate tumors more effectively when rates of antibody–antigen dissociation are higher than those of antigen internalization. Together, our findings offer insights into how to optimize the ability of therapeutic antibodies to penetrate tumors. Cancer Res; 71(6); 2250–9. ©2011 AACR.
MAP Kinase-Interacting Kinase 1 Regulates SMAD2-Dependent TGF-β Signaling Pathway in Human Glioblastoma
Authors: Grzmil Michal , Morin Pier , Lino Maria Maddalena , Merlo Adrian , Frank Stephan , Wang Yuhua , Moncayo Gerald , Hemmings Brian A. 
Published: March 2011

Abstract
Glioblastoma multiforme (GBM) is the most common aggressive brain cancer with a median survival of approximately 1 year. In a search for novel molecular targets that could be therapeutically developed, our kinome-focused microarray analysis identified the MAP (mitogen-activated protein) kinase-interacting kinase 1 (MNK1) as an attractive theranostic candidate. MNK1 overexpression was confirmed in both primary GBMs and glioma cell lines. Inhibition of MNK1 activity in GBM cells by the small molecule CGP57380 suppressed eIF4E phosphorylation, proliferation, and colony formation whereas concomitant treatment with CGP57380 and the mTOR inhibitor rapamycin accentuated growth inhibition and cell-cycle arrest. siRNA-mediated knockdown of MNK1 expression reduced proliferation of cells incubated with rapamycin. Conversely, overexpression of full-length MNK1 reduced rapamycin-induced growth inhibition. Analysis of polysomal profiles revealed inhibition of translation in CGP57380 and rapamycin-treated cells. Microarray analysis of total and polysomal RNA from MNK1-depleted GBM cells identified mRNAs involved in regulation of TGF-β pathway. Translation of SMAD2 mRNA as well as TGF-β–induced cell motility and vimentin expression was regulated by MNK1 signaling. Tissue microarray analysis revealed a positive correlation between the immunohistochemical staining of MNK1 and SMAD2. Taken together, our findings offer insights into how MNK1 pathways control translation of cancer-related mRNAs including SMAD2, a key component of the TGF-β signaling pathway. Furthermore, they suggest MNK1-controlled translational pathways in targeted strategies to more effectively treat GBM. Cancer Res; 71(6); 2392–402. ©2011 AACR.
Spontaneous Cytotoxic T-Cell Reactivity against Indoleamine 2,3-Dioxygenase-2
Authors: Sørensen Rikke Bæk , Køllgaard Tania , Andersen Rikke Sick , van den Berg Joost Huibert , Svane Inge Marie , Straten Per thor , Andersen Mads Hald 
Published: March 2011

Abstract
Several lines of data have suggested a possible link between the indoleamine 2,3-dioxygenase (IDO)-like protein IDO2 and cancer. First, IDO2 expression has been described in human tumors, including renal, gastric, colon, and pancreatic tumors. Second, the apparent selective inhibition of IDO2 by the D stereoisomer of the IDO blocker 1-methyl-tryptophan (1MT), which tends to be more active than the L-isomer in a variety of biological assays for IDO function, suggests that IDO2 may be important to sustain immune escape and growth of tumors. Especially, D-1MT heightens chemotherapeutic efficacy in mouse models of cancer in a nontoxic fashion. Here, we describe the immunogenicity of IDO2 by showing the presence of spontaneous cytotoxic T-cell reactivity against IDO2 in peripheral blood of both healthy donors and cancer patients. Furthermore, we show that these IDO2-specific T cells are cytotoxic effector cells that recognize and kill tumor cells. Our data suggest that IDO2 might be a useful target for anticancer immunotherapeutic strategies. Cancer Res; 71(6); 2038–44. ©2011 AACR.
Interaction between MYC and MCL1 in the Genesis and Outcome of Non–Small-Cell Lung Cancer
Authors: Allen Thaddeus D. , Zhu Chang Qi , Jones Kirk D. , Yanagawa Naoki , Tsao Ming-Sound , Bishop J. Michael 
Published: March 2011

Abstract
MYC exerts both positive and negative functions in cancer cells, such that its procancerous effects are unmasked only after its anticancer effects are blocked. Here we used multiple mouse models of lung adenocarcinoma to identify genetic events that can cooperate with MYC activation to promote the genesis of non–small-cell lung cancer (NSCLC), the most common form of lung cancer in humans. MYC overexpression targeted to pulmonary alveolar cells was sufficient to induce lung adenomas and carcinomas. Tumorigenesis was assisted by either spontaneous mutations in Kras or experimental introduction of activated RAS, but investigations revealed that additional events were required to circumvent apoptosis, one of the most significant negative functions exerted by MYC. We determined that overexpression of the antiapoptotic protein MCL1 was sufficient to circumvent apoptosis in this setting. Previous clinical studies have indicated that prognosis of human NSCLC is not associated with MCL1, despite its overexpression in many NSCLCs. In reexamining the prognostic value in this setting, we found that MCL1 overexpression does correlate with poor patient survival, but only when accompanied by MYC overexpression. Our findings therefore produce a convergence of mouse and human results that explain how MCL1 can block an important negative consequence of MYC overexpression in both experimental models and clinical cases of NSCLC. Cancer Res; 71(6); 2212–21. ©2011 AACR.
CCL11–CCR3 Interactions Promote Survival of Anaplastic Large Cell Lymphoma Cells via ERK1/2 Activation
Authors: Miyagaki Tomomitsu , Sugaya Makoto , Murakami Takashi , Asano Yoshihide , Tada Yayoi , Kadono Takafumi , Okochi Hitoshi , Tamaki Kunihiko , Sato Shinichi 
Published: March 2011

AbstractCCR3 is a specific marker of anaplastic large cell lymphoma (ALCL) cells. ALCL cells also express CCL11, a ligand for CCR3, leading to the hypothesis that CCL11 may play an autocrine role in ALCL progression. In this study, we investigated a role of CCL11 in cell survival and growth of human Ki-JK cells, established from an ALCL patient, and murine EL-4 lymphoma cells. Both Ki-JK and EL-4 cells expressed cell surface CCR3. CCL11 increased cell survival rates of Ki-JK cells in a dose-dependent manner, whereas it promoted EL-4 cell proliferation. Furthermore, CCL11 induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in both Ki-JK cells and EL-4 cells. Cell survival and tumor proliferation promoted by CCL11 was completely blocked by inhibition of ERK phosphorylation. CCL11 induced expression of antiapoptotic proteins, Bcl-xL and survivin, in Ki-JK cells. CCL11 also enhanced tumor growth of EL-4 and Ki-JK cells in vivo. Consistent with these results, tumor cells of cutaneous ALCL expressed CCR3 and increased levels of phosphorylated ERK1/2, Bcl-xL, and survivin in situ. Thus, our findings prompt a novel therapeutic approach to treat relapses of an aggressive form of lymphoma based on the discovery that a cell surface marker of disease functions as a critical autocrine growth receptor. Cancer Res; 71(6); 2056–65. ©2011 AACR.
MYC and Metastasis
Authors: Wolfer Anita , Ramaswamy Sridhar 
Published: March 2011

Abstract
Aggressive primary tumors express transcriptional signatures that correlate with their metastatic propensity. A number of these signatures have been deployed in the clinic as risk stratification tools. However, the molecular basis of these clinically useful prognostic signatures has remained a largely unresolved area of controversy. We recently found that many prognostic signatures reflect the activity of the MYC oncogene, which in turn regulates tumor metastasis through specific effects on cancer cell invasion and migration. These findings offer a general framework for understanding the molecular basis of clinically prognostic transcriptional signatures and suggest potentially new avenues for studying metastasis. Cancer Res; 71(6); 2034–7. ©2011 AACR.
Perspectives on Emerging Trends in Cancer Research
Authors: Prendergast George C. 
Published: March 2011

Abstract
‘‘Cancer poses enormous personal, clinical, and societal challenges, but it is exciting to consider prospects for historic progress in treatment this decade based on developments emerging in many areas of the field. Here, I offer a personal perspective on core problems, emerging developments, and responses which investigators and their advocates may benefit from considering. This is the first of a series of editorials which will delve into the issues introduced below.’’
Mechanisms of Abnormal Systolic Motion of the Interventricular Septum During Left Bundle-Branch Block
Authors: Gjesdal Ola , Remme Espen W. , Opdahl Anders , Skulstad Helge , Russell Kristoffer , Kongsgaard Erik , Edvardsen Thor , Smiseth Otto A. 
Published: March 2011

Background—
In a majority of patients with left bundle-branch block (LBBB), there is abnormal leftward motion of the interventricular septum during the preejection phase. This motion was considered to be passive, caused by early rise in right ventricular (RV) pressure, and has therefore been excluded from most indices of left ventricular (LV) dyssynchrony. If considered active, however, the leftward motion reflects onset of septal activation and should be included. We therefore investigated if the motion was a passive response to pressure changes or caused by active contraction.

Methods and Results—

LBBB was induced in 8 anesthetized dogs with micromanometers. Cardiac dimensions were measured by sonomicrometry and echocardiography. Induction of LBBB resulted in preejection leftward motion of the septum, simultaneously with shortening of septal segments (
P
<0.01). In each experiment, preejection septal shortening occurred against rising LV pressure, consistent with active contraction. Furthermore, the LV pressure–segment length relationships were shifted upward (
P
<0.01) relative to the passive elastic curve, indicating stiffening of septal myocardium, confirming an active mechanism. Initially, RV pressure increased faster than LV pressure, suggesting that the leftward septal motion may have a passive pressure component. However, the passive component appeared to play a minor role. The magnitude of preejection septal shortening was modified by load alterations.

Conclusions—
Leftward preejection motion of the septum during LBBB is mainly a result of active septal contraction, whereas alterations in diastolic ventricular pressures modulate the amplitude of this motion. The findings imply that the preejection phase should be included when assessing LV dyssynchrony.
Association of Incident Cardiovascular Disease With Progression of Sleep-Disordered Breathing
Authors: Chami Hassan A. , Resnick Helaine E. , Quan Stuart F. , Gottlieb Daniel J. 
Published: March 2011

Background—
Prospective data suggest that sleep-disordered breathing enhances risk for incident and recurrent cardiovascular disease (CVD). However, a reverse causal pathway whereby incident CVD causes or worsens sleep-disordered breathing has not been studied.

Methods and Results—

A total of 2721 Sleep Heart Health Study participants (mean age 62, standard deviation=10 years; 57% women; 23% minority) without CVD at baseline underwent 2 polysomnograms 5 years apart. Incident CVD events, including myocardial infarction, congestive heart failure, and stroke, were ascertained and adjudicated. The relation of incident CVD to change in apnea-hypopnea index between the 2 polysomnograms was tested with general linear models, with adjustment for age, sex, race, study center, history of diabetes mellitus, change in body mass index, change in neck circumference, percent sleep time spent in supine sleep, and time between the 2 polysomnograms. Incident CVD occurred in 95 participants between the first and second polysomnograms. Compared with participants without incident CVD, those with incident CVD experienced larger increases in apnea-hypopnea index between polysomnograms. The difference in adjusted mean apnea-hypopnea index change between subjects with and without incident CVD was 2.75 events per hour (95% confidence interval, 0.26 to 5.24;
P
=0.032). This association persisted after subjects with central sleep apnea were excluded. Compared with participants without incident CVD, participants with incident CVD had greater increases in both mean obstructive and central apnea indices, by 1.75 events per hour (95% confidence interval, 0.10 to 1.75;
P
=0.04) and by 1.07 events per hour (95% confidence interval, 0.40 to 1.74;
P
=0.001), respectively.

Conclusions—
In a diverse, community-based sample of middle-aged and older adults, incident CVD was associated with worsening sleep-disordered breathing over 5 years.
Fallacies of the Enthalpy Transfer Coefficient over the Ocean in High Winds
Authors: Andreas Edgar L 
Published: March 2011

Abstract
Mesoscale and large-scale atmospheric models use a bulk surface flux algorithm to compute the turbulent flux boundary conditions at the bottom of the atmosphere from modeled mean meteorological quantities such as wind speed, temperature, and humidity. This study, on the other hand, uses a state-of-the-art bulk air–sea flux algorithm in stand-alone mode to compute the surface fluxes of momentum, sensible and latent heat, and enthalpy for a wide range of typical (though randomly generated) meteorological conditions over the open ocean. The flux algorithm treats both interfacial transfer (controlled by molecular processes right at the air–sea interface) and transfer mediated by sea spray. Because these two transfer routes obey different scaling laws, neutral-stability, 10-m transfer coefficients for enthalpy CKN10, latent heat CEN10, and sensible heat CHN10 are quite varied when calculated from the artificial flux data under the assumption of only interfacial transfer—the assumption in almost all analyses of measured air–sea fluxes. That variability increases with wind speed because of increasing spray-mediated transfer and also depends on surface temperature and atmospheric stratification. The analysis thereby reveals as fallacious several assumptions that are common in air–sea interaction research—especially in high winds. For instance, CKN10, CEN10, and CHN10 are not constants; they are not even single-valued functions of wind speed, nor must they increase monotonically with wind speed if spray-mediated transfer is important. Moreover, the ratio CKN10/CDN10, where CDN10 is the neutral-stability, 10-m drag coefficient, does not need to be greater than 0.75 at all wind speeds, as many have inferred from Emanuel’s seminal paper in this journal. Data from the literature and from the Coupled Boundary Layers and Air–Sea Transfer (CBLAST) hurricane experiment tend to corroborate these results.
Benefits of moderate-intensity exercise during a calorie-restricted low-fat diet
Authors: Apekey Tanefa A , Morris AEJ , Fagbemi S , Griffiths GJ 
Published: March 2011

Objective: Despite the health benefits, many people do not undertake regular exercise. This study investigated the effects of moderate-intensity exercise on cardiorespiratory fitness (lung age, blood pressure and maximal aerobic power, VO2max), serum lipids concentration and body mass index (BMI) in sedentary overweight/obese adults consuming a calorie-restricted low-fat diet. Design: Randomized diet and exercise intervention. Setting: Lincolnshire, UK. Methods: Sixty overweight/obese (BMI ≥ 25kgm−2) adults were randomized to either a calorie restricted low-fat diet (20 per cent of total energy as fat) or the same diet with the addition of moderate-intensity physical exercise (30 minutes, twice a week) for eight weeks; 20 completed the study. Participants’ serum lipids concentrations, BMI, blood pressure, resting pulse rate, VO2max and lung age were measured before the start of the intervention and during the fourth and eighth weeks. Results: Reductions in blood pressure (10 per cent versus 1 per cent), pulse rate (13 per cent versus 8 per cent) and weight (5 per cent versus 2 per cent) were greatest for the diet with exercise group. Exercise resulted in a significant ( p ≤ 0.05) increase in average VO2max (by 17 per cent) and reduction in average lung age by about 19 years. Further, reduction in participants’ lung age ranged from 1 to 37 years. However, there was no significant difference in BMI, blood pressure and serum lipids concentration between groups. Conclusion: Although exercise on most days of the week would result in maximum health benefits, 30 minutes of moderate-intensity exercise twice a week could significantly improve cardiorespiratory fitness (blood pressure and lung age) and the risk of cardiovascular diseases in previously sedentary overweight/obese adults.