bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased running speed and previous cramps rather than dehydration or serum sodium changes predict exercise-associated muscle cramping: a prospective cohort study in 210 Ironman triathletes
Authors: Schwellnus Martin P , Drew Nichola , Collins Malcolm 
Published: December 2010

BackgroundDespite the high prevalence of exercise-associated muscle cramping (EAMC) in endurance athletes, the aetiology and risk factors for this condition are not fully understood.AimThe aim of this prospective cohort study was to identify risk factors associated with EAMC in endurance triathletes.Methods210 triathletes competing in an Ironman triathlon were recruited. Prior to the race, subjects completed a detailed validated questionnaire and blood samples were taken for serum electrolytes. Immediately before the race, pre-race body weight was obtained. Body weight and blood samples for serum electrolyte concentrations were obtained immediately after the race. Clinical data on EAMC experienced during or immediately after the race were also collected.Results43 triathletes reported EAMC (cramping group) and were compared with the 166 who did not report EAMC (non-cramping group). There were no significant differences between groups in any pre-race–post-race serum electrolyte concentrations and body weight changes. The development of EAMC was associated with faster predicted race times and faster actual race times, despite similarly matched preparation and performance histories in subjects from both groups. A regression analysis identified faster overall race time (and cycling time) and a history of cramping (in the last 10 races) as the only two independent risk factors for EAMC.ConclusionThe results from this study add to the evidence that dehydration and altered serum electrolyte balance are not causes for EAMC. Rather, endurance runners competing at a fast pace, which suggests that they exercise at a high intensity, are at risk for EAMC.
Dual role of physical workload and occupational noise in the association of the metabolic syndrome with risk of coronary heart disease: findings from the Helsinki Heart Study
Authors: Koskinen Hanna-Leena , Kauppinen Timo , Tenkanen Leena 
Published: December 2010

ObjectivesPrevious evidence indicates that occupational exposure to physical workload or noise entails development of hypertension and risk of coronary heart disease (CHD). However, vigorous physical activity lessens the risks of the metabolic syndrome (MetS) and CHD. We explored this issue by studying the joint effect of physical workload or noise and MetS on risk of CHD.MethodsThis 18-year follow-up study comprised 1502 middle-aged men employed in industry who participated in the second screening for the Helsinki Heart Study but were not treated with gemfibrozil, the trial drug. The CHD endpoints (ICD-9 codes 410–414 and ICD-10 codes 120–125) were obtained from official Finnish registers. The Finnish job-exposure matrix FINJEM provided information on occupational exposures. The joint effect of baseline MetS levels and both occupational exposures was estimated using Cox's regression models.ResultsWorkload and noise increased CHD risk due to increased blood pressure, glucose or body mass index (BMI), separately or combined: the joint effect of workload and MetS defined using these three components yielded an RR of 5.21 (95% CI 2.70 to 10.05). However, when MetS was defined using elevated BMI, high triglycerides and low high-density lipoprotein cholesterol, an RR of 2.19 (95% CI 1.11 to 4.30) among those with MetS only reduced to 1.20 (95% CI 0.61 to 2.35) if concurrently exposed to workload.ConclusionsOccupational exposure to workload or noise modifies CHD risk differently depending on which definition of MetS is used. In the presence of physical workload or noise, hypertension and blood glucose were the best predictors.
Oncogenic Kras Promotes Chemotherapy-Induced Growth Factor Shedding via ADAM17
Authors: Van Schaeybroeck Sandra , Kyula Joan N. , Fenton Audrey , Fenning Catherine S. , Sasazuki Takehiko , Shirasawa Senji , Longley Daniel B. , Johnston Patrick G. 
Published: December 2010

Abstract
Oncogenic mutations in Kras occur in 40% to 45% of patients with advanced colorectal cancer (CRC). We have previously shown that chemotherapy acutely activates ADAM17, resulting in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. In this study, we examined the role of mutant Kras in regulating growth factor shedding and ADAM17 activity, using isogenic Kras mutant (MT) and wild-type (WT) HCT116 CRC cells. Significantly higher levels of TGF-α and VEGF were shed from KrasMT HCT116 cells, both basally and following chemotherapy treatment, and this correlated with increased pErk (phosphorylated extracellular signal regulated kinase)1/2 levels and ADAM17 activity. Inhibition of Kras, MEK (MAP/ERK kinase)1/2, or Erk1/2 inhibition abrogated chemotherapy-induced ADAM17 activity and TGF-α shedding. Moreover, we found that these effects were not drug or cell line specific. In addition, MEK1/2 inhibition in KrasMT xenografts resulted in significant decreases in ADAM17 activity and growth factor shedding in vivo, which correlated with dramatically attenuated tumor growth. Furthermore, we found that MEK1/2 inhibition significantly induced apoptosis both alone and when combined with chemotherapy in KrasMT cells. Importantly, we found that sensitivity to MEK1/2 inhibition was ADAM17 dependent in vitro and in vivo. Collectively, our findings indicate that oncogenic Kras regulates ADAM17 activity and thereby growth factor ligand shedding in a MEK1/2/Erk1/2-dependent manner and that KrasMT CRC tumors are vulnerable to MEK1/2 inhibitors, at least in part, due to their dependency on ADAM17 activity. Cancer Res; 71(3); 1071–80. ©2010 AACR.
Src and Caveolin-1 Reciprocally Regulate Metastasis via a Common Downstream Signaling Pathway in Bladder Cancer
Authors: Thomas Shibu , Overdevest Jonathan B. , Nitz Matthew D. , Williams Paul D. , Owens Charles R. , Sanchez-Carbayo Marta , Frierson Henry F. , Schwartz Martin A. , Theodorescu Dan 
Published: December 2010

Abstract
In bladder cancer, increased caveolin-1 (Cav-1) expression and decreased Src expression and kinase activity correlate with tumor aggressiveness. Here, we investigate the clinical and functional significance, if any, of this reciprocal expression in bladder cancer metastasis. We evaluated the ability of tumor Cav-1 and Src RNA and protein expression to predict outcome following cystectomy in 257 patients enrolled in two independent clinical studies. In both, high Cav-1 and low Src levels were associated with metastasis development. We overexpressed or depleted Cav-1 and Src protein levels in UMUC-3 and RT4 human bladder cancer cells and evaluated the effect of this on actin stress fibers, migration using Transwells, and lung metastasis following tail vein inoculation. Cav-1 depletion or expression of active Src in metastatic UMUC-3 cells decreases actin stress fibers, cell migration, and metastasis, while Cav-1 overexpression or Src depletion increased the migration of nonmetastatic RT4 cells. Biochemical studies indicated that Cav-1 mediates these effects via its phosphorylated form (pY14), whereas Src effects are mediated through phosphorylation of p190RhoGAP and these pathways converge to reduce activity of RhoA, RhoC, and Rho effector ROCK1. Treatment with a ROCK inhibitor reduced UMUC-3 lung metastasis in vivo, phenocopying the effect of Cav-1 depletion or expression of active Src. Src suppresses whereas Cav-1 promotes metastasis of bladder cancer through a pharmacologically tractable common downstream signaling pathway. Clinical evaluation of personalized therapy to suppress metastasis development based on Cav-1 and Src profiles seems warranted. Cancer Res; 71(3); 832–41. ©2010 AACR.
Phase I Assessment of New Mechanism-Based Pharmacodynamic Biomarkers for MLN8054, a Small-Molecule Inhibitor of Aurora A Kinase
Authors: Chakravarty Arijit , Shinde Vaishali , Tabernero Josep , Cervantes Andres , Cohen Roger B. , Dees E. Claire , Burris Howard , Infante Jeffrey R. , Macarulla Teresa , Elez Elena , Andreu Jordi , Rodriguez-Braun Edith , Rosello Susana , von Mehren Margaret , Meropol Neal J. , Langer Corey J. , ONeil Bert , Bowman Douglas , Zhang Mengkun , Danaee Hadi , Faron-Yowe Laura , Gray Gary , Liu Hua , Pappas Jodi , Silverman Lee , Simpson Chris , Stringer Bradley , Tirrell Stephen , Veiby Ole Petter , Venkatakrishnan Karthik , Galvin Katherine , Manfredi Mark , Ecsedy Jeffrey A. 
Published: December 2010

Abstract
The mitotic kinase Aurora A is an important therapeutic target for cancer therapy. This study evaluated new mechanism-based pharmacodynamic biomarkers in cancer patients in two phase I studies of MLN8054, a small-molecule inhibitor of Aurora A kinase. Patients with advanced solid tumors received MLN8054 orally for 7 consecutive days in escalating dose cohorts, with skin and tumor biopsies obtained before and after dosing. Skin biopsies were evaluated for increased mitotic cells within the basal epithelium. Tumor biopsies were assessed for accumulation of mitotic cells within proliferative tumor regions. Several patients in the highest dose cohorts showed marked increases in the skin mitotic index after dosing. Although some tumors exhibited increases in mitotic cells after dosing, others displayed decreases, a variable outcome consistent with dual mechanisms of mitotic arrest and mitotic slippage induced by antimitotics in tumors. To provide a clearer picture, mitotic cell chromosome alignment and spindle bipolarity, new biomarkers of Aurora A inhibition that act independently of mitotic arrest or slippage, were assessed in the tumor biopsies. Several patients, primarily in the highest dose cohorts, had marked decreases in the percentage of mitotic cells with aligned chromosomes and bipolar spindles after dosing. Evidence existed for an exposure–effect relationship for mitotic cells with defects in chromosome alignment and spindle bipolarity that indicated a biologically active dose range. Outcomes of pharmacodynamic assays from skin and tumor biopsies were concordant in several patients. Together, these new pharmacodynamic assays provide evidence for Aurora A inhibition by MLN8054 in patient skin and tumor tissues. Cancer Res; 71(3); 675–85. ©2010 AACR.
Cyclophosphamide Induces Differentiation of Th17 Cells in Cancer Patients
Authors: Viaud Sophie , Flament Caroline , Zoubir Mustapha , Pautier Patricia , LeCesne Axel , Ribrag Vincent , Soria Jean-Charles , Marty Virginie , Vielh Philippe , Robert Caroline , Chaput Nathalie , Zitvogel Laurence 
Published: December 2010

Abstract
Low doses of the alkylating agent cyclophosphamide (CTX) mediate antiangiogenic and immunostimulatory effects, leading to potent tumoricidal activity in association with various immunotherapeutic strategies. Here, we show in rodents and cancer patients that CTX markedly promotes the differentiation of CD4+ T helper 17 (Th17) cells that can be recovered in both blood and tumor beds. However, CTX does not convert regulatory T cells into Th17 cells. Because Th17 are potent inducers of tissue inflammation and autoimmunity, these results suggest impact on the clinical management of various types of malignancies treated with alkylating agents and a potential need to optimize CTX-based immunotherapy in patients. Cancer Res; 71(3); 661–5. ©2010 AACR.
The Novel Metastasis Promoter Merm1/Wbscr22 Enhances Tumor Cell Survival in the Vasculature by Suppressing Zac1/p53-Dependent Apoptosis
Authors: Nakazawa Youya , Arai Hiroyuki , Fujita Naoya 
Published: December 2010

Abstract
Understanding metastasis is integral to curative cancer treatments. Using a mouse genetic screening model, we identified Merm1/Wbscr22 as a novel metastasis promoter that includes a methyltransferase fold in its structure. Merm1 showed high levels of expression in invasive breast cancer. Ectopic expression of Merm1 in nonmetastatic cells enhanced metastasis formation without affecting cell growth and motility. The intact methyltransferase fold of Merm1 was required for metastasis formation. Interestingly, Merm1 expression promoted cell survival after entrapment in the lung microvasculature. Consistent with these results, knockdown of endogenous Merm1 in tumor cells reduced lung retention and metastasis formation. On the basis of comparative transcriptome analysis, Merm1 expression was negatively correlated with the expression of tumor suppressor Zac1. We confirmed that Merm1 suppressed Zac1 expression with histone H3 methylation at Lys9 in the Zac1 promoter region. Zac1 can induce apoptosis through its ability to transcriptionally coactivate p53, which regulates apoptosis in the vasculature and is often downregulated in metastasis. We found that Zac1 knockdown reduced the p53-dependent apoptosis that was enhanced by Merm1 knockdown, thereby increasing lung retention of metastatic cells. Our findings show that Merm1 enhances cancer cell survival in the vasculature by suppressing Zac1/p53-dependent apoptosis, thereby enhancing metastasis. Cancer Res; 71(3); 1146–55. ©2010 AACR.
ETV6-NTRK3–Mediated Breast Epithelial Cell Transformation Is Blocked by Targeting the IGF1R Signaling Pathway
Authors: Tognon Cristina E. , Somasiri Aruna M. , Evdokimova Valentina E. , Trigo Genny , Uy Evett E. , Melnyk Nataliya , Carboni Joan M. , Gottardis Marco M. , Roskelley Calvin D. , Pollak Michael , Sorensen Poul H.B. 
Published: December 2010

Abstract
The insulin-like growth factor (IGF) 1 receptor (IGF1R) is an important therapeutic target under study in many cancers. Here, we describe a breast cancer model based on expression of the ETV6-NTRK3 (EN) chimeric tyrosine kinase that suggests novel therapeutic applications of IGF1R inhibitors in secretory breast cancers. Originally discovered in congenital fibrosarcomas with t(12;15) translocations, EN was identified subsequently in secretory breast carcinoma (SBC) which represent a variant of invasive ductal carcinoma. Because fibroblast transformation by EN requires the IGF1R axis, we hypothesized a similar dependency may exist in mammary cells and, if so, that IGF1R inhibitors might be useful to block EN-driven breast oncogenesis. In this study, we analyzed EN expressing murine and human mammary epithelial cell lines for transformation properties. Various IGF1R signaling inhibitors, including the dual specificity IGF1R/insulin receptor (INSR) inhibitor BMS-536924, were then tested for effects on three-dimensional Matrigel cell growth, migration, and tumor formation. We found that EN expression increased acinar size and luminal filling in Matrigel cultures and promoted orthotopic tumor growth in mice. Tumors were well differentiated and nonmetastatic, similar to human SBC. The known EN effector pathway, PI3K-Akt, was activated in an IGF1- or insulin-dependent manner. BMS-536924 blocked EN transformation in vitro, whereas BMS-754807, another IGIFR/INSR kinase inhibitor currently in clinical trials, significantly reduced tumor growth in vivo. Importantly, EN model systems mimic the clinical phenotype observed in human SBC. Moreover, EN has a strict requirement for IGF1R or INSR in breast cell transformation. Thus, our findings strongly encourage the evaluation of IGF1R/INSR inhibitors to treat EN-driven breast cancers. Cancer Res; 71(3); 1060–70. ©2010 AACR.
Both Gene Amplification and Allelic Loss Occur at 14q13.3 in Lung Cancer
Authors: Harris Thomas , Pan Qiulu , Sironi Juan , Lutz Dionne , Tian Jianmin , Sapkar Jana , Perez-Soler Roman , Keller Steven , Locker Joseph 
Published: December 2010

Abstract
Purpose: Because loss of Nkx2-8 increases lung cancer in the mouse, we studied suppressive mechanisms in human lung cancer.
Experimental Design: NKX2-8 is located within 14q13.3, adjacent to its close relative TTF1/NKX2-1. We first analyzed LOH of 14q13.3 in forty-five matched human lung cancer and control specimens. DNA from tumors with LOH was then analyzed with high-density single-nucleotide polymorphism (SNP) arrays. For correlation with this genetic analysis, we quantified expression of Nkx2-8 and TTF1 mRNA in tumors. Finally, suppressive function of Nkx2-8 was assessed via colony formation assays in five lung cancer cell lines.
Results: Thirteen of forty-five (29%) tumors had LOH. In six tumors, most adenocarcinomas, LOH was caused by gene amplification. The 0.8-Mb common region of amplification included MBIP, SFTA, TTF1, NKX2-8, and PAX9. In 4 squamous or adenosquamous cancers, LOH was caused by deletion. In three other tumors, LOH resulted from whole chromosome mechanisms (14−, 14+, or aneuploidy). The 1.2-Mb common region of deletion included MBIP, SFTA, TTF1, NKX2-8, PAX9, SLC25A21, and MIPOL1. Most tumors had low expression of Nkx2-8. Nevertheless, sequencing did not show NKX2-8 mutations that could explain the low expression. TTF1 overexpression, in contrast, was common and usually independent of Nkx2-8 expression. Finally, stable transfection of Nkx2-8 selectively inhibited growth of H522 lung cancer cells.
Conclusions: 14q13.3, which contains NKX2-8, is subject to both amplification and deletion in lung cancer. Most tumors have low expression of Nkx2-8, and its expression can inhibit growth of some lung cancer cells. Clin Cancer Res; 17(4); 690–9. ©2010 AACR.
siRNA-Mediated Downregulation of MMP-9 and uPAR in Combination with Radiation Induces G2/M Cell-Cycle Arrest in Medulloblastoma
Authors: Ganji Purna Chandra Nagaraju , Nalla Arun Kumar , Gupta Reshu , Mohanam Sanjeeva , Gujrati Meena , Dinh Dzung H. , Rao Jasti S. 
Published: December 2010

Abstract
Our previous work and that of other investigators strongly suggest a relationship between the upregulation of metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator receptor (uPAR) in tumor angiogenesis and metastasis. In this study, we evaluated the role of MMP-9 and uPAR in medulloblastoma cancer cell resistance to ionizing irradiation (IR) and tested the antitumor efficacy of siRNA (short interfering RNA) against MMP-9 [plasmid siRNA vector for MMP-9 (pM)] and uPAR [plasmid vector for uPAR (pU)] either alone or in combination [plasmid siRNA vector for both uPAR and MMP-9 (pUM)]. Cell proliferation (BrdU assay), apoptosis (in situ TUNEL for DNA fragmentation), and cell-cycle (FACS) analyses were carried out to determine the effect of siRNA either alone or in combination with IR on G2/M cell-cycle arrest in medulloblastoma cells. IR upregulated MMP-9 and uPAR expression in medulloblastoma cells; pM, pU, and pUM in combination with IR effectively reduced both MMP-9 and uPAR expression, thereby leading to increased radiosensitivity of medulloblastoma cells. siRNA treatments (pM, pU, and pUM) also promoted IR-induced apoptosis and enhanced IR-induced G2/M arrest during cell-cycle progression. While IR induces G2/M cell-cycle arrest through inhibition of the pCdc2- and cyclin B–regulated signaling pathways involving p53, p21/WAF1, and Chk2 gene expression, siRNA (pM, pU, and pUM) alone or in combination with IR induced G2/M arrest mediated through inhibition of the pCdc2- and cyclin B1-regulated signaling pathways involving Chk1 and Cdc25A gene expression. Taken together, our data suggest that downregulation of MMP-9 and uPAR induces Chk1-mediated G2/M cell-cycle arrest, whereas the disruption caused by IR alone is dependent on p53- and Chk2-mediated G2/M cell-cycle arrest. Mol Cancer Res; 9(1); 51–66 ©2010 AACR.
High-dose frequency beta-interferons increase the risk of liver test abnormalities in multiple sclerosis: a longitudinal study
Authors: Chan S , Kingwell E , Oger J , Yoshida E , Tremlett H 
Published: December 2010

Background: Post-marketing studies and case reports have linked beta-interferon (IFNβ) treatment with liver enzyme abnormalities and liver injuries in patients with multiple sclerosis (MS). Few predictors of risk exist. Objective: We investigated the effect of IFNβ and other patient characteristics on levels of the liver enzyme, alanine aminotransferase (ALT). Method: Repeated ALT test results were reviewed retrospectively for 1064 MS patients prescribed an IFNβ as their first immunomodulatory drug. Liver enzyme abnormality was defined as an ALT elevation twice the upper limit of normal (≥2 ULN). The Generalized Estimating Equation (GEE) was used to analyze the effect of age (≤35, >35–40, >40–45, >45 years), gender, disease duration, IFNβ product, and duration of treatment (≤5, >5–15, >15–40, >40 months) on de novo liver enzyme abnormality. Results: Over a mean treatment period of 38.7 months (SD = 34.9), 12.4% (95/766) of MS patients developed de novo liver enzyme abnormality. Multivariable GEE results showed a dose frequency response effect of IFNβs on liver enzyme abnormality: OR = 3.8(95% CI: 1.6–9.2) for IFNβ-1a 44 µg SC, and OR = 3.4 (95% CI: 1.5–7.9) for IFNβ-1b 250 µg SC compared with the lower frequency IFNβ-1a 30 µg IM. Younger age (≤40 years), male gender, and ≤15 months of IFNβ exposure were also independent predictors. Conclusion: A dose frequency response effect was observed, with high-frequency IFNβs having the greatest risk. The first 15 months of treatment, men, and younger patients were also associated with elevated risk. Regular ALT monitoring in MS patients appears prudent; long-term consequences of ALT elevations should be further investigated.
TLR2-dependent pathway of heterologous down-modulation for the CC chemokine receptors 1, 2, and 5 in human blood monocytes
Authors: Fox James M. , Letellier Elisa , Oliphant Christopher J. , Signoret Nathalie 
Published: December 2010

AbstractDuring innate immune responses, the inflammatory CC chemokine receptors CCR1, CCR2, and CCR5 mediate the recruitment of blood monocytes to infected tissues by promoting cell migration in response to chemokines CCL2-5. Toll-like receptors also play an essential role, allowing pathogen recognition by the recruited monocytes. Here, we demonstrate that Toll-like receptor 2 (TLR2) stimulation by lipoteichoic acid (LTA) from Staphylococcus aureus leads to gradual down-modulation of CCR1, CCR2, and CCR5 from the plasma membrane of human blood-isolated monocytes and inhibits chemotaxis. Interestingly, LTA does not promote rapid desensitization of chemokine-mediated calcium responses. We found that the TLR2 crosstalk with chemokine receptors is not dependent on the Toll/interleukin-1 receptor domain-containing adaptor protein, but instead involves phospholipase C, the small G protein Rac1, and is phorbol ester sensitive. Activation of this pathway by LTA lead to β-arrestin–mediated endocytosis of Ser349-phosphorylated CCR5 into recycling endosomes, as does CCL5 treatment. However, LTA-induced internalization of CCR5 is a slower process associated with phospholipase C–mediated and phorbol ester–sensitive phosphorylation. Overall, our data indicate that TLR2 negatively regulates CCR1, CCR2, and CCR5 on human blood monocytes by activating the machinery used to support chemokine-dependent down-modulation and provide a molecular mechanism for inhibiting monocyte migration after pathogen recognition.