bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence-based risk assessment and recommendations for physical activity clearance: cancer1This paper is one of a selection of papers published in this Special Issue, entitled Evidence-based risk assessment and recommendations for physical activity clearance, and has undergone the Journal’s usual peer review process.
Authors: Jones Lee W. 
Published: July 2011

Physical activity is becoming increasingly acknowledged as an integral component of in the multidisciplinary management of cancer patients. Intensive inquiry in this area is likely to increase further over the next decade; however, cancer-specific, evidence-based risk assessment and recommendations for physical activity are not available. A systematic literature review was performed of all studies conducting an exercise training intervention and (or) any form of objective exercise test among adults diagnosed with cancer. Studies were assessed according to evaluation criteria developed by a panel of experts. A total of 118 studies involving 5529 patients were deemed eligible. Overall, the results suggest that exercise training and maximal and submaximal exercise testing are relatively safe procedures with a total nonlife-threatening adverse event rate of <2%. There was only 1 exercise training-related death. However, the quality of exercise testing methodology and data reporting is less than optimal. Thus, whether the low incidence of events reflects the true safety of exercise training and exercise testing in cancer patients or less than optimal methodology and (or) data reporting remains to be determined. Evidence-based absolute and relative contraindications to physical activity and exercise training and testing are provided as well as probing decision-trees to optimize the adoption and safety of physical activity in persons diagnosed with cancer.
Evidence-based risk assessment and recommendations for physical activity clearance: diabetes mellitus and related comorbidities1This paper is one of a selection of papers published in this Special Issue, entitled Evidence-based risk assessment and recommendations for physical activity clearance, and has undergone the Journal’s usual peer review process.
Authors: Riddell Michael C. , Burr Jamie 
Published: July 2011

Physical activity (PA) is one of the most powerful treatment options for persons with prediabetes or diabetes. However, some elevation in risk occurs with increased PA, at least initially, and certain precautions need to be made to lower these risks, particularly if these persons are unaccustomed to exercise. We conducted a standardized search of all adverse events associated with increased PA in persons with prediabetes or diabetes (type 1 or type 2) and provided evidence-based guidelines on PA screening in these apparently high-risk individuals. A systematic literature review was performed of all studies reporting on adverse events in persons with prediabetes or diabetes. Studies included were from all designs (retrospective and prospective including randomized controlled trials) and were assessed according to evaluation criteria adapted by a consensus panel. A total of 47 studies, involving >8000 individuals, were deemed eligible. A number of these studies identified a range of mild to severe acute risks with exercise (musculoskeletal injury, hypoglycemia, foot ulceration, proliferative retinopathy, hypotension, sudden death) but the overall prevalence was low. Based on several randomized controlled trials and prospective studies in which prescribed exercise was performed at a wide range of intensities, it appears that increased PA is a relatively safe procedure with no evidence of a loss of life. Based on our assessment of the available literature, we provide a new PA risk algorithm for persons with prediabetes and diabetes and comment on the role of the patient, the qualified exercise professional, and the patient’s physician in the risk screening process.
Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1-Interacting Genes
Authors: Rebbeck Timothy R. , Mitra Nandita , Domchek Susan M. , Wan Fei , Friebel Tara M. , Tran Teo V. , Singer Christian F. , Tea Muy-Kheng Maria , Blum Joanne L. , Tung Nadine , Olopade Olufunmilayo I. , Weitzel Jeffrey N. , Lynch Henry T. , Snyder Carrie L. , Garber Judy E. , Antoniou Antonis C. , Peock Susan , Evans D. Gareth , Paterson Joan , Kennedy M. John , Donaldson Alan , Dorkins Huw , Easton Douglas F. , Rubinstein Wendy S. , Daly Mary B. , Isaacs Claudine , Nevanlinna Heli , Couch Fergus J. , Andrulis Irene L. , Freidman Eitan , Laitman Yael , Ganz Patricia A. , Tomlinson Gail E. , Neuhausen Susan L. , Narod Steven A. , Phelan Catherine M. , Greenberg Roger , Nathanson Katherine L. 
Published: July 2011

Abstract
Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (PFDR) with breast cancer were identified at ATM (PFDR = 0.029), BRCC45 (PFDR = 0.019), BRIP1 (PFDR = 0.008), CTIP (PFDR = 0.017), MERIT40 (PFDR = 0.019), NBS1 (PFDR = 0.003), RAD50 (PFDR = 0.014), and TOPBP1 (PFDR = 0.011). Haplotypes at ABRA1 (PFDR = 0.007), BRCC45 (PFDR = 0.016 and PFDR = 0.005 in two haplotype blocks), and RAP80 (PFDR &lt; 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations. Cancer Res; 71(17); 5792–805. ©2011 AACR.
Taxane-Induced Blockade to Nuclear Accumulation of the Androgen Receptor Predicts Clinical Responses in Metastatic Prostate Cancer
Authors: Darshan Medha S. , Loftus Matthew S. , Thadani-Mulero Maria , Levy Benjamin P. , Escuin Daniel , Zhou Xi Kathy , Gjyrezi Ada , Chanel-Vos Chantal , Shen Ruoqian , Tagawa Scott T. , Bander Neil H. , Nanus David M. , Giannakakou Paraskevi 
Published: July 2011

AbstractProstate cancer progression requires active androgen receptor (AR) signaling which occurs following translocation of AR from the cytoplasm to the nucleus. Chemotherapy with taxanes improves survival in patients with castrate resistant prostate cancer (CRPC). Taxanes induce microtubule stabilization, mitotic arrest, and apoptotic cell death, but recent data suggest that taxanes can also affect AR signaling. Here, we report that taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as prostate-specific antigen. AR nuclear translocation was not inhibited in cells with acquired β-tubulin mutations that prevent taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking. Upon ligand activation, AR associated with the minus-end-microtubule motor dynein, thereby trafficking on microtubules to translocate to the nucleus. Analysis of circulating tumor cells (CTC) isolated from the peripheral blood of CRPC patients receiving taxane chemotherapy revealed a significant correlation between AR cytoplasmic sequestration and clinical response to therapy. These results indicate that taxanes act in CRPC patients at least in part by inhibiting AR nuclear transport and signaling. Further, they suggest that monitoring AR subcellular localization in the CTCs of CRPC patients might predict clinical responses to taxane chemotherapy. Cancer Res; 71(18); 6019–29. ©2011 AACR.
Discovery of Mdm2-MdmX E3 Ligase Inhibitors Using a Cell-Based Ubiquitination Assay
Authors: Herman Ariel G. , Hayano Miki , Poyurovsky Masha V. , Shimada Kenichi , Skouta Rachid , Prives Carol , Stockwell Brent R. 
Published: July 2011

Abstract
E3 ubiquitin ligases are of interest as drug targets for their ability to regulate protein stability and function. The oncogene Mdm2 is an attractive E3 ligase to target, as it is the key negative regulator of the tumor suppressor p53, which controls the transcription of genes involved in cell fate. Overexpression of Mdm2 facilitates tumorigenesis by inactivating p53, and through p53-independent oncogenic effects. We developed a high-throughput cellular Mdm2 auto-ubiquitination assay, which we used to discover a class of small-molecule Mdm2 ligase activity inhibitors. These compounds inhibit Mdm2 and p53 ubiquitination in cells, reduce viability of cells with wild-type p53, and synergize with DNA-damaging agents to cause cell death. We determined that these compounds effectively inhibit the E3 ligase activity of the Mdm2-MdmX hetero-complex. This mechanism may be exploitable to create a new class of anti-tumor agents.
Significance: We identified a class of small-molecule inhibitors of the Mdm2-MdmX hetero-complex E3 ligase activity through a high-throughput cell-based Mdm2 ubiquitination screen. This is a new target for small-molecule therapeutics and may be developed to treat specific cancers. Cancer Discovery; 1(4); 312–25. ©2011 AACR.
This article is highlighted in the In This Issue feature, p. 275
Validation of the CHADS2 clinical prediction rule to predict ischaemic stroke
Authors: Wallace Emma , Dillon Ciara , Dimitrov Borislav , Fahey Tom , Keogh Claire 
Published: July 2011

SummaryThe CHADS2 predicts annual risk of ischaemic stroke in non-valvular atrial fibrillation. This systematic review and meta-analysis aims to determine the predictive value of CHADS2. The literature was systematically searched from 2001 to October 2010. Data was pooled and analysed using discrimination and calibration statistical measures, using a random effects model. Eight data sets (n=2815) were included. The diagnostic accuracy suggested a cut-point of ≥1 has higher sensitivity (92%) than specificity (12%) and a cut-point of ≥4 has higher specificity (96%) than sensitivity (33%). Lower summary estimates were observed for cut-points ≥2 (sensitivity 79%, specificity 42%) and ≥3 (specificity 77%, sensitivity 50%). There was insufficient data to analyse cut-points ≥5 or ≥6. Moderate pooled c statistic values were identified for the classic (0.63, 95% CI 0.52–0.75) and revised (0.60, 95% CI 0.43–0.72) view of stratification of the CHADS2 . Calibration analysis in-dicated no significant difference between the predicted and observed strokes across the three risk strata for the classic or revised view. All results were associated with high heterogeneity, and conclusions should be made cautiously. In conclusion, the pooled c statistic and calibration analysis suggests minimal clinical utility of both the classic and revised view of the CHADS2 in predicting ischaemic stroke across all risk strata. Due to high heterogeneity across studies and low event rates across all risk strata, the results should be interpreted cautiously. Further validation of CHADS2 should perhaps be undertaken, given the methodological differences between many of the available validation studies and the original CHADS2 derivation study.
Binding characteristics of thrombin-activatable fibrinolysis inhibitor to streptococcal surface collagen-like proteins A and B
Authors: Serón Mercedes , Plug Tom , Arnoud Marquart J. , Marx Pauline , Herwald Heiko , de Groot Philip , Meijers Joost 
Published: July 2011

SummaryStreptococcus pyogenes is the causative agent in a wide range of diseases in humans. Thrombin-activatable fibrinolysis inhibitor (TAFI) binds to collagen-like proteins SclA and SclB at the surface of S. pyogenes. Activation of TAFI at this surface redirects inflammation from a transient to chronic state by modulation of the kallikrein/kinin system. We investigated TAFI binding characteristics to SclA/SclB. Thirty-four overlapping TAFI peptides of ∼20 amino acids were generated. Two of these peptides (P18: residues G205-S221, and P19: R214-D232) specifically bound to SclA/SclB with high affinity, and competed in a dose-dependent manner with TAFI binding to SclA/SclB. In another series of experiments, the binding properties of activated TAFI (TAFIa) to SclA/SclB were studied with a quadruple TAFI mutant (TAFI-IIYQ) that after activation is a 70-fold more stable enzyme than wild-type TAFIa. TAFI and TAFI-IIYQ bound to the bacterial proteins with similar affinities. The rate of dissociation was different between the proenzyme (both TAFI and TAFI-IIYQ) and the stable enzyme TAFIa-IIYQ. TAFIa-IIYQ bound to SclA/ SclB, but dissociated faster than TAFI-IIYQ. In conclusion, the bacterial proteins SclA and SclB bind to a TAFI fragment encompassing residues G205-D232. Binding of TAFI to the bacteria may allow activation of TAFI, whereafter the enzyme easily dissociates.
Differentiation of cGMP-dependent and -independent nitric oxide effects on platelet apoptosis and reactive oxygen species production using platelets lacking soluble guanylyl cyclase
Authors: Rukoyatkina Natalia , Walter Ulrich , Friebe Andreas , Gambaryan Stepan 
Published: July 2011

SummaryPlatelet activation is an irreversible process resulting in platelet apoptosis and necrosis, and circulating platelets contain many components of the apoptotic machinery. Cyclic guanosine monophosphate (cGMP) generated by nitric oxide (NO) activated soluble guanylyl cyclase (sGC) plays a crucial role in preventing platelet activation. However, in addition to activation of sGC, cGMP-independent NO effects in platelets have been described. To differentiate between cGMP-dependent and -independent NO effects on platelet apoptosis and reactive oxygen species (ROS) production, we generated platelet-specific sGC-deficient mice (PS-GCKO). Platelet apoptosis was induced by a combination of thrombin/convulxin (Thr/Cvx) and assessed by phosphatidylserine (PS) surface exposure, and loss of the mitochondrial membrane potential. NO-induced inhibition of PS externalisation was mediated only by cGMP-dependent mechanisms. Inhibition of the mitochondrial membrane potential decrease at low NO concentration was also cGMP-dependent but became cGMP-independent at high NO concentrations. In contrast, inhibition of ROS formation at any NO concentration was mediated by cGMP-independent mechanisms, very likely due to direct radical scavenging. NO inhibits platelet apoptosis by cGMP-dependent mechanisms and ROS production by cGMP-independent mechanisms. The PS-GCKO mouse model is an important tool for the differentiation of cGMP-dependent and -independent NO effects on platelets.
Cilostazol Suppresses Angiotensin II–Induced Vasoconstriction via Protein Kinase A–Mediated Phosphorylation of the Transient Receptor Potential Canonical 6 Channel
Authors: Nishioka Kinue , Nishida Motohiro , Ariyoshi Marina , Jian Zhong , Saiki Shota , Hirano Mayumi , Nakaya Michio , Sato Yoji , Kita Satomi , Iwamoto Takahiro , Hirano Katsuya , Inoue Ryuji , Kurose Hitoshi 
Published: July 2011

Objective—
The goal of this study was to determine whether inhibition of transient receptor potential canonical (TRPC) channels underlies attenuation of angiotensin II (Ang II)–induced vasoconstriction by phosphodiesterase (PDE) 3 inhibition.

Methods and Results—

Pretreatment of rat thoracic aorta with cilostazol, a selective PDE3 inhibitor, suppressed vasoconstriction induced by Ang II but not that induced by KCl. The Ang II–induced contraction was largely dependent on Ca
2+
influx via receptor-operated cation channels. Cilostazol specifically suppressed diacylglycerol-activated TRPC channels (TRPC3/TRPC6/TRPC7) through protein kinase A (PKA)–dependent phosphorylation of TRPC channels in HEK293 cells. In contrast, we found that phosphorylation of TRPC6 at Thr69 was essential for the suppression of Ang II–induced Ca
2+
influx by PDE3 inhibition in rat aortic smooth muscle cells (RAoSMCs). Cilostazol specifically induced phosphorylation of endogenous TRPC6 at Thr69. The endogenous TRPC6, but not TRPC3, formed a ternary complex with PDE3 and PKA in RAoSMCs, suggesting the specificity of TRPC6 phosphorylation by PDE3 inhibition. Furthermore, inhibition of PDE3 suppressed the Ang II–induced contraction of reconstituted ring with RAoSMCs, which were abolished by the expression of a phosphorylation-deficient mutant of TRPC6.

Conclusion—
PKA-mediated phosphorylation of TRPC6 at Thr69 is essential for the vasorelaxant effects of PDE3 inhibition against the vasoconstrictive actions of Ang II.
Overexpression of Catalase in Myeloid Cells Causes Impaired Postischemic Neovascularization
Authors: Hodara Roberto , Weiss Daiana , Joseph Giji , Velasquez-Castano Juan C. , Landázuri Natalia , Han Ji Woong , Yoon Young-sup , Taylor W. Robert 
Published: July 2011

Objective—
Myeloid lineage cells (MLCs) such as macrophages are known to play a key role in postischemic neovascularization. However, the role of MLC-derived reactive oxygen species in this process and their specific chemical identity remain unknown.

Methods and Results—

Transgenic mice with MLC-specific overexpression of catalase (Tg
Cat-MLC
mice) were created on a C57BL/6 background. Macrophage catalase activity was increased 3.4-fold compared with wild-type mice. After femoral artery ligation, laser Doppler perfusion imaging revealed impaired perfusion recovery in Tg
Cat-MLC
mice. This was associated with fewer collateral vessels, as assessed by microcomputed tomography angiography, and decreased capillary density. Impaired functional recovery of the ischemic limb was also evidenced by a 50% reduction in spontaneous running activity. The deficient neovascularization was associated with a blunted inflammatory response, characterized by decreased macrophage infiltration of ischemic tissues, and lower mRNA levels of inflammatory markers, such as tumor necrosis factor-α, osteopontin, and matrix mettaloproteinase-9. In vitro macrophage migration was impaired in Tg
Cat-MLC
mice, suggesting a role for H
2
O
2
in regulating the ability of macrophages to infiltrate ischemic tissues.

Conclusion—

MLC-derived H
2
O
2
plays a key role in promoting neovascularization in response to ischemia and is a necessary factor for the development of ischemia-induced inflammation.
Association Between Mycoplasma Pneumonia and Increased Risk of Ischemic Stroke
Authors: Chiang Chia-Hung , Huang Chin-Chou , Chan Wan-Leong , Chen Yu-Chun , Chen Tzeng-Ji , Lin Shing-Jong , Chen Jaw-Wen , Leu Hsin-Bang 
Published: July 2011

Background and Purpose—
Infections have been hypothesized to play a role in vascular disease. The association between Mycoplasma pneumoniae (MP) infection and ischemic stroke remained undetermined.

Methods—
A total of 1094 patients with MP infection were enrolled as the study group and compared with 5168 sex-, age-, and comorbidity-matched subjects without MP, to be followed up prospectively from January 2003 to December 2007 for development of ischemic stroke.

Results—

During a maximum 5-year follow-up period, 49 patients with ischemic stroke were identified. Subjects with MP infection were significantly associated with increased risk of ischemic stroke compared with controls (1.10% versus 0.72%, respectively;
P
=0.01). The logrank test showed that patients with MP had significantly higher incidence of stroke development than did those without MP (
P
=0.046). After Cox model adjustment for risk factors and comorbidities, MP infection was still independently associated with increased risk of stroke (hazard ratio [HR], 2.07; 95% CI, 1.05–4.03).

Conclusions—
We conclude that MP infection is independently associated with risk of subsequent ischemic stroke development.
Efficacy and Safety of Combination Antiplatelet Therapies in Patients With Symptomatic Intracranial Atherosclerotic Stenosis
Authors: Kwon Sun U. , Hong Keun-Sik , Kang Dong-Wha , Park Jong-Moo , Lee Ju-Hun , Cho Yong-Jin , Yu Kyung-Ho , Koo Ja-Seong , Wong K.S. Lawrence , Lee Seung-Hoon , Lee Kyung Bok , Kim Dong-Eog , Jeong Sang-Wook , Bae Hee-Joon , Lee Byung-Chul , Han Moon-Ku , Rha Joung-Ho , Kim Hahn Young , Mok Vincent C. , Lee Yong-Seok , Kim Gyeong-Moon , Suwanwela Nijasri Charnnarong , Yun Sung-Cheol , Nah Hyun-Wook , Kim Jong S. 
Published: July 2011

Background and Purpose—
An optimal strategy for management of symptomatic intracranial atherosclerotic stenosis (ICAS) has not yet been established. We compared the efficacy of 2 combinations of antiplatelets, aspirin plus cilostazol (cilostazol group) verus aspirin plus clopidogrel (clopidogrel group), on the progression of ICAS, which is known to be associated with clinical stroke recurrence.

Methods—
In this investigator-initiated double-blind trial, 457 patients with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or the basilar artery were randomly allocated into either a cilostazol group or a clopidogrel group. After 7 months of treatment, follow-up MR angiogram and MRI were performed. The primary end point was the progression of ICAS in comparison with stenosis on the baseline MR angiogram. Secondary end points included the occurrence of new ischemic lesions on MRI, composite of cardiovascular events, and major bleeding complications.

Results—

Cardiovascular events occurred in 15 of 232 patients (6.4%) in the cilostazol group and 10 of 225 (4.4%) in the clopidogrel group (
P
=0.312). Cilostazol did not reduce the progression of symptomatic ICAS (20 of 202) compared to clopidogrel (32 of 207) (odds ratio, 0.61;
P
=0.092), although favorable changes in serum lipoproteins were observed in the cilostazol group. There were no significant differences between the 2 groups with respect to new ischemic lesions (18.7% versus 12.0%;
P
=0.078) and major hemorrhagic complications (0.9% versus 2.6%;
P
=0.163).

Conclusions—
This trial failed to show significant difference in preventing progression of ICAS and new ischemic lesions between the 2 combination antiplatelet therapies in the patients with symptomatic ICAS.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00130039.
Effect of Increased Warfarin Use on Warfarin-Related Cerebral Hemorrhage
Authors: Huhtakangas Juha , Tetri Sami , Juvela Seppo , Saloheimo Pertti , Bode Michaela K. , Hillbom Matti 
Published: July 2011

Background and Purpose—
Warfarin use has rapidly increased with the aging of the population. We investigated the temporal trends in the incidence and outcome of warfarin-related intracerebral hemorrhages (ICHs) in a defined population.

Methods—
We identified all subjects with first-ever primary ICH during 1993 to 2008 among the population of Northern Ostrobothnia, Finland. The number of warfarin users was obtained from the national register of prescribed medicines kept by the Social Insurance Institution of Finland. We calculated the annual incidence of warfarin-related ICHs, 28-day case fatality, and deaths from the primary bleed.

Results—

The proportion of warfarin users among the population increased 3.6-fold from 0.68% in 1993 to 2.28% in 2008. Of a total of 982 patients with ICH, 182 (18.5%) had warfarin-related ICH. One-year survival rate after onset of stroke was 35.2% among warfarin users and 67.9% among nonusers. The annual incidence (
P
=0.062) and 28-day case fatality of warfarin-related ICHs (
P
=0.002) decreased during the observation period. Warfarin users were older (mean difference 6.6; 95% CI, 5.0 to 8.1;
P
<0.001) than nonusers. Admission international normalized ratio values above the therapeutic range (2.0 to 3.0) decreased through the observation period, suggesting improved control of anticoagulant therapy over time.

Conclusions—
The annual incidence and case fatality of warfarin-related ICHs decreased, although the proportion of warfarin users almost quadrupled in our population.