bluuebunny/crossref_metadata_2025_split huggingface dataset:
PIK3CA Mutations May Be Discordant between Primary and Corresponding Metastatic Disease in Breast Cancer
Authors: Dupont Jensen Jeanette , Laenkholm Anne-Vibeke , Knoop Ann , Ewertz Marianne , Bandaru Raj , Liu Weihua , Hackl Wolfgang , Barrett J. Carl , Gardner Humphrey 
Published: October 2010

Abstract
Purpose: PIK3CA mutations are frequent in breast cancer and activate the PI3K/Akt pathway. Unexpectedly, PIK3CA mutation appears in general to be associated with better outcome. In a cohort of patients where both primary and metastatic lesions were available, the objective was to assess changes in PIK3CA mutations. We wished to discern whether selective pressures occur and the influence of PIK3CA mutation on time to recurrence.
Experimental Design: Formalin-fixed paraffin-embedded tumor blocks were obtained from 104 patients with paired samples from primary tumors and corresponding asynchronous metastatic breast tumors. Samples were analyzed for PIK3CA mutations (exons 9 and 20) as well as immunohistochemical evaluation for PTEN, pAKT, Ki67, ER, and HER2.
Results: PIK3CA mutation was detected in 45% of the primary tumors. Overall, there was a net gain in mutation in metastatic disease, to 53%; nonetheless, there were instances where metastases were wild type in patients with PIK3CA mutant primary tumors. Laser capture microdissection on a subset of cases revealed microheterogeneity for PIK3CA mutational status in the primary tumor. PIK3CA mutants overall showed a significantly longer time to first recurrence than wild type cases (P = 0.03).
Conclusion: PIK3CA mutations occur at high frequency in primary and metastatic breast cancer; these may not necessarily confer increased aggressiveness as mutants had a longer time to recurrence. Because PIK3CA status quite frequently changes between primary and metastatic disease, it emphasizes the necessity of assessing the PIK3CA status in the metastatic lesion for selection of PIK3CA inhibitor therapy. Clin Cancer Res; 17(4); 667–77. ©2010 AACR.
Resistance May Not Be Futile: microRNA Biomarkers for Chemoresistance and Potential Therapeutics
Authors: Allen Kristi E. , Weiss Glen J. 
Published: October 2010

Abstract
Chemoresistance to many commercially available cancer therapeutic drugs is a common occurrence and contributes to cancer mortality as it often leads to disease progression. There have been a number of studies evaluating the mechanisms of resistance and the biological factors involved. microRNAs have recently been identified as playing a role in the regulation of key genes implicated as cancer therapeutic targets or in mechanisms of chemoresistance including EGFR, MDR1, PTEN, Bak1, and PDCD4 among others. This article briefly reviews chemoresistance mechanisms, discusses how microRNAs can play a role in those mechanisms, and summarizes current research involving microRNAs as both regulators of key target genes for chemoresistance and biomarkers for treatment response. It is clear from the accumulating literature that microRNAs can play an important role in chemoresistance and hold much promise for the development of targeted therapies and personalized medicine. This review brings together much of this new research as a starting point for identifying key areas of interest and potentials for future study. Mol Cancer Ther; 9(12); 3126–36. ©2010 AACR.
A Comprehensive Survey of Clonal Diversity Measures in Barrett's Esophagus as Biomarkers of Progression to Esophageal Adenocarcinoma
Authors: Merlo Lauren M.F. , Shah Najaf A. , Li Xiaohong , Blount Patricia L. , Vaughan Thomas L. , Reid Brian J. , Maley Carlo C. 
Published: October 2010

AbstractNeoplastic progression is an evolutionary process driven by the generation of clonal diversity and natural selection on that diversity within a neoplasm. We hypothesized that clonal diversity is associated with risk of progression to cancer. We obtained molecular data from a cohort of 239 participants with Barrett's esophagus, including microsatellite shifts and loss of heterozygosity, DNA content tetraploidy and aneuploidy, methylation, and sequence mutations. Using these data, we tested all major diversity measurement methods, including genetic divergence and entropy-based measures, to determine which measures are correlated with risk of progression to esophageal adenocarcinoma. We also tested whether the use of different sets of loci and alterations to define clones (e.g., selectively advantageous versus evolutionarily neutral) improved the predictive value of the diversity indices. All diversity measures were strong and highly significant predictors of progression (Cox proportional hazards model, P &lt; 0.001). The type of alterations evaluated had little effect on the predictive value of most of the diversity measures. In summary, diversity measures are robust predictors of progression to cancer in this cohort. Cancer Prev Res; 3(11); 1388–97. ©2010 AACR.
Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation
Authors: Takemitsu Tetsushi , Hatada Tsuyoshi , Ohmori Yukinari , Ishikura Ken , Takeda Taichi , Sugiyama Takashi , Yamada Norikazu , Maruyama Kazuo , Katayama Naoyuki , Isaji Shuji , Shimpo Hideto , Kusunoki Masato , Nobori Tsutomu , Wada Hideo 
Published: October 2010

SummaryThere are three different diagnostic score systems for disseminated intravascular coagulation (DIC) established by the Japanese Ministry Health and Welfare (JMHW), the International Society on Thrombosis and Haemostasis (ISTH) and the Japanese Association for Acute Medicine (JAAM). The JMHW criteria are still used in Japan. In the present study, all three diagnostic criteria were used to prospectively evaluate 413 patients with different underlying diseases of DIC who were treated at the Mie University Hospital (JMHW, n= 166; ISTH, n=143; JAAM, n=291). The odds ratio (95% confidence interval) for death was 1.88 (1.22 – 2.90) in JMHW, 2.55 (1.65 – 3.95) in ISHT and 1.99 (1.19 – 3.32) in JAAM. The platelet count, prothrombin time, fibrin and fibri-nogen degradation products and fibrinogen were significantly important for diagnosis of DIC by all three diagnostic criteria. Haemostatic molecular markers were significantly high in all patients and were useful for the diagnosis of DIC. The JAAM diagnostic criteria displayed a high sensitivity for DIC and the ISTH overt-DIC diagnostic criteria displayed a high specificity for DIC. All three diagnostic criteria for DIC were related to a poor patient outcome.
Megakaryocyte gene targeting mediated by restricted expression of recombinase Cre
Authors: Nowakowski Adam , Alonso-Martín Sonia , Arias-Salgado Elena , Fernández Darío , Vilar MariPaz , Ayuso Matilde , Parrilla Roberto 
Published: October 2010

SummaryThe availability of mice with tissue-specific expression of recombinase Cre is the limiting step for a successful gene targeting by the Cre-LoxP methodology. This work aimed at generating transgenic mice with restricted expression of recombinase Cre in megakaryocytes and platelets, driven by the promoter of the αIIb gene (mαIIb-cre). Mice oocytes were microinjected with a 4.1 Kb construct comprising a 2.7 Kb promoter fragment of the glycoprotein αIIb gene, linked to the CrecDNA and followed by the polyA tail of the SV40. We found four mice with positive DNA genotype and three probable sites of genomic integration of the transgene. Only two of the founders showed presence of Cre-mRNA and production of Cre protein, restricted to megakaryocytes. The activity of Cre in mediating gene targeting was assessed by crossing mαIIb-cre mice to Cre-reporter mice (ROSA26-lacZ). The activity of β-galactosidase, detected only in megakaryocytes, was sufficient to generate intense staining of X-Gal in hepatic haematopoietic islands of 14.5 dpc fetuses, in bone marrow megakaryocytes and platelets from adult mice as well as in vitro cultured megakaryocytes differentiated from bone marrow hematopoietic stem cells. Moreover, the recombinase activity was sufficient to produce the specific gene targeting of a floxed CD40L allele in megakaryocytes. The mαIIb-cre transgenic mice with restricted production of Cre in megakaryocytes, offers a selective, alternative, new tool for the genetic analysis of platelet pathophysiology.
Apixaban versus enoxaparin in patients with total knee arthroplasty
Authors: Huang Jiahao , Liao Cun , Wu Liucheng , Cao Yunfei , Gao Feng 
Published: October 2010

SummaryIt was the objective of this study to systematically compare the effects of apixaban versus enoxaparin in patients following total knee arthroplasty (TKA). A systematic search of Medline, EMBASE, Cochrane Central Register of Controlled Trials was conducted. Eligible studies were prospective, randomised control trials (RCT) of apixaban therapy, comparing with enoxaparin, in patients who have a high risk of venous thromboembolism (VTE) after TKA. Three RCTs involving 7,337 individuals were identified, of whom 4,057 were treated with apixaban 2.5 mg once daily, and 3280 were subcutaneous enoxaparin (40 mg once-daily or 30 mg twice-daily). Meta-analysis demonstrated the odds ratio (OR) for the composite of major VTE (proximal deep-vein thrombosis and pulmonary embolism) for apixaban versus enoxaparin was 0.47 (95% confidence interval [CI]: 0.27 to 0.82, 0.6% vs. 1.2%) and 2.09 (95%CI: 0.99 to 4.45, 0.6% vs. 0.3%), respectively. All-cause mortality occurred in 0.2% of the apixaban group versus 0.09% of the enoxaparin group (OR=1.74; 95%CI, 0.51 to 5.95). With respect to safety outcomes, apixaban was associated with a lower major bleeding rate than enoxaparin (OR=0.55, 95%CI: 0.32 to 0.96). No significant differences were detected between two strategies in other endpoints of safety profile analysed: clinically relevant non-major bleeding, raised hepatic transaminase enzyme or bilirubin concentrations and arterial thromboembolic events. In conclusion, apixaban is non-inferior to subcutaneous enoxaparin when used for the same duration, with considerable advantage regarding safety profile of major bleeding after TKA.
Endothelial, Sympathetic, and Cardiac Function in Inherited (6
R
)-
l
-Erythro-5,6,7,8-Tetrahydro-
l
-Biopterin Deficiency
Authors: Mayahi Lila , Mason Lydia , Bleasdale-Barr Katherine , Donald Ann , Trender-Gerhard Iris , Sweeney Mary G. , Davis Mary B. , Wood Nicholas , Mathias Christopher J. , Watson Laura , Pellerin Denis , Heales Simon , Deanfield John E. , Bhatia Kailash , Murray-Rust Judith , Hingorani Aroon D. 
Published: October 2010

Background—

(6
R
)-5,6,7,8-Tetrahydro-
l
-biopterin (BH4) is a cofactor for enzymes involved in catecholamine and nitric oxide generation whose synthesis is initiated by GTP cyclohydrolase I (GTPCH-1), encoded by
GCH1
. In the absence of a potent, specific GTPCH-1 inhibitor, natural BH4 deficiency caused by mutations in
GCH1
in the rare movement disorder, DOPA-responsive dystonia (OMIM DYT5), offers the opportunity to study the role of endogenous BH4 in humans.

Methods and Results—

In 16 DOPA-responsive dystonia patients with mutations predicted to affect GTPCH-1 expression or function and in age- and sex-matched control subjects, we measured plasma biopterin and nitrogen oxides by high-performance liquid chromatography and the Griess reaction, respectively, endothelial function by brachial artery flow-mediated dilation (FMD), sympathetic function by measurement of plasma norepinephrine, epinephrine, and heart rate and blood pressure in response. Cardiac function and structure were assessed by echocardiography. Plasma biopterin was lower in patients (5.76±0.53 versus 8.43±0.85 nmol/L,
P
=0.03), but plasma NO
2
−
/NO
3
−
(NOx) (median, 9.06 [interquartile range, 5.35 to 11.04] versus 8.40 [interquartile range, 5.28 to 11.44] μmol/L,
P
=1) and FMD were not lower (7.7±0.8% versus 7.9±0.9%,
P
=0.91). In patients but not control subjects, FMD was insensitive to nitric oxide synthase inhibition (FMD at baseline, 6.7±2.1%; FMD during
l
-NMMA infusion, 6.2±2.5,
P
=0.68). The heart rate at rest was higher in patients, but the heart rate and blood pressure response to sympathetic stimulation did not differ in patients and control subjects despite lower concentrations of norepinepherine (264±8 pg/mL versus 226±9 pg/mL,
P
=0.006) and epinephrine (33.8±5.2 pg/mL versus 17.8±4.6 pg/mL,
P
=0.03) in patients. There was also no difference in cardiac function and structure.

Conclusions—
Sympathetic, cardiac, and endothelial functions are preserved in patients with GCH1 mutations despite a neurological phenotype, reduced plasma biopterin, and norepinepherine and epinephrine concentrations. Lifelong endogenous BH4 deficiency may elicit developmental adaptation through mechanisms that are inaccessible during acquired BH4 deficiency in adulthood.
Geographic Variation and Trends in Carotid Imaging Among Medicare Beneficiaries, 2001 to 2006
Authors: Curtis Lesley H. , Greiner Melissa A. , Patel Manesh R. , Duncan Pamela W. , Schulman Kevin A. , Matchar David B. 
Published: October 2010

Background—
Diagnostic imaging among Medicare beneficiaries is an important contributor to rising health care costs. We examined temporal trends and geographic variation in the use of carotid ultrasound, carotid magnetic resonance angiography (MRA), and carotid x-ray angiography.

Methods and Results—
Analysis of a 5% national sample of claims from the Centers for Medicare and Medicaid Services for 1999 through 2006. Patients were 65 years or older and underwent carotid ultrasound, carotid MRA, carotid x-ray angiography, or a carotid intervention. The main outcome measures were annual age-adjusted rates of carotid imaging and interventions and factors associated with the use of carotid imaging. Rates of imaging increased by 27%, from 98.2 per 1000 person-years in 2001 to 124.3 per 1000 in 2006. Rates of carotid ultrasound increased by 23%, and rates of MRA increased by 66%. Carotid intervention rates decreased from 3.6 per 1000 person-years in 2001 to 3.1 per 1000 person-years in 2006. In 2006, rates of carotid ultrasound were lowest in the New England, Mountain, and West North Central regions and highest in the Middle Atlantic and South Atlantic regions. Regional differences persisted after adjustment for patient demographic characteristics, history of vascular disease and other comorbid conditions, and study year.

Conclusions—
From 2001 through 2006, there was substantial growth and variation in the use of carotid imaging, including a marked increase in the use of MRA, and a decrease in the overall rate of carotid intervention.
High-Resolution Magnetic Resonance Imaging Enhanced With Superparamagnetic Nanoparticles Measures Macrophage Burden in Atherosclerosis
Authors: Morishige Kunio , Kacher Daniel F. , Libby Peter , Josephson Lee , Ganz Peter , Weissleder Ralph , Aikawa Masanori 
Published: October 2010

Background—
Macrophages contribute to the progression and acute complications of atherosclerosis. Macrophage imaging may serve as a biomarker to identify subclinical inflamed lesions, to predict future risk, and to aid in the assessment of novel therapies.

Methods and Results—

To test the hypothesis that nanoparticle-enhanced, high-resolution magnetic resonance imaging (MRI) can measure plaque macrophage accumulation, we used 3-T MRI with a macrophage-targeted superparamagnetic nanoparticle preparation (monocrystalline iron oxide nanoparticles-47 [MION-47]) in cholesterol-fed New Zealand White rabbits 6 months after balloon injury. In vivo MRI visualized thickened abdominal aortas on both T1- and T2-weighted spin-echo images (T1 spin echo, 20 axial slices per animal; T2 spin echo, 28 slices per animal). Seventy-two hours after MION-47 injection, aortas exhibited lower T2 signal intensity compared with before contrast imaging (signal intensity ratio, aortic wall/muscle: before, 1.44±0.26 versus after, 0.95±0.22; 164 slices;
P
<0.01), whereas T1 spin echo images showed no significant change. MRI on ex vivo specimens provided similar results. Histological studies colocalized iron accumulation with immunoreactive macrophages in atheromata. The magnitude of signal intensity reduction on T2 spin echo in vivo images further correlated with macrophage areas in situ (150 slices;
r
=0.73). Treatment with rosuvastatin for 3 months yielded diminished macrophage content (
P
<0.05) and reversed T2 signal intensity changes (
P
<0.005). Signal changes in rosuvastatin-treated rabbits correlated with reduced macrophage burden (
r
=0.73). In vitro validation studies showed concentration-dependent MION-47 uptake by human primary macrophages.

Conclusion—
The magnitude of T2 signal intensity reduction in high-resolution MRI after administration of superparamagnetic phagocytosable nanoparticles can assess macrophage burden in atheromata, providing a clinically translatable tool to identify inflamed plaques and to monitor therapy-mediated changes in plaque inflammation.
Electropathological Substrate of Longstanding Persistent Atrial Fibrillation in Patients With Structural Heart Disease
Authors: de Groot Natasja M.S. , Houben Richard P.M. , Smeets Joep L. , Boersma Eric , Schotten Ulrich , Schalij Martin J. , Crijns Harry , Allessie Maurits A. 
Published: October 2010

Background—
During persistent atrial fibrillation (AF), waves with a focal spread of activation are frequently observed. The origin of these waves and their relevance for the persistence of AF are unknown.

Methods and Results—

In 24 patients with longstanding persistent AF and structural heart disease, high-density mapping of the right and left atria was performed during cardiac surgery. In a reference group of 25 patients, AF was induced by rapid pacing. For data analysis, a mapping algorithm was developed that separated the fibrillatory process into its individual wavelets and identified waves with a focal origin. During persistent AF, the incidence of focal fibrillation waves in the right atrium was almost 4-fold higher than during acute AF (median, 0.46 versus 0.12 per cycle per 1 cm
2
(25th to 75th percentile, 0.40 to 0.77 and 0.01 to 0.27;
P
<0.0001). They were widely distributed over both atria and were recorded at 46±18 of all electrodes. A large majority (90.5) occurred as single events. Repetitive focal activity (>3) happened in only 0.8. The coupling interval was not more than 11 ms shorter than the average AF cycle length (
P
=0.04), and they were not preceded by a long interval. Unipolar electrograms at the site of origin showed small but clear R waves. These data favor epicardial breakthrough rather than a cellular focal mechanism as the underlying mechanism. Often, conduction from a site of epicardial breakthrough was blocked in 1 or more directions. This generated separate multiple wave fronts propagating in different directions over the epicardium.

Conclusions—
Focal fibrillation waves are due to epicardial breakthrough of waves propagating in deeper layers of the atrial wall. In patients with longstanding AF, the frequency of epicardial breakthroughs was 4 times higher than during acute AF. Because they provide a constant source of independent fibrillation waves originating over the entire epicardial surface, they offer an adequate explanation for the high persistence of AF in patients with structural heart disease.
Vascular Endothelial Growth Factor-B Acts as a Coronary Growth Factor in Transgenic Rats Without Inducing Angiogenesis, Vascular Leak, or Inflammation
Authors: Bry Maija , Kivelä Riikka , Holopainen Tanja , Anisimov Andrey , Tammela Tuomas , Soronen Jarkko , Silvola Johanna , Saraste Antti , Jeltsch Michael , Korpisalo Petra , Carmeliet Peter , Lemström Karl B. , Shibuya Masabumi , Ylä-Herttuala Seppo , Alhonen Leena , Mervaala Eero , Andersson Leif C. , Knuuti Juhani , Alitalo Kari 
Published: October 2010

Background—
Vascular endothelial growth factor-B (VEGF-B) binds to VEGF receptor-1 and neuropilin-1 and is abundantly expressed in the heart, skeletal muscle, and brown fat. The biological function of VEGF-B is incompletely understood.

Methods and Results—

Unlike placenta growth factor, which binds to the same receptors, adeno-associated viral delivery of VEGF-B to mouse skeletal or heart muscle induced very little angiogenesis, vascular permeability, or inflammation. As previously reported for the VEGF-B
167
isoform, transgenic mice and rats expressing both isoforms of VEGF-B in the myocardium developed cardiac hypertrophy yet maintained systolic function. Deletion of the VEGF receptor-1 tyrosine kinase domain or the arterial endothelial Bmx tyrosine kinase inhibited hypertrophy, whereas loss of VEGF-B interaction with neuropilin-1 had no effect. Surprisingly, in rats, the heart-specific VEGF-B transgene induced impressive growth of the epicardial coronary vessels and their branches, with large arteries also seen deep inside the subendocardial myocardium. However, VEGF-B, unlike other VEGF family members, did not induce significant capillary angiogenesis, increased permeability, or inflammatory cell recruitment.

Conclusions—
VEGF-B appears to be a coronary growth factor in rats but not in mice. The signals for the VEGF-B–induced cardiac hypertrophy are mediated at least in part via the endothelium. Because cardiomyocyte damage in myocardial ischemia begins in the subendocardial myocardium, the VEGF-B–induced increased arterial supply to this area could have therapeutic potential in ischemic heart disease.
Anterior Mitral Leaflet Curvature During the Cardiac Cycle in the Normal Ovine Heart
Authors: Kvitting John-Peder Escobar , Bothe Wolfgang , Göktepe Serdar , Rausch Manuel K. , Swanson Julia C. , Kuhl Ellen , Ingels Neil B. , Miller D. Craig 
Published: October 2010

Background—
The dynamic changes of anterior mitral leaflet (AML) curvature are of primary importance for optimal left ventricular filling and emptying but are incompletely characterized.

Methods and Results—

Sixteen radiopaque markers were sutured to the AML in 11 sheep, and 4-dimensional marker coordinates were acquired with biplane videofluoroscopy. A surface subdivision algorithm was applied to compute the curvature across the AML at midsystole and at maximal valve opening. Septal-lateral (SL) and commissure-commissure (CC) curvature profiles were calculated along the SL AML meridian (M
SL
)and CC AML meridian (M
CC
), respectively, with positive curvature being concave toward the left atrium. At midsystole, the M
SL
was concave near the mitral annulus, turned from concave to convex across the belly, and was convex along the free edge. At maximal valve opening, the M
SL
was flat near the annulus, turned from slightly concave to convex across the belly, and flattened toward the free edge. In contrast, the M
CC
was concave near both commissures and convex at the belly at midsystole but convex near both commissures and concave at the belly at maximal valve opening.

Conclusions—

While the SL curvature of the AML along the M
SL
is similar across the belly region at midsystole and early diastole, the CC curvature of the AML along the M
CC
flips, with the belly being convex to the left atrium at midsystole and concave at maximal valve opening. These curvature orientations suggest optimal left ventricular inflow and outflow shapes of the AML and should be preserved during catheter or surgical interventions.
Pre-Conviction Detention before the International Criminal Court: Compliance or Fragmentation?
Authors: Golubok Sergey 
Published: October 2010

AbstractThis article analyses nascent case law of the International Criminal Court on provisional detention at the investigation stage and in the course of trial (together referred to as “pre-conviction detention”) vis-à-vis the standards developed in the jurisprudence of the European Court of Human Rights, being a reflection of “internationally recognized human rights” to which the ICC, according to its Statute, must adhere. At least several instances of presumed inconsistencies are detected. It is argued that international criminal tribunals should above all comply with standards set by international human rights law for domestic criminal proceedings, in particular when the most fundamental and basic human right ‐ the right to personal liberty ‐ is affected. Failure to comply entails a serious risk of hazardous fragmentation.