bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developing and Validating Continuous Genomic Signatures in Randomized Clinical Trials for Predictive Medicine
Authors: Matsui Shigeyuki , Simon Richard , Qu Pingping , Shaughnessy John D. , Barlogie Bart , Crowley John 
Published: August 2012

Abstract
Purpose: It is highly challenging to develop reliable diagnostic tests to predict patients' responsiveness to anticancer treatments on clinical endpoints before commencing the definitive phase III randomized trial. Development and validation of genomic signatures in the randomized trial can be a promising solution. Such signatures are required to predict quantitatively the underlying heterogeneity in the magnitude of treatment effects.
Experimental Design: We propose a framework for developing and validating genomic signatures in randomized trials. Codevelopment of predictive and prognostic signatures can allow prediction of patient-level survival curves as basic diagnostic tools for treating individual patients.
Results: We applied our framework to gene-expression microarray data from a large-scale randomized trial to determine whether the addition of thalidomide improves survival for patients with multiple myeloma. The results indicated that approximately half of the patients were responsive to thalidomide, and the average improvement in survival for the responsive patients was statistically significant. Cross-validated patient-level survival curves were developed to predict survival distributions of individual future patients as a function of whether or not they are treated with thalidomide and with regard to their baseline prognostic and predictive signature indices.
Conclusion: The proposed framework represents an important step toward reliable predictive medicine. It provides an internally validated mechanism for using randomized clinical trials to assess treatment efficacy for a patient population in a manner that takes into consideration the heterogeneity in patients' responsiveness to treatment. It also provides cross-validated patient-level survival curves that can be used for selecting treatments for future patients. Clin Cancer Res; 18(21); 6065–73. ©2012 AACR.
Increasing Use of Radical Prostatectomy for Nonlethal Prostate Cancer in Sweden
Authors: Etzioni Ruth , Mucci Lorelei , Chen Shu , Johansson Jan-Erik , Fall Katja , Adami Hans-Olov 
Published: August 2012

Abstract
Purpose: The number of patients in Sweden treated with radical prostatectomy for localized prostate cancer has increased exponentially. The extent to which this increase reflects treatment of nonlethal disease detected through prostate-specific antigen (PSA) screening is unknown.
Experimental Design: We undertook a nationwide study of all 18,837 patients with prostate cancer treated with radical prostatectomy in Sweden from 1988 to 2008 with complete follow-up through 2009. We compared cumulative incidence curves, fit Cox regression and cure models, and conducted a simulation study to determine changes in treatment of nonlethal cancer, in cancer-specific survival over time, and effect of lead-time due to PSA screening.
Results: The annual number of radical prostatectomies increased 25-fold during the study period. The 5-year cancer-specific mortality rate decreased from 3.9% [95% confidence interval (CI), 2.5–5.3] among patients diagnosed between 1988 and 1992 to 0.7% (95% CI, 0.4–1.1) among those diagnosed between 1998 and 2002 (Ptrend &lt; 0.001). According to the cure model, the risk of not being cured declined by 13% (95% CI, 12%–14%) with each calendar year. The simulation study indicated that only about half of the improvement in disease-specific survival could be accounted for by lead-time.
Conclusion: Patients overdiagnosed with nonlethal prostate cancer appear to account for a substantial and growing part of the dramatic increase in radical prostatectomies in Sweden, but increasing survival rates are likely also due to true reductions in the risk of disease-specific death over time. Because the magnitude of harm and costs due to overtreatment can be considerable, identification of men who likely benefit from radical prostatectomy is urgently needed. Clin Cancer Res; 18(24); 6742–7. ©2012 AACR.
Ontogeny and Sorafenib Metabolism
Authors: Zimmerman Eric I. , Roberts Justin L. , Li Lie , Finkelstein David , Gibson Alice , Chaudhry Amarjit S. , Schuetz Erin G. , Rubnitz Jeffrey E. , Inaba Hiroto , Baker Sharyn D. 
Published: August 2012

Abstract
Purpose: To investigate the role of ontogeny in sorafenib metabolism to the equipotent active metabolite sorafenib N-oxide.
Experimental Design: Steady-state pharmacokinetic studies of sorafenib and metabolites were conducted in 30 children and young adults (17 males; median age, 9.5 years) receiving sorafenib 150 mg/m2 or 200 mg/m2 twice daily. Sorafenib metabolism was evaluated in vitro at 10 μmol/L using a panel of purified human cytochrome P450 (CYP) enzymes. Sorafenib metabolism and CYP3A4 expression was evaluated in 52 human liver samples from donors of ≤20 years old. The drug–drug interaction potential between sorafenib and azole antifungal agents was evaluated in vitro and in vivo.
Results: No age-related differences in sorafenib apparent oral clearance were observed. Mean sorafenib N-oxide metabolite ratio was 0.27 ± 0.14. In children of ≤10 years of age, boys had approximately 2-fold higher N-oxide ratios than girls (0.40 ± 0.15 vs. 0.22 ± 0.12, P = 0.026). Of the CYPs evaluated, sorafenib was exclusively metabolized to sorafenib N-oxide by CYP3A4. A trend for increased N-oxide formation in boys was observed in liver samples, which correlated with CYP3A4 mRNA expression. Posaconazole and voriconazole potently inhibited sorafenib N-oxide formation in vitro, and reduced sorafenib N-oxide formation in 3 children given sorafenib concurrent with azoles.
Conclusion: We have identified several factors affecting interpatient variability in sorafenib metabolism to the active N-oxide metabolite including age, sex, and concurrent treatment with azole antifungals. This knowledge may provide important considerations for the clinical use of sorafenib in children and possibly other kinase inhibitors undergoing CYP3A4-mediated metabolism. Clin Cancer Res; 18(20); 5788–95. ©2012 AACR.
Introduction
Authors: Kemp-Welch Klara , Freire Cristina 
Published: August 2012

Abstract
The guest editors' introduction to ARTMargins Issue 1:2–3 proposes that the dynamic marginal art scenes that developed under Latin American military dictatorships and in Late Socialist Eastern Europe in the 1960s and 1970s were characterized by their commitment to freedom and its furthering through cultural exchange and networking. To the extent that direct exchange was controlled from above, its significance, from below, increased in inverse proportion. From the peripheries of the Cold War, a marginal cultural intelligentsia sought creative ways to inhabit counter-cartographies and to foster an alternative sense of belonging. The introduction gives an overview of the transnational networks developed by artists operating outside a market framework, with a view to highlighting the need for scholars to rethink the complexity of past, present and future fields of international artistic exchange.
Odds Ratio Forecasts Increase Precautionary Action for Extreme Weather Events
Authors: LeClerc Jared , Joslyn Susan 
Published: August 2012

Abstract
What is the best way to communicate the risk of rare but extreme weather to the public? One suggestion is to communicate the relative risk of extreme weather in the form of odds ratios; but, to the authors’ knowledge, this suggestion has never been tested systematically. The experiment reported here provides an empirical test of this hypothesis. Participants performed a realistic computer simulation task in which they assumed the role of the manager of a road maintenance company and used forecast information to decide whether to take precautionary action to prevent icy conditions on a town’s roads. Participants with forecasts expressed as odds ratios were more likely to take appropriate precautionary action on a single target trial with an extreme low temperature forecast than participants using deterministic or probabilistic forecasts. However, participants using probabilistic forecasts performed better on trials involving weather within the normal range than participants with only deterministic forecast information. These results may provide insight into how best to communicate extreme weather risk. This paper offers clear evidence that people given relative risk information are more inclined to take precautionary action when threatened with an extreme weather event with a low probability than people given only single-value or probabilistic forecasts.
High Prevalence of Self-Reported Symptoms of Digital Ischemia in Elite Male Volleyball Players in the Netherlands
Authors: van de Pol Daan , Kuijer P. Paul F.M. , Langenhorst Ton , Maas Mario 
Published: August 2012

Background: In the past 3 years, 6 volleyball players with ischemic digits and small microemboli in the digital arteries of the dominant hand presented themselves in our hospital. These complaints were caused by an aneurysmatic dilation of the posterior circumflex humeral artery (PCHA) with distal occlusion and digital emboli in the isolateral limb. All were elite male volleyball players active in the national top league. Little is known about the exact symptoms associated with PCHA pathological lesions with digital emboli (PCHAP with DE) and its prevalence in elite volleyball players. If vascular injury can be identified at an early stage, thromboembolic complications and irreversible damage to the digits might be prevented. Purpose: To assess the prevalence of symptoms that are consistent with digital ischemia and may be caused by PCHAP with DE in elite male volleyball players in the Netherlands. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A questionnaire survey was performed among elite volleyball players in the Dutch national top league and the Dutch beach volleyball team. The questionnaire was constructed using literature-based data on symptoms associated with PCHAP with DE, together with data retrieved from medical files. Results: A total of 99 of the 107 athletes participated, with a response rate of 93%. The most frequently reported symptoms associated with PCHAP with DE were cold, blue, or pale digits in the dominant hand during or immediately after practice or competition. The prevalence of these symptoms ranged from 11% to 27%. The prevalence of cold digits during practice and competition was 27%. The prevalence of cold, blue, and pale digits during or immediately after practice and competition was 12%. Conclusion: An unexpectedly high percentage of elite volleyball players reported symptoms that are associated with PCHAP with DE in the dominant hand. Because these athletes are considered potentially at risk for developing critical digital ischemia, further analysis of the presence of digital ischemia and PCHA injury is warranted.
Single-Legged Hop Tests as Predictors of Self-Reported Knee Function After Anterior Cruciate Ligament Reconstruction
Authors: Logerstedt David , Grindem Hege , Lynch Andrew , Eitzen Ingrid , Engebretsen Lars , Risberg May Arna , Axe Michael J. , Snyder-Mackler Lynn 
Published: August 2012

Background: Single-legged hop tests are commonly used functional performance measures that can capture limb asymmetries in patients after anterior cruciate ligament (ACL) reconstruction. Hop tests hold potential as predictive factors of self-reported knee function in individuals after ACL reconstruction. Hypothesis: Single-legged hop tests conducted preoperatively would not and 6 months after ACL reconstruction would predict self-reported knee function (International Knee Documentation Committee [IKDC] 2000) 1 year after ACL reconstruction. Study Design: Cohort study (prognosis); Level of evidence, 2. Methods: One hundred twenty patients who were treated with ACL reconstruction performed 4 single-legged hop tests preoperatively and 6 months after ACL reconstruction. Self-reported knee function within normal ranges was defined as IKDC 2000 scores greater than or equal to the age- and sex-specific normative 15th percentile score 1 year after surgery. Logistic regression analyses were performed to identify predictors of self-reported knee function within normal ranges. The area under the curve (AUC) from receiver operating characteristic curves was used as a measure of discriminative accuracy. Results: Eighty-five patients completed single-legged hop tests 6 months after surgery and the 1-year follow-up with 68 patients classified as having self-reported knee function within normal ranges 1 year after reconstruction. The crossover hop and 6-m timed hop limb symmetry index (LSI) 6 months after ACL reconstruction were the strongest individual predictors of self-reported knee function (odds ratio, 1.09 and 1.10) and the only 2 tests in which the confidence intervals of the discriminatory accuracy (AUC) were above 0.5 (AUC = 0.68). Patients with knee function below normal ranges were over 5 times more likely of having a 6-m timed hop LSI lower than the 88% cutoff than those with knee function within normal ranges. Patients with knee function within normal ranges were 4 times more likely to have a crossover hop LSI greater than the 95% cutoff than those with knee function below normal ranges. No preoperative single-legged hop test predicted self-reported knee function within normal ranges 1 year after ACL reconstruction (all P > .353). Conclusion: Single-legged hop tests conducted 6 months after ACL reconstruction can predict the likelihood of successful and unsuccessful outcome 1 year after ACL reconstruction. Patients demonstrating less than the 88% cutoff score on the 6-m timed hop test at 6 months may benefit from targeted training to improve limb symmetry in an attempt to normalize function. Patients with minimal side-to-side differences on the crossover hop test at 6 months possibly will have good knee function at 1 year if they continue with their current training regimen. Preoperative single-legged hop tests are not able to predict postoperative outcomes.
Telmisartan Prevents Excess-Salt-Induced Exacerbated (Malignant) Hypertension in Spontaneously Hypertensive Rats
Authors: Susic Dinko , Fares Hassan , Frohlich Edward D. 
Published: August 2012

The effects of angiotensin receptor blocker, diuretic, a calcium antagonist, and their combination were evaluated on the progression of cardiovascular and renal damage in spontaneously hypertensive rats (SHRs) given excess salt. To this end, 8-week male SHRs were divided into 7 groups. The control group (C) received normal NaCl (0.6%) diet. All other groups were given 8% NaCl rat chow. In addition, group 2 was given placebo (tap water alone), group 3 the angiotensin receptor antagonist telmisartan (10 mg/kg per d), group 4 received the diuretic chlorothiazide (80 mg/kg per d), group 5 was given telmisartan plus the diuretic, group 6 was given the calcium antagonist amlodipine (10 mg/kg per d), and group 7 was given telmisartan plus amlodipine. All treatments lasted for 8 weeks. Compared with controls, mean arterial pressure (MAP), renal blood flow, coronary flow reserve, minimal coronary vascular resistance, diastolic time constant, and maximal rate of ventricular pressure fall were all adversely affected by salt loading. Increased left ventricular mass with marked cardiac fibrosis was also found in the salt-overloaded SHR group. Telmisartan normalized all indices except MAP, whereas diuretic and amlodipine only partially restored cardiac functional and mass indexes. Combination therapy with telmisartan and either diuretic or amlodipine also normalized all indices including arterial pressure. These data suggest that (1) cardiovascular damage induced by excess salt in the SHRs was not pressure dependent; (2) compared with the calcium antagonist and diuretic, blockade of angiotensin receptors was extremely effective in this model.
Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjögren syndrome
Authors: Xu Junji , Wang Dandan , Liu Dayong , Fan Zhipeng , Zhang Huayong , Liu Ousheng , Ding Gang , Gao Runtao , Zhang Chunmei , Ding Yaozhong , Bromberg Jonathan S. , Chen Wanjun , Sun Lingyun , Wang Songlin 
Published: August 2012

Abstract
Sjögren syndrome (SS) is a systemic autoimmune disease characterized by dry mouth and eyes, and the cellular and molecular mechanisms for its pathogenesis are complex. Here we reveal, for the first time, that bone marrow mesenchymal stem cells in SS-like NOD/Ltj mice and human patients were defective in immunoregulatory functions. Importantly, treatment with mesenchymal stem cells (MSCs) suppressed autoimmunity and restored salivary gland secretory function in both mouse models and SS patients. MSC treatment directed T cells toward Treg and Th2, while suppressing Th17 and Tfh responses, and alleviated disease symptoms. Infused MSCs migrated toward the inflammatory regions in a stromal cell–derived factor-1–dependent manner, as neutralization of stromal cell–derived factor-1 ligand CXCR4 abolished the effectiveness of bone marrow mesenchymal stem cell treatment. Collectively, our study suggests that immunologic regulatory functions of MSCs play an important role in SS pathogenesis, and allogeneic MSC treatment may provide a novel, effective, and safe therapy for patients with SS. This study was registered at www.clinicaltrials.gov as NCT00953485.
Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13–driven mouse model
Authors: Xu Haiming , Menendez Silvia , Schlegelberger Brigitte , Bae Narae , Aplan Peter D. , Göhring Gudrun , Deblasio Tony R. , Nimer Stephen D. 
Published: August 2012

Abstract
The nucleoporin gene NUP98 is fused to several genes including HOXD13 in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia, and chronic myeloid leukemia, blast crisis. Genetically engineered mice that express a NUP98-HOXD13 (NHD13) transgene (Tg) display the phenotypic features of MDS, including cytopenias, bone marrow dysplasia, and transformation to acute leukemia. Here we show that short-term treatment with the p53 inhibitor Pifithrin-α partially and transiently rescued the myeloid and lymphoid abnormalities found in NHD13+ Tg mice, with no improvement in the anemia, while the genetic deletion of 2 alleles of p53 rescued both the myeloid progenitor cell and long-term hematopoietic stem cell compartments. Nonetheless, loss of one or both alleles of p53 did not rescue the MDS phenotype, but instead exacerbated the MDS phenotype and accelerated the development of acute myeloid leukemia. Our studies suggest that while targeting p53 may transiently improve hematopoiesis in MDS, over the long-term, it has detrimental effects, raising caution about abrogating its function to treat the cytopenias that accompany this disease.
Process attributes in bio-ontologies
Authors: Andrade André Q , Blondé Ward , Hastings Janna , Schulz Stefan 
Published: August 2012

Abstract

Background
Biomedical processes can provide essential information about the (mal-) functioning of an organism and are thus frequently represented in biomedical terminologies and ontologies, including the GO Biological Process branch. These processes often need to be described and categorised in terms of their attributes, such as rates or regularities. The adequate representation of such process attributes has been a contentious issue in bio-ontologies recently; and domain ontologies have correspondingly developed ad hoc workarounds that compromise interoperability and logical consistency.

Results
We present a design pattern for the representation of process attributes that is compatible with upper ontology frameworks such as BFO and BioTop. Our solution rests on two key tenets: firstly, that many of the sorts of process attributes which are biomedically interesting can be characterised by the ways that repeated parts of such processes constitute, in combination, an overall process; secondly, that entities for which a full logical definition can be assigned do not need to be treated as primitive within a formal ontology framework. We apply this approach to the challenge of modelling and automatically classifying examples of normal and abnormal rates and patterns of heart beating processes, and discuss the expressivity required in the underlying ontology representation language. We provide full definitions for process attributes at increasing levels of domain complexity.

Conclusions
We show that a logical definition of process attributes is feasible, though limited by the expressivity of DL languages so that the creation of primitives is still necessary. This finding may endorse current formal upper-ontology frameworks as a way of ensuring consistency, interoperability and clarity.
Indehiscent sporangia enable the accumulation of local fern diversity at the Qinghai-Tibetan Plateau
Authors: Wang Li , Schneider Harald , Wu Zhiqiang , He Lijuan , Zhang Xianchun , Xiang Qiaoping 
Published: August 2012

Abstract

Background
Indehiscent sporangia are reported for only a few of derived leptosporangiate ferns. Their evolution has been likely caused by conditions in which promotion of self-fertilization is an evolutionary advantageous strategy such as the colonization of isolated regions and responds to stressful habitat conditions. The Lepisorus clathratus complex provides the opportunity to test this hypothesis because these derived ferns include specimens with regular dehiscent and irregular indehiscent sporangia. The latter occurs preferably in well-defined regions in the Himalaya. Previous studies have shown evidence for multiple origins of indehiscent sporangia and the persistence of populations with indehiscent sporangia at extreme altitudinal ranges of the Qinghai-Tibetan Plateau (QTP).

Results
Independent phylogenetic relationships reconstructed using DNA sequences of the uniparentally inherited chloroplast genome and two low-copy nuclear genes confirmed the hypothesis of multiple origins of indehiscent sporangia and the restriction of particular haplotypes to indehiscent sporangia populations in the Lhasa and Nyingchi regions of the QTP. In contrast, the Hengduan Mountains were characterized by high haplotype diversity and the occurrence of accessions with and without indehiscent sporangia. Evidence was found for polyploidy and reticulate evolution in this complex. The putative case of chloroplast capture in the Nyingchi populations provided further evidence for the promotion of isolated but persistent populations by indehiscent sporangia.

Conclusions
The presented results confirmed the hypothesis that indehiscent sporangia promote the establishment of persistent population in different regions of the QTP. These results are consistent with the expectations of reproductive reassurance by promotion of self-fertilization that played a critical role in the assembly of populations in isolated locations and/or extreme habitats.