bluuebunny/crossref_metadata_2025_split huggingface dataset:
Opposing Effects of Androgen Deprivation and Targeted Therapy on Prostate Cancer Prevention
Authors: Jia Shidong , Gao Xueliang , Lee Sang Hyun , Maira Sauveur-Michel , Wu Xiaoqiu , Stack Edward C. , Signoretti Sabina , Loda Massimo , Zhao Jean J. , Roberts Thomas M. 
Published: December 2012

Abstract
Prostate cancer is an ideal target for chemoprevention. To date, chemoprevention clinical trials with 5α-reductase inhibitors have yielded encouraging yet ultimately confounding results. Using a preclinical mouse model of high-grade prostatic intraepithelial neoplasia (HG-PIN) induced by PTEN loss, we observed unprecedented deteriorating effects of androgen deprivation, in which surgical castration or MDV3100 treatment accelerated disease progression of the otherwise stable HG-PIN to invasive castration-resistant prostate cancer (CRPC). As an alternative, targeting the phosphoinositide 3-kinase (PI3K) signaling pathway via either genetic ablation of genes encoding PI3K components or pharmacologic inhibition of the PI3K pathway reversed the PTEN loss–induced HG-PIN phenotype. Finally, concurrent inhibition of the PI3K and mitogen-activated protein kinase (MAPK) pathways was effective in blocking the growth of PTEN-null CRPC. Together, these data have revealed the potential adverse effects of antiandrogen chemoprevention in certain genetic contexts (such as PTEN loss) while showing the promise of targeted therapy in the clinical management of this complex and prevalent disease.
Significance: Chemoprevention with antiandrogen therapies is attractive for prostate cancer, given its prevalence and established hormonally mediated pathogenesis. However, because PTEN loss has been found in 9% to 45% of HG-PIN in the clinic, the current findings suggest that patients with PTEN-deficient prostate tumors might be better treated with PI3K-targeted therapies. Cancer Discov; 3(1); 44–51. ©2012 AACR.
This article is highlighted in the In This Issue feature, p. 1
A Systems Approach to Designing Effective Clinical Trials Using Simulations
Authors: Fusaro Vincent A. , Patil Prasad , Chi Chih-Lin , Contant Charles F. , Tonellato Peter J. 
Published: December 2012

Background—
Pharmacogenetics in warfarin clinical trials have failed to show a significant benefit in comparison with standard clinical therapy. This study demonstrates a computational framework to systematically evaluate preclinical trial design of target population, pharmacogenetic algorithms, and dosing protocols to optimize primary outcomes.

Methods and Results—

We programmatically created an end-to-end framework that systematically evaluates warfarin clinical trial designs. The framework includes options to create a patient population, multiple dosing strategies including genetic-based and nongenetic clinical-based, multiple-dose adjustment protocols, pharmacokinetic/pharmacodynamics modeling and international normalization ratio prediction, and various types of outcome measures. We validated the framework by conducting 1000 simulations of the Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin (CoumaGen) clinical trial primary end points. The simulation predicted a mean time in therapeutic range of 70.6% and 72.2% (
P
=0.47) in the standard and pharmacogenetic arms, respectively. Then, we evaluated another dosing protocol under the same original conditions and found a significant difference in the time in therapeutic range between the pharmacogenetic and standard arm (78.8% versus 73.8%;
P
=0.0065), respectively.

Conclusions—
We demonstrate that this simulation framework is useful in the preclinical assessment phase to study and evaluate design options and provide evidence to optimize the clinical trial for patient efficacy and reduced risk.
And Say the Cat Responded? Getting Closer to the Feline Gaze
Authors: White Kara 
Published: December 2012

Abstract
Within the field of multispecies ethnography, a lingering question remains regarding how we can understand the nonhuman side of the human–nonhuman encounter. Many authors have ventured into this topic on a theoretical level, but none have proposed an effective methodological approach for how to achieve their goals. After examining the pitfalls experienced when acting as a volunteer at an animal shelter, I propose that in order to get closer to the feline gaze, we must first utilize an understanding of a cat’s sensory capabilities. Recognizing that a cat’s subjectivities are necessarily mediated by their bodies, understanding how they perceive the world involves a sensory experiential methodology. Highlighting the many contributions of phenomenological frameworks along with their limitations, I argue that getting closer to the feline gaze means appreciating species differences rather than arguing for the shared qualities held across species. Because of the species barrier, an interdisciplinary approach must meld phenomenological with ethological methods to grasp the interspecies relationships created by the cat–human encounter.
Impact of Bt cotton on the immune system and histology of the midgut of the fall armyworm Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae)
Authors: Cunha Franklin M. , Wanderley-Teixeira Valéria , Torres Jorge B. , Teixeira Álvaro A.C. , Alves Thiago J.S. , Brayner Fábio A. 
Published: December 2012

Despite the efficiency of transgenic plants expressing Bacillus thuringiensis (Bt) toxins as insecticides against several lepidopterans, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) is one species that presents low susceptibility to most Bt crops. This study investigated the effects of the Cry1Ac toxin expressed by Bt cotton in the midgut of S. frugiperda and its effects on the humoral and cellular immune responses. Three hypotheses were proposed and tested with contributing factors for the natural tolerance of S. frugiperda: (i) midgut regenerative cells are activated by the Cry1Ac toxin, and thus renew the epithelial cells damaged by the protein, (ii) Cry1Ac increased production of nitric oxide or phenoloxidase in the hemolymph, and (iii) there are qualitative and quantitative variations in the hemocyte levels of S. frugiperda. Caterpillars were reared using Bt cotton (Acala 90B) and non-Bt isolines (Acala 90), from the first to the fourth instar. The Bt cotton promoted elongation of the epithelial cells in the midgut of S. frugiperda caterpillars. Hence, evidence only supported the hypothesised increase of phenoloxidase (ii) and qualitative and quantitative differences in hemocyte levels (iii) in insects that were fed with Bt and non-Bt cotton. These parameters seem to explain the low susceptibility of S. frugiperda to Cry1Ac toxin and they are a viable set of responses for the evaluation of other xenobiotic factors.
Body shape evolution of Chromis and Azurina species (Percifomes, Pomacentridae) of the eastern Pacific
Authors: Aguilar-Medrano Rosalía 
Published: December 2012

Chromis is a circumglobal tropical and temperate genus with over 84 species of damselfishes. Studies based in osteological and molecular data have cited the relationship between Azurina and Chromis in the eastern Pacific. The main objectives of the study are: (1) to characterize size and shape in all Chromis and Azurina species of the eastern Pacific, (2) explore the phylogenetic signal of external morphology, and (3) present a hypothesis of the diversification process of this group. According to the results, there is no significant relationship between size and shape. The variation in body shape among all species is related to the height of the trunk, position of the snout and eye, and length of the caudal peduncle. The main morphologic variation between Azurina and Chromis is the degree of elongation of the body. Both Azurina species are closely related to C. punctipinnis and C. atrilobata. The morphological pattern of Azurina integrated it into Chromis. The phylogenetic pattern found by geometric morphometric analyses presented a high similarity with previous results based on molecular data. Phylogeny recovered two main clades, slender-bodied and deep-bodied species. This pattern of morphometric variation is closely related to exploitation of two different reef environments.
On Thermally Forced Circulations over Heated Terrain
Authors: Kirshbaum Daniel J. 
Published: December 2012

Abstract
A combination of analytical and numerical models is used to gain insight into the dynamics of thermally forced circulations over diurnally heated terrain. Solutions are obtained for two-layer flows (representing the boundary layer and the overlying free troposphere) over an isolated mountainlike heat source. A scaling based on the linearized Boussinesq system of equations is developed to quantify the strength of thermally forced updrafts and to identify three flow regimes, each with distinct dynamics and parameter sensitivities. This scaling closely matches corresponding numerical simulations in two of these regimes: the first characterized by a weakly stable boundary layer and significant background winds and the second by a strongly stable boundary layer. In the third regime, characterized by weak winds and weak boundary layer stability, this scaling is outperformed by a fundamentally different scaling based on thermodynamic heat engines. Within this regime, the inability of wind ventilation or static stability to diminish the buoyancy over the heat source leads to intense updrafts that are controlled by nonlinear dynamics. These nonlinearities create a positive feedback loop between the thermal forcing and vorticity that rapidly strengthens the circulation and contracts its central updraft into a narrow core. As the circulation intensifies under daytime heating, the warmest surface-based air is ventilated into the upper boundary layer, where it spreads laterally to occupy a broader area and, ultimately, restrain the circulation strength. The success demonstrated herein of simple theoretical models at predicting key aspects of thermally forced circulations offers hope for improved parameterization of related processes (e.g., convection initiation and aerosol venting) in large-scale models.
How Are Spring Snow Conditions in Central Canada Related to Early Warm-Season Precipitation?
Authors: Su Hua , Dickinson Robert E. , Findell Kirsten L. , Lintner Benjamin R. 
Published: December 2012

AbstractThe response of the warm-season atmosphere to antecedent snow anomalies has long been an area of study. This paper explores how the spring snow depth relates to subsequent precipitation in central Canada using ground observations, reanalysis datasets, and offline land surface model estimates. After removal of low-frequency ocean influences, April snow depth is found to correlate negatively with early warm-season (May–June) precipitation across a large portion of the study area. A chain of mechanisms is hypothesized to account for this observed negative relation: 1) a snow depth anomaly leads to a soil moisture anomaly, 2) the subsequent soil moisture anomaly affects ground turbulent fluxes, and 3) the atmospheric vertical structure allows dry soil to promote local convection. A detailed analysis supports this chain of mechanisms for those portions of the domain manifesting a statistically significant negative snow–precipitation correlation. For a portion of the study area, large-scale atmospheric circulation patterns also affect the early warm-season rainfall, indicating that the snow–precipitation feedback may depend on large-scale atmospheric dynamical features. This analysis suggests that spring snow conditions can contribute to warm-season precipitation predictability on a subseasonal to seasonal scale, but that the strength of such predictability varies geographically as it depends on the interplay of hydroclimatological conditions across multiple spatial scales.
Determining optimal sample sizes for multistage adaptive randomized clinical trials from an industry perspective using value of information methods
Authors: Chen Maggie H , Willan Andrew R 
Published: December 2012

Background  Most often, sample size determinations for randomized clinical trials are based on frequentist approaches that depend on somewhat arbitrarily chosen factors, such as type I and II error probabilities and the smallest clinically important difference. As an alternative, many authors have proposed decision-theoretic (full Bayesian) approaches, often referred to as value of information methods that attempt to determine the sample size that maximizes the difference between the trial’s expected utility and its expected cost, referred to as the expected net gain. Taking an industry perspective, Willan proposes a solution in which the trial’s utility is the increase in expected profit. Furthermore, Willan and Kowgier, taking a societal perspective, show that multistage designs can increase expected net gain. Purpose  The purpose of this article is to determine the optimal sample size using value of information methods for industry-based, multistage adaptive randomized clinical trials, and to demonstrate the increase in expected net gain realized. At the end of each stage, the trial’s sponsor must decide between three actions: continue to the next stage, stop the trial and seek regulatory approval, or stop the trial and abandon the drug. Methods  A model for expected total profit is proposed that includes consideration of per-patient profit, disease incidence, time horizon, trial duration, market share, and the relationship between trial results and probability of regulatory approval. The proposed method is extended to include multistage designs with a solution provided for a two-stage design. An example is given. Results  Significant increases in the expected net gain are realized by using multistage designs. Limitations  The complexity of the solutions increases with the number of stages, although far simpler near-optimal solutions exist. The method relies on the central limit theorem, assuming that the sample size is sufficiently large so that the relevant statistics are normally distributed. Conclusion  From a value of information perspective, the use of multistage designs in industry trials leads to significant gains in the expected net gain.
Bipolar plasma vaporization versus standard transurethral resection in secondary bladder neck sclerosis: a prospective, medium-term, randomized comparison
Authors: Geavlete Bogdan , Moldoveanu Cristian , Iacoboaie Catalin , Geavlete Petrisor 
Published: December 2012

Objectives: This prospective, randomized, medium-term trial aimed to assess the efficiency, safety and postoperative results of bipolar plasma vaporization (BPV) in comparison with monopolar transurethral resection (TUR) in cases of secondary bladder neck sclerosis (BNS). Methods: A total of 70 patients with BNS secondary to transurethral resection of the prostate (TURP; 46 cases), open prostatectomy for benign prostatic hypertrophy (BPH; 18 cases) and radical prostatectomy for prostate cancer (6 cases) were enrolled in the trial. The inclusion criteria consisted of maximum flow rate ( Qmax) <10 ml/s and International Prostate Symptom Score (IPSS) >19. All patients were evaluated preoperatively and at 1, 3, 6, 12 and 18 months after surgery by IPSS, quality of life score (QoL), Qmax and postvoiding residual urinary volume (PVR). Results: The mean operation time (10.3 versus 14.9 minutes), catheterization period (0.75 versus 2.1 days) and hospital stay (1.1 versus 3.2 days) were significantly reduced in the BPV series. During the immediate postoperative follow up, recatheterization for acute urinary retention only occurred in the TUR series (5.7%). The medium-term retreatment requirements due to BNS recurrence were lower in the BPV study arm (2.8% versus 8.5%). At the 1, 3, 6, 12 and 18 months assessments, statistically similar parameters were found concerning the IPSS and QoL symptom scores, Qmax and PVR values specific for the two therapeutic alternatives. Conclusions: BPV constitutes a valuable endoscopic treatment approach for secondary BNS. The method emphasized superior efficacy, a satisfactory safety profile and similar medium-term follow-up features when compared with standard TUR.
Cutaneous Myoepithelioma in the Foot
Authors: Dix Brian T. , Hentges Matthew J. , Saltrick Karl R. , Krishnamurti Uma 
Published: December 2012

Cutaneous myoepithelioma is a very rare, benign, subcutaneous and dermal tumor. It usually presents as a slow-growing and painless mass on the extremities. We report a case of cutaneous myoepithelioma that was located on the foot. A 68-yearold woman presented with a slowly growing pain-free mass on the right third toe measuring 0.8 × 0.7 × 0.4 cm3. We performed an elliptical excision, with histological and immunohistochemical analysis. The lesion showed dermis with cords of cytologically uniform ovoid cells with moderate amount of pale cytoplasm. No pleomorphism, mitotic activity, or necrosis was visualized. The tumor cells were positive for S-100 protein, epithelial membrane antigen and negative for smooth-muscle actin. From these findings, the tumor was diagnosed as a cutaneous myoepithelioma extending to the deep resection margin. To our knowledge, there are only 2 documented cases in the literature in English, and none have been reported in the foot and ankle literature. Levels of Evidence: Therapeutic, Level IV, Case study
Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation
Authors: Haroche Julien , Cohen-Aubart Fleur , Emile Jean-François , Arnaud Laurent , Maksud Philippe , Charlotte Frédéric , Cluzel Philippe , Drier Aurélie , Hervier Baptiste , Benameur Neïla , Besnard Sophie , Donadieu Jean , Amoura Zahir 
Published: December 2012

Key Points
Treatment with vemurafenib induced a dramatic response in 3 patients with histiocytosis harboring BRAF V600E mutations. Tumor response was observed in both Erdheim-Chester disease and Langerhans cell histiocytosis.
Parthenolide eliminates leukemia-initiating cell populations and improves survival in xenografts of childhood acute lymphoblastic leukemia
Authors: Diamanti Paraskevi , Cox Charlotte V. , Moppett John P. , Blair Allison 
Published: December 2012

Key Points
First report demonstrating in vivo elimination of multiple LIC populations from childhood ALL cases using animal models. In vivo models of leukemia are essential for drug evaluation studies.
HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α–induced excessive erythropoiesis
Authors: Franke Kristin , Kalucka Joanna , Mamlouk Soulafa , Singh Rashim Pal , Muschter Antje , Weidemann Alexander , Iyengar Vasuprada , Jahn Steffen , Wieczorek Kathrin , Geiger Kathrin , Muders Michael , Sykes Alex M. , Poitz David M. , Ripich Tatsiana , Otto Teresa , Bergmann Sybille , Breier Georg , Baretton Gustavo , Fong Guo-Hua , Greaves David R. , Bornstein Stefan , Chavakis Triantafyllos , Fandrey Joachim , Gassmann Max , Wielockx Ben 
Published: December 2012

Abstract
Erythropoiesis must be tightly balanced to guarantee adequate oxygen delivery to all tissues in the body. This process relies predominantly on the hormone erythropoietin (EPO) and its transcription factor hypoxia inducible factor (HIF). Accumulating evidence suggests that oxygen-sensitive prolyl hydroxylases (PHDs) are important regulators of this entire system. Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis because of severe overproduction of EPO, exclusively driven by HIF-2α. In contrast, HIF-1α served as a protective factor, ensuring survival of cKO P2 mice with HCT values up to 86%. Using different genetic approaches, we show that simultaneous inactivation of PHD2 and HIF-1α resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2α-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2α–dependent erythrocytosis, whereas HIF-1α protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia.
Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins
Authors: Schaer Dominik J. , Buehler Paul W. , Alayash Abdu I. , Belcher John D. , Vercellotti Gregory M. 
Published: December 2012

AbstractHemolysis occurs in many hematologic and nonhematologic diseases. Extracellular hemoglobin (Hb) has been found to trigger specific pathophysiologies that are associated with adverse clinical outcomes in patients with hemolysis, such as acute and chronic vascular disease, inflammation, thrombosis, and renal impairment. Among the molecular characteristics of extracellular Hb, translocation of the molecule into the extravascular space, oxidative and nitric oxide reactions, hemin release, and molecular signaling effects of hemin appear to be the most critical. Limited clinical experience with a plasma-derived haptoglobin (Hp) product in Japan and more recent preclinical animal studies suggest that the natural Hb and the hemin-scavenger proteins Hp and hemopexin have a strong potential to neutralize the adverse physiologic effects of Hb and hemin. This includes conditions that are as diverse as RBC transfusion, sickle cell disease, sepsis, and extracorporeal circulation. This perspective reviews the principal mechanisms of Hb and hemin toxicity in different disease states, updates how the natural scavengers efficiently control these toxic moieties, and explores critical issues in the development of human plasma–derived Hp and hemopexin as therapeutics for patients with excessive intravascular hemolysis.
Echocardiography and pulmonary embolism severity index have independent prognostic roles in pulmonary embolism
Authors: Sanchez Olivier , Trinquart Ludovic , Planquette Benjamin , Couturaud Francis , Verschuren Franck , Caille Vincent , Meneveau Nicolas , Pacouret Gérard , Roy Pierre-Marie , Righini Marc , Perrier Arnaud , Bertoletti Laurent , Parent Florence , Lorut Christine , Meyer Guy 
Published: December 2012

We analysed a cohort of patients with normotensive pulmonary embolism (PE) in order to assess whether combining echocardiography and biomarkers with the pulmonary embolism severity index (PESI) improves the risk stratification in comparison to the PESI alone.The PESI was calculated in normotensive patients with PE who also underwent echocardiography and assays of cardiac troponin I and brain natriuretic peptide. 30-day adverse outcome was defined as death, recurrent PE or shock.529 patients were included, 25 (4.7%, 95% CI 3.2–6.9%) had at least one outcome event. The proportion of patients with adverse events increased from 2.1% in PESI class I–II to 8.4% in PESI class III–IV, and to 14.3% in PESI class V (p<0.001). In PESI class I–II, the rate of outcome events was significantly higher in patients with abnormal values of biomarkers or right ventricular dilatation. In multivariate analysis, the PESI (class III–IVversusI–II, OR 3.1, 95% CI 1.2–8.3; class VversusI–II, OR 5.5, 95% CI 1.5–25.5 and echocardiography (right ventricular/left ventricular ratio, OR (for an increase of 0.1) 1.3, 95% CI 1.1–1.5) were independent predictors of an adverse outcome.In patients with normotensive PE, biomarkers and echocardiography provided additional prognostic information to the PESI.