bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Mitochondrial Oxidative Metabolism in Melanoma Causes Metabolic Compensation through Glucose and Glutamine Utilization
Authors: Lim Ji-Hong , Luo Chi , Vazquez Francisca , Puigserver Pere 
Published: May 2014

Abstract
Metabolic targets offer attractive opportunities for cancer therapy. However, their targeting may activate alternative metabolic pathways that can still support tumor growth. A subset of human melanomas relies on PGC1α-dependent mitochondrial oxidative metabolism to maintain growth and survival. Herein, we show that loss of viability caused by suppression of PGC1α in these melanomas is rescued by induction of glycolysis. Suppression of PGC1α elevates reactive oxygen species levels decreasing hypoxia-inducible factor-1α (HIF1α) hydroxylation that, in turn, increases its protein stability. HIF1α reprograms melanomas to become highly glycolytic and dependent on this pathway for survival. Dual suppression of PGC1α and HIF1α causes energetic deficits and loss of viability that are partially compensated by glutamine utilization. Notably, triple suppression of PGC1α, HIF1α, and glutamine utilization results in complete blockage of tumor growth. These results show that due to high metabolic and bioenergetic flexibility, complete treatment of melanomas will require combinatorial therapy that targets multiple metabolic components. Cancer Res; 74(13); 3535–45. ©2014 AACR.
Galectin-1 Drives Pancreatic Carcinogenesis through Stroma Remodeling and Hedgehog Signaling Activation
Authors: Martínez-Bosch Neus , Fernández-Barrena Maite G. , Moreno Mireia , Ortiz-Zapater Elena , Munné-Collado Jessica , Iglesias Mar , André Sabine , Gabius Hans-Joachim , Hwang Rosa F. , Poirier Françoise , Navas Carolina , Guerra Carmen , Fernández-Zapico Martin E. , Navarro Pilar 
Published: May 2014

Abstract
Despite some advances, pancreatic ductal adenocarcinoma (PDAC) remains generally refractory to current treatments. Desmoplastic stroma, a consistent hallmark of PDAC, has emerged as a major source of therapeutic resistance and thus potentially promising targets for improved treatment. The glycan-binding protein galectin-1 (Gal1) is highly expressed in PDAC stroma, but its roles there have not been studied. Here we report functions and molecular pathways of Gal1 that mediate its oncogenic properties in this setting. Genetic ablation of Gal1 in a mouse model of PDAC (EIa-myc mice) dampened tumor progression by inhibiting proliferation, angiogenesis, desmoplasic reaction and by stimulating a tumor-associated immune response, yielding a 20% increase in relative lifesplan. Cellular analyses in vitro and in vivo suggested these effects were mediated through the tumor microenvironment. Importantly, acinar-to-ductal metaplasia, a crucial step for initiation of PDAC, was found to be regulated by Gal1. Mechanistic investigations revealed that Gal1 promoted Hedgehog pathway signaling in PDAC cells and stromal fibroblasts as well as in Ela-myc tumors. Taken together, our findings establish a function for Gal1 in tumor-stroma crosstalk in PDAC and provide a preclinical rationale for Gal1 targeting as a microenvironment-based therapeutic strategy. Cancer Res; 74(13); 3512–24. ©2014 AACR.
The Cancer Stem Cell Marker Aldehyde Dehydrogenase Is Required to Maintain a Drug-Tolerant Tumor Cell Subpopulation
Authors: Raha Debasish , Wilson Timothy R. , Peng Jing , Peterson David , Yue Peng , Evangelista Marie , Wilson Catherine , Merchant Mark , Settleman Jeff 
Published: May 2014

Abstract
Selective kinase inhibitors have emerged as an important class of cancer therapeutics, and several such drugs are now routinely used to treat advanced-stage disease. However, their clinical benefit is typically short-lived because of the relatively rapid acquisition of drug resistance following treatment response. Accumulating preclinical and clinical data point to a role for a heterogeneous response to treatment within a subpopulation of tumor cells that are intrinsically drug-resistant, such as cancer stem cells. We have previously described an epigenetically determined reversibly drug-tolerant subpopulation of cancer cells that share some properties with cancer stem cells. Here, we define a requirement for the previously established cancer stem cell marker ALDH (aldehyde dehydrogenase) in the maintenance of this drug-tolerant subpopulation. We find that ALDH protects the drug-tolerant subpopulation from the potentially toxic effects of elevated levels of reactive oxygen species (ROS) in these cells, and pharmacologic disruption of ALDH activity leads to accumulation of ROS to toxic levels, consequent DNA damage, and apoptosis specifically within the drug-tolerant subpopulation. Combining ALDH inhibition with other kinase-directed treatments delayed treatment relapse in vitro and in vivo, revealing a novel combination treatment strategy for cancers that might otherwise rapidly relapse following single-agent therapy. Cancer Res; 74(13); 3579–90. ©2014 AACR.
Presence of Somatic Mutations within PIK3CA, AKT, RAS, and FGFR3 but not BRAF in Cisplatin-Resistant Germ Cell Tumors
Authors: Feldman Darren R. , Iyer Gopa , Van Alstine Lindsay , Patil Sujata , Al-Ahmadie Hikmat , Reuter Victor E. , Bosl George J. , Chaganti Raju S. , Solit David B. 
Published: May 2014

Abstract
Purpose: A previous study noted frequent B-RAF mutations among European patients with cisplatin-resistant but not cisplatin-sensitive germ cell tumors (GCT). We sought to validate this finding by assessing for these mutations among patients with GCT at our center.
Experimental Design: Adolescent and adult patients with GCT who received cisplatin-based chemotherapy and had tumor tissue available were eligible for participation. Response to cisplatin was reviewed to determine sensitivity and resistance. Tumor DNA was extracted and subjected to Sequenom analysis to detect hotspot alterations in FGFR3, AKT1, PIK3CA, KRAS, HRAS, NRAS, and BRAF with Sanger sequencing for confirmation. Nine GCT cell lines with varying degrees of cisplatin sensitivity and resistance were also assayed by Sequenom.
Results: Seventy (24 cisplatin-sensitive; 46 cisplatin-resistant) of 75 patients had tumors with sufficient quality DNA to perform Sequenom. Nineteen mutations were detected among 16 (23%) patients but no BRAF mutations were identified. Similarly, none of the cell lines harbored BRAF mutations. FGFR3 was the most frequent mutation, identified in 13% of both sensitive and resistant samples. All other mutations were exclusive to resistant cases (3 KRAS, 3 AKT1, 3 PIK3CA, and 1 HRAS).
Conclusions:BRAF mutations are rare in American patients with GCT, including those with cisplatin resistance. However, other potentially targetable mutations occur in more than 25% of cisplatin-resistant patients. FGFR3, AKT1, and PIK3CA mutations are all reported for the first time in GCT. Whereas FGFR3 mutations occurred with equal frequency in both sensitive and resistant GCTs, mutations in AKT1 and PIK3CA were observed exclusively in cisplatin-resistant tumors. Clin Cancer Res; 20(14); 3712–20. ©2014 AACR.
Preclinical Optimization of MDM2 Antagonist Scheduling for Cancer Treatment by Using a Model-Based Approach
Authors: Higgins Brian , Glenn Kelli , Walz Antje , Tovar Christian , Filipovic Zoran , Hussain Sazzad , Lee Edmund , Kolinsky Kenneth , Tannu Shahid , Adames Violeta , Garrido Rosario , Linn Michael , Meille Christophe , Heimbrook David , Vassilev Lyubomir , Packman Kathryn 
Published: May 2014

Abstract
Purpose: Antitumor clinical activity has been demonstrated for the MDM2 antagonist RG7112, but patient tolerability for the necessary daily dosing was poor. Here, utilizing RG7388, a second-generation nutlin with superior selectivity and potency, we determine the feasibility of intermittent dosing to guide the selection of initial phase I scheduling regimens.
Experimental Design: A pharmacokinetic–pharmacodynamic (PKPD) model was developed on the basis of preclinical data to determine alternative dosing schedule requirements for optimal RG7388-induced antitumor activity. This PKPD model was used to investigate the pharmacokinetics of RG7388 linked to the time-course of the antitumor effect in an osteosarcoma xenograft model in mice. These data were used to prospectively predict intermittent and continuous dosing regimens, resulting in tumor stasis in the same model system.
Results: RG7388-induced apoptosis was delayed relative to drug exposure with continuous treatment not required. In initial efficacy testing, daily dosing at 30 mg/kg and twice a week dosing at 50 mg/kg of RG7388 were statistically equivalent in our tumor model. In addition, weekly dosing of 50 mg/kg was equivalent to 10 mg/kg given daily. The implementation of modeling and simulation on these data suggested several possible intermittent clinical dosing schedules. Further preclinical analyses confirmed these schedules as viable options.
Conclusion: Besides chronic administration, antitumor activity can be achieved with intermittent schedules of RG7388, as predicted through modeling and simulation. These alternative regimens may potentially ameliorate tolerability issues seen with chronic administration of RG7112, while providing clinical benefit. Thus, both weekly (qw) and daily for five days (5 d on/23 off, qd) schedules were selected for RG7388 clinical testing. Clin Cancer Res; 20(14); 3742–52. ©2014 AACR.
Testis Cancer: The Forgotten Poster Child
Authors: Raghavan Derek 
Published: May 2014

Abstract
In germ cell cancers, the unique reversibility of malignancy and the balance between somatic differentiation and dedifferentiation may be critical to late relapse that is dominated by non–germ cell elements. Targeting regulators of differentiation may provide a solution, and this may be elucidated via serial liquid biopsies (via circulating tumor cells). Clin Cancer Res; 20(14); 3630–1. ©2014 AACR.
CXCR3 Controls T-Cell Accumulation in Fat Inflammation
Authors: Rocha Viviane Zorzanelli , Folco Eduardo J. , Ozdemir Cafer , Sheikine Yuri , Christen Thomas , Sukhova Galina K. , Tang Eva H.C. , Bittencourt Marcio Sommer , Santos Raul D. , Luster Andrew D. , Cohen David E. , Libby Peter 
Published: May 2014

Objective—
Obesity associates with increased numbers of inflammatory cells in adipose tissue (AT), including T cells, but the mechanism of T-cell recruitment remains unknown. This study tested the hypothesis that the chemokine (C-X-C motif) receptor 3 (CXCR3) participates in T-cell accumulation in AT of obese mice and thus in the regulation of local inflammation and systemic metabolism.

Approach and Results—

Obese wild-type mice exhibited higher mRNA expression of CXCR3 in periepididymal AT-derived stromal vascular cells compared with lean mice. We evaluated the function of CXCR3 in AT inflammation in vivo using CXCR3-deficient and wild-type control mice that consumed a high-fat diet. Periepididymal AT from obese CXCR3-deficient mice contained fewer T cells than obese controls after 8 and 16 weeks on high-fat diet, as assessed by flow cytometry. Obese CXCR3-deficient mice had greater glucose tolerance than obese controls after 8 weeks, but not after 16 weeks. CXCR3-deficient mice fed high-fat diet had reduced mRNA expression of proinflammatory mediators, such as monocyte chemoattractant protein-1 and regulated on activation, normal T cell expressed and secreted, and anti-inflammatory genes, such as
Foxp3
,
IL-10
, and arginase-1 in periepididymal AT, compared with obese controls.

Conclusions—
These results demonstrate that CXCR3 contributes to T-cell accumulation in periepididymal AT of obese mice. Our results also suggest that CXCR3 regulates the accumulation of distinct subsets of T cells and that the ratio between these functional subsets across time likely modulates local inflammation and systemic metabolism.
Overdrive Pacing From Downstream Sites on Multielectrode Catheters to Rapidly Detect Fusion and to Diagnose Macroreentrant Atrial Arrhythmias
Authors: Barbhaiya Chirag R. , Kumar Saurabh , Ng Justin , Tedrow Usha , Koplan Bruce , John Roy , Epstein Laurence M. , Stevenson William G. , Michaud Gregory F. 
Published: May 2014

Background—
Entrainment criteria for macroreentrant arrhythmias are based on detecting fusion between tachycardia and paced wavefronts, but this is often difficult for atrial tachycardias (AT) after ablation of atrial fibrillation.

Methods and Results—

With the use of a multipolar catheter, pacing was performed from electrodes within the coronary sinus showing activation later than adjacent electrodes (downstream overdrive pacing) during 66 ATs in 62 patients: 20 cavotricuspid isthmus–dependent ATs, 20 perimitral ATs, 13 focal ATs with sequential coronary sinus activation, and 13 other macroreentrant left atrial ATs. The paced cycle length was 10 to 30 milliseconds below the tachycardia cycle length (TCL), and activation at the neighboring upstream electrodes was assessed. Downstream overdrive pacing at 48 sites close to a macroreentrant circuit (PPI−TCL <40 milliseconds, where PPI is postpacing interval) produced constant fusion demonstrated by a long stimulus to upstream atrial electrogram interval (S-A
u
) >75% TCL and was consistent with orthodromic activation of the upstream site despite its close proximity to the pacing site. In contrast, downstream overdrive pacing at 18 sites during focal AT or remote from the macroreentrant AT circuit (PPI−TCL >40 milliseconds) always demonstrated a comparatively short S-A
u
<25% of TCL (12±4% versus 89±4% of TCL;
P
<0.001), consistent with direct activation.

Conclusions—

Selection of a downstream activation site for overdrive pacing can facilitate rapid recognition of macroreentry and proximity to the reentry circuit using a single multielectrode catheter by recognizing a PPI–TCL <40 milliseconds and S-A
u
>75% of TCL. Recognition of intracardiac constant fusion with this method is a novel criterion for transient entrainment.
Fruits and Vegetables Consumption and Risk of Stroke
Authors: Hu Dan , Huang Junqian , Wang Yuchun , Zhang Dongfeng , Qu Yan 
Published: May 2014

Background and Purpose—
We conducted a meta-analysis to summarize evidence from prospective cohort studies about the association of fruits and vegetables consumption with the risk of stroke.

Methods—
Pertinent studies were identified by a search of Embase and PubMed databases to January 2014. Study-specific relative risks with 95% confidence intervals were pooled using a random-effects model. Dose–response relationship was assessed by restricted cubic spline.

Results—

Twenty prospective cohort studies were included, involving 16 981 stroke events among 760 629 participants. The multivariable relative risk (95% confidence intervals) of stroke for the highest versus lowest category of total fruits and vegetables consumption was 0.79 (0.75–0.84), and the effect was 0.77 (0.71–0.84) for fruits consumption and 0.86 (0.79–0.93) for vegetables consumption. Subgroup and meta-regression showed that the inverse association of total fruits and vegetables consumption with the risk of stroke was consistent in subgroup analysis. Citrus fruits, apples/pears, and leafy vegetables might contribute to the protection. The linear dose–response relationship showed that the risk of stroke decreased by 32% (0.68 [0.56–0.82]) and 11% (0.89 [0.81–0.98]) for every 200 g per day increment in fruits consumption (
P
for nonlinearity=0.77) and vegetables consumption (
P
for nonlinearity=0.62), respectively.

Conclusions—
Fruits and vegetables consumption are inversely associated with the risk of stroke.
Political Corruption in the Age of Transnational Capitalism
Authors: Bratsis Peter 
Published: May 2014

AbstractThe emergence of the ever-growing anti-corruption movement from the early ’90s onwards has proven itself to be of considerable importance in how we understand and explain global inequalities as well as in redefining corruption as a lack of transparency. This paper examines the timing and content of this international anti-corruption movement. It argues that, following the collapse of the Soviet Union and the deepening of an increasingly transnational capitalism, anti-corruption discourse has arisen as a new version of the ‘white man’s burden’, a justification for intervention into the domestic politics of less powerful states as well as an explanation for their relative poverty. Concurrently, the anti-corruption movement has functioned to push states into increasing their autonomy with respect to local interests and fractions of capital in order to become more subservient and hospitable to transnational capital as a whole.
Failed Abstraction – The Problem of Uno Kōzō’s Reading of Marx’s Theory of the Value Form
Authors: Lange Elena Louisa 
Published: May 2014

AbstractUno Kōzō (1897–1977) was Japan’s foremost Marxian economist. His critique of Marx’s method inCapital, especially regarding the ‘premature’ introduction of value-form analysis in Volume I, motivated him to rewrite all three volumes ofCapitalin his bookThe Principles of Political Economy(1950–2).Notwithstanding Uno’s increasing popularity in international Marx research, I will present a critical paper that looks at a fundamental misunderstanding in Uno’s reading of the value form. In what is one of the most significant discussions of the value form in postwar Japan, Uno argues that ‘value’ and money as its ‘bearer’ cannot be understood in abstraction frompersonalinteraction and human wants in commodity exchange. By drawing on the Japanese documents and supporting the view of Uno’s rival Kuruma Samezō (1893–1982), I want to show that it can, and how Marx understood the ‘law of value’ as anon-personallaw of social domination.
Book review: L’Insurrection qui vient, written by Comité Invisible
Authors: de Bloois Joost 
Published: May 2014

Abstract
In this review article, I take a closer look at the French journal Tiqqun (1999–2001) and the pamphlet The Coming Insurrection (originally published in 2007). In particular, I consider the overarching political project advanced in these texts as ‘sectarian reason’, that is to say, as a form of bio-politics that is deeply rooted in anthropological and ethical assumptions. Moreover, I identify the intrinsic deadlocks of these suppositions, in particular their latent voluntarism, which they claim to reject if not to have overcome.
Searching for the Elusive Cold-Type Occluded Front
Authors: Schultz David M. , Antonescu Bogdan , Chiariello Alessandro 
Published: May 2014

Abstract
According to the Norwegian cyclone model, whether a warm-type or cold-type occluded front forms depends upon which cold air mass is colder: the prewarm-frontal air mass or the postcold-frontal air mass. For example, a cold-type occlusion is said to occur when the occluded front slopes rearward with height because the prewarm-frontal air mass is warmer than the postcold-frontal air mass. This temperature difference and the resulting occluded-frontal structure in the Norwegian cyclone model is part of what is called the temperature rule. Paradoxically, no clear example of a rearward-sloping, cold-type occluded front has been found in the literature, even though the required temperature difference has been documented in several cases. This article presents the first documented, rearward-sloping, cold-type occluded front. This occluded front forms in a cyclone over the North Atlantic Ocean on 3–5 January 2003 and is documented in model output from the European Centre for Medium-Range Weather Forecasts. Cross sections through the evolving cyclone show the occluded front forms as the less statically stable warm-frontal zone ascends over the more stable cold-frontal zone. Such a stability difference between the cold- and warm-frontal zones is consistent with a previously published hypothesis that the less stable air is lifted by the more stable air to form occluded fronts, in disagreement with the temperature rule. Because warm-frontal zones and the cold air underneath tend to be more stable than cold-frontal zones and the postcold-frontal air, warm-type occluded fronts are much more common than cold-type occluded fronts, explaining why well-defined, rearward-sloping, cold-type occluded fronts are not common in the meteorological literature.
Probability Distributions and Threshold Selection for Monte Carlo–Type Tropical Cyclone Wind Speed Forecasts
Authors: Splitt Michael E. , Lazarus Steven M. , Collins Sarah , Botambekov Denis N. , Roeder William P. 
Published: May 2014

Abstract
Probabilistic wind speed forecasts for tropical cyclones from Monte Carlo–type simulations are assessed within a theoretical framework for a simple unbiased Gaussian system that is based on feature size and location error that mimic tropical cyclone wind fields. Aspects of the wind speed probability data distribution, including maximum expected probability and forecast skill, are assessed. Wind speed probability distributions are shown to be well approximated by a bounded power-law distribution when the feature size is smaller than the location error and tends toward a U-shaped distribution as the location error becomes small. Forecast skill (i.e., true and Heidke skill scores) is shown to be highly dependent on the probability forecast data distribution. Forecasts from the National Hurricane Center (NHC) Wind Speed Probability Forecast Product are used to assess the applicability of the simple system in the interpretation and evaluation of a more advanced system.
The impact of 5-HTTLPR on acute serotonin transporter blockade by escitalopram on emotion processing: Preliminary findings from a randomised, crossover fMRI study
Authors: Outhred Tim , Das Pritha , Dobson-Stone Carol , Felmingham Kim L , Bryant Richard A , Nathan Pradeep J , Malhi Gin S , Kemp Andrew H 
Published: May 2014

Objective: Benefit from antidepressant treatment such as selective serotonin reuptake inhibitors (SSRIs) may depend on individual differences in acute effects on neural emotion processing. The short (‘S’) allele of the serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) is associated with both negative emotion processing biases and poorer treatment outcomes. Therefore, the aim of the present study was to explore the effects of 5-HTTLPR on the impact of the SSRI escitalopram during processing of positive and negative emotional images, as well as neutral stimuli. Methods: The study employed a double-blind, randomised, placebo-controlled crossover design on 36 healthy Caucasian female participants who underwent functional magnetic resonance imaging (fMRI) scanning following placebo or escitalopram treatment, separated by a 7-day washout period. Results: Changes in the left amygdala signal with escitalopram treatment during processing of emotional stimuli were linearly related to the 5-HTTLPR ‘S’ allele load such that the signal to positive stimuli decreased and the signal to negative stimuli increased with an increasing number of low-expressing ‘S’ alleles. While 5-HTTLPR subgroups were small in size, individual subject changes with treatment and task condition increase confidence in the findings. Conclusions: While preliminary, our findings comprise the first pharmacogenetic study demonstrating an effect of the 5-HTTLPR ‘S’ allele load on escitalopram-induced changes in amygdala activity during emotional processing, consistent with a 5-HTT expression dosage model. The present findings have implications for the impact of this polymorphism on antidepressant efficacy in patients with mood and anxiety disorders.