bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Translation Initiation Bypasses Signaling Crosstalk Mechanisms That Maintain High MYC Levels in Colorectal Cancer
Authors: Wiegering Armin , Uthe Friedrich W. , Jamieson Thomas , Ruoss Yvonne , Hüttenrauch Melanie , Küspert Maritta , Pfann Christina , Nixon Colin , Herold Steffi , Walz Susanne , Taranets Lyudmyla , Germer Christoph-Thomas , Rosenwald Andreas , Sansom Owen J. , Eilers Martin 
Published: May 2015

Abstract
Deregulated expression of MYC is a driver of colorectal carcinogenesis, suggesting that inhibiting MYC may have significant therapeutic value. The PI3K and mTOR pathways control MYC turnover and translation, respectively, providing a rationale to target both pathways to inhibit MYC. Surprisingly, inhibition of PI3K does not promote MYC turnover in colon carcinoma cells, but enhances MYC expression because it promotes FOXO-dependent expression of growth factor receptors and MAPK-dependent transcription of MYC. Inhibition of mTOR fails to inhibit translation of MYC, because levels of 4EBPs are insufficient to fully sequester eIF4E and because an internal ribosomal entry site element in the 5′-untranslated region of the MYC mRNA permits translation independent of eIF4E. A small-molecule inhibitor of the translation factor eIF4A, silvestrol, bypasses the signaling feedbacks, reduces MYC translation, and inhibits tumor growth in a mouse model of colorectal tumorigenesis. We propose that targeting translation initiation is a promising strategy to limit MYC expression in colorectal tumors.
Significance: Inhibiting MYC function is likely to have a significant therapeutic impact in colorectal cancers. Here, we explore several strategies to target translation initiation in order to block MYC expression. We show that a small-molecule inhibitor of eIF4A inhibits MYC expression and suppresses tumor growth in vivo. Cancer Discov; 5(7); 768–81. ©2015 AACR.
See related commentary by Castell and Larsson, p. 701.
This article is highlighted in the In This Issue feature, p. 681
Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor
Authors: Piotrowska Zofia , Niederst Matthew J. , Karlovich Chris A. , Wakelee Heather A. , Neal Joel W. , Mino-Kenudson Mari , Fulton Linnea , Hata Aaron N. , Lockerman Elizabeth L. , Kalsy Anuj , Digumarthy Subba , Muzikansky Alona , Raponi Mitch , Garcia Angel R. , Mulvey Hillary E. , Parks Melissa K. , DiCecca Richard H. , Dias-Santagata Dora , Iafrate A. John , Shaw Alice T. , Allen Andrew R. , Engelman Jeffrey A. , Sequist Lecia V. 
Published: May 2015

Abstract
Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790–wild-type rociletinib-resistant biopsies. Two T790–wild-type cancers underwent small cell lung cancer transformation; three T790M-positive cancers acquired EGFR amplification. We documented T790–wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. The pretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulating tumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790M heralded rociletinib resistance in some patients, whereas in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are used. To further improve outcomes, combination regimens that also target T790–wild-type clones are required.
Significance: This report documents that half of T790M-positive EGFR-mutant lung cancers treated with rociletinib are T790–wild-type upon progression, suggesting that T790–wild-type clones can emerge as the dominant source of resistance. We show that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses can sometimes predict emerging resistance mechanisms. Cancer Discov; 5(7); 713–22. ©2015 AACR.
See related commentary by Ichihara and Lovly, p. 694.
This article is highlighted in the In This Issue feature, p. 681
Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors
Authors: Wang Enxiu , Wang Liang-Chuan , Tsai Ching-Yi , Bhoj Vijay , Gershenson Zack , Moon Edmund , Newick Kheng , Sun Jing , Lo Albert , Baradet Timothy , Feldman Michael D. , Barrett David , Puré Ellen , Albelda Steven , Milone Michael C. 
Published: May 2015

AbstractChimeric antigen receptors (CAR) bearing an antigen-binding domain linked in cis to the cytoplasmic domains of CD3ζ and costimulatory receptors have provided a potent method for engineering T-cell cytotoxicity toward B-cell leukemia and lymphoma. However, resistance to immunotherapy due to loss of T-cell effector function remains a significant barrier, especially in solid malignancies. We describe an alternative chimeric immunoreceptor design in which we have fused a single-chain variable fragment for antigen recognition to the transmembrane and cytoplasmic domains of KIR2DS2, a stimulatory killer immunoglobulin-like receptor (KIR). We show that this simple, KIR-based CAR (KIR-CAR) triggers robust antigen-specific proliferation and effector function in vitro when introduced into human T cells with DAP12, an immunotyrosine-based activation motifs-containing adaptor. T cells modified to express a KIR-CAR and DAP12 exhibit superior antitumor activity compared with standard first- and second-generation CD3ζ-based CARs in a xenograft model of mesothelioma highly resistant to immunotherapy. The enhanced antitumor activity is associated with improved retention of chimeric immunoreceptor expression and improved effector function of isolated tumor-infiltrating lymphocytes. These results support the exploration of KIR-CARs for adoptive T-cell immunotherapy, particularly in immunotherapy-resistant solid tumors. Cancer Immunol Res; 3(7); 815–26. ©2015 AACR.
Stent Thrombosis and Dual Antiplatelet Therapy Interruption With Everolimus-Eluting Stents
Authors: Généreux Philippe , Rutledge David R. , Palmerini Tullio , Caixeta Adriano , Kedhi Elvin , Hermiller James B. , Wang Jin , Krucoff Mitchell W. , Jones-McMeans Jennifer , Sudhir Krishnankutty , Simonton Charles A. , Serruys Patrick W. , Stone Gregg W. 
Published: May 2015

Background—
Whether premature dual antiplatelet therapy (DAPT) interruption is safe in patients receiving cobalt chromium everolimus–eluting stents remains controversial. We sought to examine the relationship between DAPT discontinuation and stent thrombosis (ST) after cobalt chromium everolimus-eluting stents.

Methods and Results—

Outcomes from 11 219 patients were pooled from 3 randomized trials and 4 registries with 2-year follow-up period after cobalt chromium everolimus–eluting stent implantation. Rates of definite/probable ST were analyzed according to DAPT discontinuation in the following time intervals: 0 to 30, 30 to 90, 90 to 180, 180 to 365, and 365 to 730 days. Eighty-five cases of ST (0.75%) occurred in 83 patients during 2 years, with 41 (48.2%) events occurring within 30 days. The 2-year ST rate in patients interrupting DAPT at any time was similar to that in patients never interrupting DAPT through 2 years (25/4067 [0.63%] versus 58/7152 [0.83%] respectively;
P
=0.27]. By propensity and DAPT usage–adjusted multivariable analysis, permanent DAPT discontinuation before 30 days was independently associated with the occurrence of ST (hazard ratio [95% confidence interval], 26.8 [8.4–85.4];
P
<0.0001), whereas permanent DAPT discontinuation in any interval after 90 days was not associated with ST. Only 2 ST events occurred after DAPT discontinuation between 30 and 90 days (both between 30 and 60 days), and the association between permanent DAPT discontinuation and ST during this period is unclear (hazard ratio [95% confidence interval], 8.7 [2.0–37.3];
P
=0.004 for adjusted analysis and 3.4 [0.8–13.8];
P
=0.07 for the unadjusted analysis).

Conclusions—
In this large pooled experience, permanent DAPT discontinuation before 30 days after cobalt chromium everolimus–eluting stent implantation was strongly associated with ST, whereas DAPT discontinuation beyond 90 days appeared safe.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00180310, NCT00180479, NCT00307047, NCT00402272, NCT00496938, NCT00676520, and NCT00631228.
Pharmacokinetics of Sirolimus-Eluting Stents Implanted in the Neonatal Arterial Duct
Authors: Lee Kyong-Jin , Seto Winnie , Benson Lee , Chaturvedi Rajiv R. 
Published: May 2015

Background—
Sirolimus-eluting stents may have clinical advantages over bare-metal stents in the extremely proliferative environment of the neonatal arterial duct. However, sirolimus has immunosuppressive actions and little is known regarding sirolimus pharmacokinetics in the newborn.

Methods and Results—
This is a retrospective review of sirolimus pharmacokinetics in neonates who underwent sirolimus-eluting stent implantation in the arterial duct for pulmonary blood flow augmentation. Pharmacokinetic parameters were obtained by noncompartmental analysis and by a Bayesian one-compartment nonlinear mixed model. Nine neonates received a single sirolimus-eluting stent with a total sirolimus dose of 245 μg (n=1), 194 μg (n=5), or 143 μg (n=3). Peak sirolimus concentrations were 13.6±4.5 μg/L (24.8 μg/L highest) and clearance was 0.042±0.03 L/hour (noncompartmental analysis) and 0.051 L/hour (95% credible intervals 0.037–0.069, nonlinear mixed model). Sirolimus remained >5 μg/L, the trough level used in oral immunosuppressive therapy, for (95% credible interval) 15.9 (11.4, 22.8), 12.9 (7.6, 19.0), and 8.4 (2.3, 14.5) days for the 245, 194, and 143 μg sirolimus dose stents, respectively. Estimates of the duration of systemic immunosuppression are provided for combinations of 2 stents.

Conclusions—
In neonates after sirolimus-eluting stent implantation, peak sirolimus levels were 20× higher and clearance 30× lower than previously reported in older children and adults. Sirolimus levels were within the immunosuppressive range for a prolonged period, but with no observable clinically significant adverse outcomes.
Platelet Extracellular Regulated Protein Kinase 5 Is a Redox Switch and Triggers Maladaptive Platelet Responses and Myocardial Infarct Expansion
Authors: Cameron Scott J. , Ture Sara K. , Mickelsen Deanne , Chakrabarti Enakshi , Modjeski Kristina L. , McNitt Scott , Seaberry Michael , Field David J. , Le Nhat-Tu , Abe Jun-ichi , Morrell Craig N. 
Published: May 2015

Background—
Platelets have a pathophysiologic role in the ischemic microvascular environment of acute coronary syndromes. In comparison with platelet activation in normal healthy conditions, less attention is given to mechanisms of platelet activation in diseased states. Platelet function and mechanisms of activation in ischemic and reactive oxygen species–rich environments may not be the same as in normal healthy conditions. Extracellular regulated protein kinase 5 (ERK5) is a mitogen-activated protein kinase family member activated in hypoxic, reactive oxygen species–rich environments and in response to receptor-signaling mechanisms. Prior studies suggest a protective effect of ERK5 in endothelial and myocardial cells after ischemia. We present evidence that platelets express ERK5 and that platelet ERK5 has an adverse effect on platelet activation via selective receptor-dependent and receptor-independent reactive oxygen species–mediated mechanisms in ischemic myocardium.

Methods and Results—

Using isolated human platelets and a mouse model of myocardial infarction (MI), we found that platelet ERK5 is activated post-MI and that platelet-specific ERK5
–/–
mice have less platelet activation, reduced MI size, and improved post-MI heart function. Furthermore, the expression of downstream ERK5-regulated proteins is reduced in ERK5
–/–
platelets post-MI.

Conclusions—
ERK5 functions as a platelet activator in ischemic conditions, and platelet ERK5 maintains the expression of some platelet proteins after MI, leading to infarct expansion. This demonstrates that platelet function in normal healthy conditions is different from platelet function in chronic ischemic and inflammatory conditions. Platelet ERK5 may be a target for acute therapeutic intervention in the thrombotic and inflammatory post-MI environment.
A Synoptic Classification of Inflow-Generating Precipitation in the Snowy Mountains, Australia
Authors: Theobald Alison , McGowan Hamish , Speirs Johanna , Callow Nik 
Published: May 2015

AbstractPrecipitation falling in the Snowy Mountains region of southeastern Australia provides fuel for hydroelectric power generation and environmental flows along major river systems, as well as critical water resources for agricultural irrigation. A synoptic climatology of daily precipitation that triggers a quantifiable increase in streamflow in the headwater catchments of the Snowy Mountains region is presented for the period 1958–2012. Here, previous synoptic-meteorological studies of the region are extended by using a longer-term, year-round precipitation and reanalysis dataset combined with a novel, automated synoptic-classification technique. A three-dimensional representation of synoptic circulation is developed by effectively combining meteorological variables through the depth of the troposphere. Eleven distinct synoptic types are identified, describing key circulation features and moisture pathways that deliver precipitation to the Snowy Mountains. Synoptic types with the highest precipitation totals are commonly associated with moisture pathways originating from the northeast and northwest of Australia. These systems generate the greatest precipitation totals across the westerly and high-elevation areas of the Snowy Mountains, but precipitation is reduced in the eastern-elevation areas in the lee of the mountain ranges. In eastern regions, synoptic types with onshore transport of humid air from the Tasman Sea are the major source of precipitation. Strong seasonality in synoptic types is evident, with frontal and cutoff-low types dominating in winter and inland heat troughs prevailing in summer. Interaction between tropical and extratropical systems is evident in all seasons.
Reversible alterations of the neuronal activity in spontaneous intracranial hypotension
Authors: Amemiya Shiori , Takahashi Koichi , Mima Tatsuo , Yoshioka Naoki , Miki Soichiro , Ohtomo Kuni 
Published: May 2015

Aim The aim of this article is to investigate the pathophysiology underlying the alternation of the cognitive function and neuronal activity in spontaneous intracranial hypotension (SIH). Methods Fifteen patients with SIH underwent resting-state functional magnetic resonance imaging and working-memory (WM) test one day before and one month after a surgical operation. Alternation of the cognitive function and spontaneous neuronal activity measured as amplitude of the low-frequency fluctuations (ALFF) and the functional connectivity of the default-mode network (DMN) and frontoparietal networks (FPNs) were evaluated. Results WM performance significantly improved post-operatively. Whole-brain linear regression analysis of the ALFF revealed a positive correlation between cognitive performance change and ALFF change in the precuneus while a negative correlation was found in the bilateral orbitofrontal cortices (OFCs) and right medial frontal cortex (MFC). The ALFF changes normalised with the WM performance improvement post-operatively. The FPN activity in the right OFC was also increased pre-operatively. Partial correlation analysis revealed a significant correlation between WM performance and right OFC activity controlled for right FPN activity. Conclusions The abnormal activity of the OFCs and MFC that is not originating from the synchronous intrinsic network activity, together with the decreased activity of the central node of the DMN, could lead to cognitive impairment in SIH that is reversible through restoration of the cerebrospinal fluid.
Leukemia stem cells in T-ALL require active Hif1α and Wnt signaling
Authors: Giambra Vincenzo , Jenkins Catherine E. , Lam Sonya H. , Hoofd Catherine , Belmonte Miriam , Wang Xuehai , Gusscott Sam , Gracias Deanne , Weng Andrew P. 
Published: May 2015

Key PointsA real-time, integrated fluorescent Wnt reporter marks rare leukemia stem cells in T-ALL. Deletion of β-catenin or Hif1α reduces LIC frequency in established tumors, but does not affect the growth of bulk cells.
Low ATM protein expression in malignant tumor as well as cancer-associated stroma are independent prognostic factors in a retrospective study of early-stage hormone-negative breast cancer
Authors: Feng Xiaolan , Li Haocheng , Dean Michelle , Wilson Holly E , Kornaga Elizabeth , Enwere Emeka K , Tang Patricia , Paterson Alexander , Lees-Miller Susan P , Magliocco Anthony M , Bebb Gwyn 
Published: May 2015

Abstract
Introduction
The serine/threonine protein kinase ataxia telangiectasia mutated (ATM) is critical in maintaining genomic integrity. Upon DNA double-strand breaks, ATM phosphorylates key downstream proteins including p53 and BRCA1/2, thereby orchestrating complex signaling pathways involved in cell cycle arrest, DNA repair, senescence and apoptosis. Although sporadic mutation of ATM occurs rarely in breast cancer, the status of its protein expression and its clinical significance in breast cancer remain not well established. Our study was designed to investigate the influence of ATM protein in both tumor and cancer-associated stroma on clinical outcome in hormone-positive (HPBC) and hormone-negative (HNBC) early-stage breast cancer (EBC).

Methods
Tissue microarrays (TMAs), containing formalin-fixed, paraffin-embedded resected tumors from two cohorts of patients (HPBC cohort: n = 130; HNBC cohort: n = 168) diagnosed at the Tom Baker Cancer Centre, Calgary, Canada, were analyzed for ATM protein expression using fluorescence immunohistochemistry (IHC) and automated quantitative analysis (AQUA). ATM expression levels were measured within the tumor as a whole (tATM) as indicated by pan-cytokeratin expression, tumor nuclear compartment (nATM) as indicated by both DAPI and pan-cytokeratin-positive results, and cancer-associated stroma (csATM) as indicated by vimentin-positive and pan-cytokeratin-negative results. ATM expression levels within these compartments were correlated with clinical outcome.

Results
While tATM and nATM were significantly lower in tumors compared to normal breast epithelial tissues, csATM was significantly higher than the corresponding normal tissue compartment. In addition, the median expression level of both tATM and nATM were two- to threefold lower (P <0.001) in HNBC than in HPBC. In both HNBC and HPBC cohorts, patients with low tATM, nATM and csATM tumors had significantly poorer survival outcomes than those with a high tATM, nATM and csATM, but this effect was more pronounced in HNBC. A multivariate analysis demonstrates that these biomarkers predict survival independent of tumor size and lymph node status, but only in the HNBC cohort (P <0.001).

Conclusions
Low ATM protein expression in both malignant tumor and stromal compartments likely contributes to the aggressive nature of breast cancer and is an independent prognostic factor associated with worse survival in HNBC patients.
Existence of extended Nash equilibriums of nonmonetized noncooperative games
Authors: Zhao Chunxiang , Hong Shihuang , Li Chunhong 
Published: May 2015

AbstractIn this paper, we consider extended Nash equilibriums of nonmonetized noncooperative games. By using a modified fixed point theorem of set-valued mappings on partially ordered sets, we prove an existence theorem of extended Nash equilibriums of the nonmonetized noncooperative game. Finally, an example is given to illustrate the advantages of our results.
Permeation thresholds for hydrophilic small biomolecules across microvascular and epithelial barriers are predictable on basis of conserved biophysical properties
Authors: Sarin Hemant 
Published: May 2015

AbstractPurposeNeutral small hydrophiles are permeable to varying degrees, across the aqueous pores of phospholipid bilayer protein channels, with their potential for permeation into cells being predictable, on the basis of hydrophilicity and size. Here, it is hypothesized that permeation thresholds for small hydrophiles, across capillary zona occludens tight junction and inter-epithelial junction pore complexes are predictable, on the basis of predicted hydrophilicity in context of predicted molecular size and charge distribution, as are those of cations and anions, on the basis of predicted ionization in context of predicted atomic size.MethodsSmall hydrophiles are categorized by charge distribution. 2-dimensional plots of predicted hydrophilic octanol-to-water partition coefficient (HOWPC; unitless) and predicted van der Waals diameter (vdWD; nm) are generated for each category. The predicted HOWPC-to-vdWD ratio (nm-1), and vdWDs for permeable hydrophile at the maximum and minimum HOWPC-to-vdWD, vdWD @ MAXimum HOWPC-to-vdWD and vdWD @ MINimum HOWPC-to-vdWD are determined. For cations and anions, the ionization-to-atomic diameter ratios (CI or AI-to-AD ratios; nm-1) are determined.ResultsPer sizes of mixed and pure polyneutral hydrophiles, the permeation size maximum for hydrophiles across tight junction pore complexes is >0.69 ≤ 0.73 nanometers and across inter-epithelial junction pore complexes is ≥ 0.81 nanometers. For hydrophiles with anionicity or cationicity, the vdWDs @ MAXimum HOWPC-to-vdWD are less than those of mixed and polyneutral hydrophiles across both tight and inter-epithelial junctions, ranges specific to category and junction type. For cations, the permeation threshold across tight junctions is between the CI-to-AD ratio of Na+ (+2.69 nm-1) and CH3-Hg+ (+2.36 nm-1), with CH3-Hg+ and K+ (+2.20 nm-1) being permeable; and for divalent cations, the threshold across inter-epithelial junctions is between the CI-to-AD ratio of Mg2+ (+6.25 nm-1) and Ca2+ (+5.08 nm-1) , Ca2+ being semi-permeable. For anions, the permeation threshold across tight junctions is between the AI-to-AD ratio of Cl- (-4.91 nm-1) and Br- (-4.17 nm-1), and the threshold across inter-epithelial junctions is between the AI-to-AD ratio of F- (-7.81 nm-1) and Cl- (-4.91 nm-1).ConclusionsIn silicomodeling reveals that permeation thresholds, of small molecule hydrophiles, cations and anions across junctional pore complexes, are conserved in the physiologic state.