bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of screen time with self-perceived attention problems and hyperactivity levels in French students: a cross-sectional study
Authors: Montagni Ilaria , Guichard Elie , Kurth Tobias
Published: February 2016

Objective

To investigate whether high levels of screen time exposure are associated with self-perceived levels of attention problems and hyperactivity in higher education students.

Design

Cross-sectional study among participants of the i-Share cohort.

Setting

French-speaking students of universities and higher education institutions.

Participants

4816 graduate students who were at least 18 years old.

Exposure

Screen time was assessed by self-report of the average time spent on five different screen activities on smartphone, television, computer and tablet and categorised into quartiles.

Main outcome measure

We used the Attention Deficit Hyperactivity Disorder Self-Report Scale (ASRS-v1.1) concerning students’ behaviour over the past 6 months to measure self-perceived levels of attention problems and hyperactivity. Responses were summarised into a global score as well as scores for attention problems and hyperactivity.

Results

The 4816 participants of this study had a mean age of 20.8 years and 75.5% were female. Multivariable ordinary regression models showed significant associations of screen time exposure with quintiles of the total score of self-perceived attention problems and hyperactivity levels as well as the individual domains. Compared to the lowest screen time exposure category, the ORs (95% CI) were 1.58 (1.37 to 1.82) for each increasing level of quintiles of the global score, 1.57 (1.36 to 1.81) for increasing quintiles of attention levels and 1.25 (1.09 to 1.44) for increasing quartiles of hyperactivity.

Conclusions

Results of this large cross-sectional study among French university and higher education students show dose-dependent associations between screen time and self-perceived levels of attention problems and hyperactivity. Further studies are warranted to evaluate whether interventions could positively influence these associations.
Natural history of brain capillary vascular malformations in hereditary hemorrhagic telangiectasia patients
Authors: Brinjikji Waleed , Iyer Vivek N , Lanzino Giuseppe , Thielen Kent R , Wood Christopher P
Published: February 2016

Background and purpose

Brain capillary vascular malformations (CVMs) are known to occur with relatively high frequency in hereditary hemorrhagic telangiectasia (HHT) patients. These lesions are thought to have a benign natural history but this has not been systematically studied. The purpose of our study was to examine the natural history of CVMs in a consecutive series of HHT patients.

Materials and methods

Consecutive patients with untreated CVMs receiving serial imaging were included. Baseline data including demographics, HHT gene mutations, and Curacao diagnostic criteria were collected. The primary outcome was rupture on follow-up. A secondary outcome was new focal neurological deficit or seizure related to the lesion.

Results

22 patients with 42 CVMs were included. Mean age was 45.9±16.9 years. 18 patients (81.8%) were women and 4 (18.2%) were men. 19 patients (86.4%) had definite HHT and 3 patients (13.6%) had probable HHT. Mean follow-up was 4.6±3.7 years. There were a total of 100.2 patient years of follow-up and 222.5 lesion years. No lesions ruptured on follow-up and no patient had focal neurological deficits or seizures related to the lesions.

Conclusions

Our study found that CVMs in HHT patients have a benign natural history as no patients had hemorrhage or other symptoms related to these lesions. These findings should be confirmed in additional multicenter longitudinal studies.
Risk factors and therapeutic coverage at 6 years in patients with previous myocardial infarction: the CASTUO study
Authors: Félix-Redondo Francisco Javier , Lozano Mera Luis , Consuegra-Sánchez Luciano , Giménez Sáez Fernando , Garcipérez de Vargas Francisco Javier , Castellano Vázquez José María , Fernández-Bergés Daniel
Published: February 2016

Objectives

To determine the degree of risk factor control, the clinical symptoms and the therapeutic management of patients with a history of previous myocardial infarction.

Methods

Cross-sectional study at 6 years of a first episode of acute myocardial infarction between 2000 and 2009, admitted at a hospital in the region of Extremadura (Spain). Of 2177 patients with this diagnosis, 1365 remained alive and therefore were included in the study.

Results

We conducted a person-to-person survey in 666 (48.8%) individuals and telephone survey in 437 (31.9%) individuals. The former are analysed. 130 were female (19.5%). The mean age was 67.4 years and the median time since the event was 5.8 (IQR 3.6–8.2) years. Active smokers made up 13.8%, low-density lipoprotein (LDL) cholesterol was ≥70 mg/dL: 82%, blood pressure ≥140/90 mm Hg (≥140/85 in diabetics): 49.8%, fasting glucose ≥126 mg/dL: 26%, heart rate 50–59 bpm: 60.7%, and obesity: 45.9%. Patients reported presenting angina comprised 22.4% and those with dyspnoea, 29.3%. Drug coverage was: 88.0% antiplatelet drugs, 86.5% statins, 75.6% β-blockers and 65.8% blockers of the renin-angiotensin system. Patients receiving all four types of drugs made up 41.9%, with only 3.0% having jointly controlled cholesterol, blood pressure, heart rate and glycaemia.

Conclusions

LDL cholesterol, heart rate and blood pressure were risk factors with less control. More than 1/5 of patients had angina and more than 1/4, dyspnoea. Risk factor control and the clinical condition were far from optimal, as was drug coverage, although to a lesser degree.
Factors affecting owners’ choice of nutritional supplements for use in dressage and eventing horses
Authors: Gemmill R. , Agar C. , Freeman S. L. , Hollands T.
Published: February 2016

The aim of this study was to investigate the factors affecting horse owners’ choice of nutritional supplements for dressage and eventing horses. An online questionnaire was distributed to owners/riders of dressage and/or event horses to collect data on the demographics of the owner/rider and their horses, the sources of information used when choosing nutritional supplements and their opinion on these different sources. Data analysis included descriptive analysis and categorisation of free text. χ2 tests were used to explore factors affecting decision‐making. In total, 757 responses were analysed. Participants obtained information on nutritional supplements from vets (49.8 per cent), internet article/review (39.4 per cent), other horse owners (38.7 per cent), coach/trainer (36.5 per cent) and nutritionists (33.4 per cent). They ranked the most reliable sources of information as vets, followed by nutritionists, then research studies, and the most influential sources of information as vets, followed by coach/trainer and nutritionists. Most participants had used other horse owners as their source of information for their most recent supplement. The age of the owner, competitive discipline, their educational qualification and their riding experience were significantly associated with aspects of decision‐making. The study also identified a need for independent, unbiased sources of information on nutrition and supplements in the horse.
Genesis and provenance of a new Middle Pleistocene diamicton unit at Happisburgh, NE Norfolk, UK
Authors: Hodkin Richard G. , Lee Jonathan R. , Riding James B. , Turner Jenni A.
Published: February 2016

Glacigenic deposits at Happisburgh, NE Norfolk, record the earliest known expansion of glaciers into lowland eastern England during the Quaternary. The sequence comprises two regionally extensive till units, the Happisburgh Till and Corton Diamicton members of the Happisburgh Glacigenic Formation, deposited during separate ice advances, and intervening glacilacustrine and outwash deposits laid down during ice-marginal retreat. During 2012, a new diamicton unit was discovered within the intervening sorted sediments and its significance is outlined here. Sedimentological and structural evidence suggests, tentatively, that the diamicton forms a small debris fan generated subaerially by a series of water-saturated hyperconcentrated or debris flows. The precise trigger mechanism for these flow deposits remains unclear, but may relate to seasonal melting of surface or buried ice followed by mass-movement, or to more abrupt geological events including periods of intense rainfall, moraine dam failure or a glacier outburst flood.
Geomaterials in construction and their sustainability: understanding their role in modern society
Authors: Přikryl R. , Török Á. , Theodoridou M. , Gomez-Heras M. , Miskovsky K.
Published: February 2016

Inorganic raw materials, here termed geomaterials, derived from the Earth's crust and used in construction after appropriate processing make a genetically and functionally varied group of mineral resources. Although their basic functions have remained almost unchanged for centuries, some new attributes, meanings and impacts on society are still emerging. Geomaterials for construction were among the first mineral raw materials exploited, processed and used by man. They helped in the development of technological and artistic skills of humankind. Accessibility, workability and serviceability are considered here as their main functional attributes, being connected with man's skills to find their occurrence, extract and process them, and then use them in the correct way. However, serviceability is a more complex functional attribute as it also encompasses durability of a material in construction. Durability, that is the ability to withstand the action of weathering/decay processes, is an expression of the dynamic interactions between material and the surrounding environment encompassing not only gradual adaptation of materials to current environmental conditions, but also interactions between materials in construction, the history of maintenance/conservation of the structure and the impact of a polluted environment. In the modern world, sustainable use of raw materials, specifically those exploited in the largest volumes such as geomaterials for construction, raises questions of reducing extraction of primary resources and thus minimizing impacts on natural systems, and also employment of materials and technologies to produce less emission of deleterious substances in to the atmosphere. Use of secondary materials such as waste produced during extraction of primary raw materials and/or re-use of existing structural elements and re- or down-cycling can be considered as modern approaches to reducing the pressure on primary resources.
S-nitrosylation regulates VE-cadherin phosphorylation and internalization in microvascular permeability
Authors: Guequén Anita , Carrasco Rodrigo , Zamorano Patricia , Rebolledo Lorena , Burboa Pia , Sarmiento José , Boric Mauricio P. , Korayem Adam , Durán Walter N. , Sánchez Fabiola A.
Published: February 2016

The adherens junction complex, composed mainly of vascular endothelial (VE)-cadherin, β-catenin, p120, and γ-catenin, is the main element of the endothelial barrier in postcapillary venules. S-nitrosylation of β-catenin and p120 is an important step in proinflammatory agents-induced hyperpermeability. We investigated in vitro and in vivo whether or not VE-cadherin is S-nitrosylated using platelet-activating factor (PAF) as agonist. We report that PAF-stimulates S-nitrosylation of VE-cadherin, which disrupts its association with β-catenin. In addition, based on inhibition of nitric oxide production, our results strongly suggest that S-nitrosylation is required for VE-cadherin phosphorylation on tyrosine and for its internalization. Our results unveil an important mechanism to regulate phosphorylation of junctional proteins in association with S-nitrosylation.
The neuropilin-like protein ESDN regulates insulin signaling and sensitivity
Authors: Li Xuan , Jung Jae-Joon , Nie Lei , Razavian Mahmoud , Zhang Jiasheng , Samuel Varman , Sadeghi Mehran M.
Published: February 2016

Insulin effects on cell metabolism, growth, and survival are mediated by its binding to, and activation of, insulin receptor. With increasing prevalence of insulin resistance and diabetes there is considerable interest in identifying novel regulators of insulin signal transduction. The transmembrane protein endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN) is a novel regulator of vascular remodeling and angiogenesis. Here, we investigate a potential role of ESDN in insulin signaling, demonstrating that Esdn gene deletion promotes insulin-induced vascular smooth muscle cell proliferation and migration. This is associated with enhanced protein kinase B and mitogen-activated protein kinase activation as well as insulin receptor phosphorylation. Likewise, insulin signaling in the liver, muscle, and adipose tissue is enhanced in Esdn−/−mice, and these animals exhibit improved insulin sensitivity and glucose homeostasis in vivo. The effect of ESDN on insulin signaling is traced back to its interaction with insulin receptor, which alters the receptor interaction with regulatory adaptor protein-E3 ubiquitin ligase pairs, adaptor protein with pleckstrin homology and Src homology 2 domain-c-Cbl and growth factor receptor bound protein 10-neuronal precursor cell-expressed developmentally downregulated 4. In conclusion, our findings establish ESDN as an inhibitor of insulin receptor signal transduction through a novel regulatory mechanism. Loss of ESDN potentiates insulin's metabolic and mitotic effects and provides insights into a novel therapeutic avenue.
Tumor necrosis factor-α impairs adiponectin signalling, mitochondrial biogenesis, and myogenesis in primary human myotubes cultures
Authors: Sente Tahnee , Van Berendoncks An M. , Fransen Erik , Vrints Christiaan J. , Hoymans Vicky Y.
Published: February 2016

Skeletal muscle metabolic changes are common in patients with chronic heart failure (HF). Previously, we demonstrated a functional skeletal muscle adiponectin resistance in HF patients with reduced left ventricular ejection fraction (HFrEF). We aimed to examine the impact of adiponectin receptor 1 (AdipoR1) deficiency and TNF-α treatment on adiponectin signaling, proliferative capacity, myogenic differentiation, and mitochondrial biogenesis in primary human skeletal muscle cells. Primary cultures of myoblasts and myotubes were initiated from the musculus vastus lateralis of 10 HFrEF patients (left ventricular ejection fraction; 31.30 ± 2.89%) and 10 age- and gender-matched healthy controls. Healthy control cultures were transfected with siAdipoR1 and/or exposed to TNF-α (10 ng/ml; 72 h). Primary cultures from HFrEF patients preserved the features of adiponectin resistance in vivo. AdipoR1 mRNA was negatively correlated with time to reach maximal cell index ( r = −0.7319, P = 0.003). SiRNA-mediated AdipoR1 silencing reduced pAMPK ( P < 0.01), AMPK activation ( P = 0.046), and myoblast proliferation rate (xCELLigence Real-Time Cellular Analysis; P < 0.0001). Moreover, TNF-α decreased the mRNA expression of genes involved in glucose (APPL1, P = 0.0002; AMPK, P = 0.021), lipid (PPARα, P = 0.025; ACADM, P = 0.003), and mitochondrial (FOXO3, P = 0.018) metabolism, impaired myogenesis (MyoD1, P = 0.053; myogenin, P = 0.048) and polarized cytokine secretion toward a growth-promoting phenotype (IL-10, IL-1β, IFN-γ, P < 0.05 for all; Meso Scale Discovery Technology). Major features of adiponectin resistance are retained in primary cultures from the skeletal muscle of HFrEF patients. In addition, our results suggest that an increased inflammatory constitution contributes to adiponectin resistance and confers alterations in skeletal muscle differentiation, growth, and function.
Keratinocyte growth factor supports pulmonary innate immune defense through maintenance of alveolar antimicrobial protein levels and macrophage function
Authors: Gardner Jason C. , Wu Huixing , Noel John G. , Ramser Benjamin J. , Pitstick Lori , Saito Atsushi , Nikolaidis Nikolaos M. , McCormack Francis X.
Published: February 2016

Keratinocyte growth factor (KGF) is an epithelial mitogen that has been reported to protect the lungs from a variety of toxic and infectious insults. In prior studies we found that recombinant human KGF accelerates clearance of bacteria from the murine lung by augmenting the function of alveolar macrophages (AM). In this study we tested the hypothesis that endogenous KGF plays a role in the maintenance of innate pulmonary defense against gram-negative bacterial infections. KGF-deficient mice exhibited delayed clearance of Escherichia coli from the lungs, attenuated phagocytosis by AM, and decreased antimicrobial activity in bronchoalveolar lavage (BAL) fluid, due in part to reductions in levels of surfactant protein A, surfactant protein D, and lysozyme. These immune deficits were accompanied by lower alveolar type II epithelial cell counts and reduced alveolar type II epithelial cell expression of collectin and lysozyme genes on a per cell basis. No significant between-group differences were detected in selected inflammatory cytokines or BAL inflammatory cell populations at baseline or after bacterial challenge in the wild-type and KGF-deficient mice. A single intranasal dose of recombinant human KGF reversed defects in bacterial clearance, AM function, and BAL fluid antimicrobial activity. We conclude that KGF supports alveolar innate immune defense through maintenance of alveolar antimicrobial protein levels and functions of AM. Together these data demonstrate a role for endogenous KGF in maintenance of normal pulmonary innate immune function.
Prolyl Hydroxylase 3 Attenuates MCL-1–Mediated ATP Production to Suppress the Metastatic Potential of Colorectal Cancer Cells
Authors: Radhakrishnan Praveenkumar , Ruh Nadine , Harnoss Jonathan M. , Kiss Judit , Mollenhauer Martin , Scherr Anna-Lena , Platzer Lisa K. , Schmidt Thomas , Podar Klaus , Opferman Joseph T. , Weitz Juergen , Schulze-Bergkamen Henning , Koehler Bruno C. , Ulrich Alexis , Schneider Martin
Published: February 2016

Hypoxia is a common feature of solid tumors. Prolyl hydroxylase enzymes (PHD1–3) are molecular oxygen sensors that regulate hypoxia-inducible factor activity, but their functions in metastatic disease remain unclear. Here, we assessed the significance of PHD enzymes during the metastatic spread of colorectal cancer. PHD expression analysis in 124 colorectal cancer patients revealed that reduced tumoral expression of PHD3 correlated with increased frequency of distant metastases and poor outcome. Tumorigenicity and metastatic potential of colorectal tumor cells over and underexpressing PHD3 were investigated in orthotopic and heterotopic tumor models. PHD3 overexpression in a syngeneic tumor model resulted in fewer liver metastases, whereas PHD3 knockdown induced tumor spread. The migration of PHD3-overexpressing tumor cells was also attenuated in vitro. Conversely, migratory potential and colony formation were enhanced in PHD3-deficient cells, and this phenotype was associated with enhanced mitochondrial ATP production. Furthermore, the effects of PHD3 deficiency were accompanied by increased mitochondrial expression of the BCL-2 family member, member myeloid cell leukemia sequence 1 (MCL-1), and could be reversed by simultaneous inhibition of MCL-1. MCL-1 protein expression was likewise enhanced in human colorectal tumors expressing low levels of PHD3. Therefore, we demonstrate that downregulation of PHD3 augments metastatic spread in human colorectal cancer and identify MCL-1 as a novel downstream effector of oxygen sensing. Importantly, these findings offer new insight into the possible, context-specific deleterious effects of pharmacologic PHD inhibition. Cancer Res; 76(8); 2219–30. ©2016 AACR.
TGFβ Signaling Intersects with CD103 Integrin Signaling to Promote T-Lymphocyte Accumulation and Antitumor Activity in the Lung Tumor Microenvironment
Authors: Boutet Marie , Gauthier Ludiane , Leclerc Marine , Gros Gwendoline , de Montpreville Vincent , Théret Nathalie , Donnadieu Emmanuel , Mami-Chouaib Fathia
Published: February 2016

Homing of CD8+ T lymphocytes to the tumor microenvironment is an important step for mounting a robust antitumor immune response. TGFβ is responsible for CD103 (αEβ7) integrin induction in activated intraepithelial CD8+ T lymphocytes. However, the interplay between TGFβ and CD103 and their contribution to T-cell infiltration and antitumor activity remain unknown. Here, we used viable human lung tumor slices and autologous tumor antigen-specific T-lymphocyte clones to provide evidence that CD103 is directly involved in T-lymphocyte recruitment within epithelial tumor islets and intratumoral early T-cell signaling. Moreover, TGFβ enhanced CD103-dependent T-cell adhesion and signaling, whereas it inhibited leukocyte function-associated antigen (LFA)-1 (αLβ2) integrin expression and LFA-1-mediated T-lymphocyte functions. Mechanistic investigations revealed that TGFβ bound to its receptors (TGFBR), which promoted the recruitment and phosphorylation of integrin-linked kinase (ILK) by TGFBR1. We further show that ILK interacted with the CD103 intracellular domain, resulting in protein kinase B (PKB)/AKT activation, thereby initiating integrin inside-out signaling. Collectively, our findings suggest that the abundance of TGFβ in the tumor microenvironment may in fact engage with integrin signaling pathways to promote T-lymphocyte antitumor functions, with potential implications for T-cell-based immunotherapies for cancer. Cancer Res; 76(7); 1757–69. ©2016 AACR.
Mutational Landscape of Aggressive Prostate Tumors in African American Men
Authors: Lindquist Karla J. , Paris Pamela L. , Hoffmann Thomas J. , Cardin Niall J. , Kazma Rémi , Mefford Joel A. , Simko Jeffrey P. , Ngo Vy , Chen Yalei , Levin Albert M. , Chitale Dhananjay , Helfand Brian T. , Catalona William J. , Rybicki Benjamin A. , Witte John S.
Published: February 2016

Prostate cancer is the most frequently diagnosed and second most fatal nonskin cancer among men in the United States. African American men are two times more likely to develop and die of prostate cancer compared with men of other ancestries. Previous whole genome or exome tumor-sequencing studies of prostate cancer have primarily focused on men of European ancestry. In this study, we sequenced and characterized somatic mutations in aggressive (Gleason ≥7, stage ≥T2b) prostate tumors from 24 African American patients. We describe the locations and prevalence of small somatic mutations (up to 50 bases in length), copy number aberrations, and structural rearrangements in the tumor genomes compared with patient-matched normal genomes. We observed several mutation patterns consistent with previous studies, such as large copy number aberrations in chromosome 8 and complex rearrangement chains. However, TMPRSS2-ERG gene fusions and PTEN losses occurred in only 21% and 8% of the African American patients, respectively, far less common than in patients of European ancestry. We also identified mutations that appeared specific to or more common in African American patients, including a novel CDC27-OAT gene fusion occurring in 17% of patients. The genomic aberrations reported in this study warrant further investigation of their biologic significant role in the incidence and clinical outcomes of prostate cancer in African Americans. Cancer Res; 76(7); 1860–8. ©2016 AACR.
Pharmacological Targeting of the Histone Chaperone Complex FACT Preferentially Eliminates Glioblastoma Stem Cells and Prolongs Survival in Preclinical Models
Authors: Dermawan Josephine Kam Tai , Hitomi Masahiro , Silver Daniel J. , Wu Qiulian , Sandlesh Poorva , Sloan Andrew E. , Purmal Andrei A. , Gurova Katerina V. , Rich Jeremy N. , Lathia Justin D. , Stark George R. , Venere Monica
Published: February 2016

The nearly universal recurrence of glioblastoma (GBM) is driven in part by a treatment-resistant subpopulation of GBM stem cells (GSC). To identify improved therapeutic possibilities, we combined the EGFR/HER2 inhibitor lapatinib with a novel small molecule, CBL0137, which inhibits FACT (facilitates chromatin transcription), a histone chaperone complex predominantly expressed in undifferentiated cells. Lapatinib and CBL0137 synergistically inhibited the proliferation of patient-derived GBM cells. Compared with non–stem tumor cells (NSTC) enriched from the same specimens, the GSCs were extremely sensitive to CBL0137 monotherapy or FACT knockdown. FACT expression was elevated in GSCs compared with matched NSTCs and decreased in GSCs upon differentiation. Acute exposure of GSCs to CBL0137 increased asymmetric cell division, decreased GSC marker expression, and decreased the capacity of GSCs to form tumor spheres in vitro and to initiate tumors in vivo. Oral administration of CBL0137 to mice bearing orthotopic GBM prolonged their survival. Knockdown of FACT reduced the expression of genes encoding several core stem cell transcription factors (SOX2, OCT4, NANOG, and OLIG2), and FACT occupied the promoters of these genes. FACT expression was elevated in GBM tumors compared with non-neoplastic brain tissues, portended a worse prognosis, and positively correlated with GSC markers and stem cell gene expression signatures. Preferential targeting of GSCs by CBL0137 and synergy with EGFR inhibitors support the development of clinical trials combining these two agents in GBM. Cancer Res; 76(8); 2432–42. ©2016 AACR.
The Deubiquitinase USP9X Maintains DNA Replication Fork Stability and DNA Damage Checkpoint Responses by Regulating CLASPIN during S-Phase
Authors: McGarry Edel , Gaboriau David , Rainey Michael D. , Restuccia Umberto , Bachi Angela , Santocanale Corrado
Published: February 2016

Coordination of the multiple processes underlying DNA replication is key for maintaining genome stability and preventing tumorigenesis. CLASPIN, a critical player in replication fork stabilization and checkpoint responses, must be tightly regulated during the cell cycle to prevent the accumulation of DNA damage. In this study, we used a quantitative proteomics approach and identified USP9X as a novel CLASPIN-interacting protein. USP9X is a deubiquitinase involved in multiple signaling and survival pathways whose tumor suppressor or oncogenic activity is highly context dependent. We found that USP9X regulated the expression and stability of CLASPIN in an S-phase–specific manner. USP9X depletion profoundly impairs the progression of DNA replication forks, causing unscheduled termination events with a frequency similar to CLASPIN depletion, resulting in excessive endogenous DNA damage. Importantly, restoration of CLASPIN expression in USP9X-depleted cells partially suppressed the accumulation of DNA damage. Furthermore, USP9X depletion compromised CHK1 activation in response to hydroxyurea and UV, thus promoting hypersensitivity to drug-induced replication stress. Taken together, our results reveal a novel role for USP9X in the maintenance of genomic stability during DNA replication and provide potential mechanistic insights into its tumor suppressor role in certain malignancies. Cancer Res; 76(8); 2384–93. ©2016 AACR.
Transcriptome Analysis of Triple-Negative Breast Cancer Reveals an Integrated mRNA-lncRNA Signature with Predictive and Prognostic Value
Authors: Jiang Yi-Zhou , Liu Yi-Rong , Xu Xiao-En , Jin Xi , Hu Xin , Yu Ke-Da , Shao Zhi-Ming
Published: February 2016

While recognized as a generally aggressive disease, triple-negative breast cancer (TNBC) is highly diverse in different patients with variable outcomes. In this prospective observational study, we aimed to develop an RNA signature of TNBC patients to improve risk stratification and optimize the choice of adjuvant therapy. Transcriptome microarrays for 33 paired TNBC and adjacent normal breast tissue revealed tumor-specific mRNAs and long noncoding RNAs (lncRNA) that were associated with recurrence-free survival. Using the Cox regression model, we developed an integrated mRNA-lncRNA signature based on the mRNA species for FCGR1A, RSAD2, CHRDL1, and the lncRNA species for HIF1A-AS2 and AK124454. The prognostic and predictive accuracy of this signature was evaluated in a training set of 137 TNBC patients and then validated in a second independent set of 138 TNBC patients. In addition, we enrolled 82 TNBC patients who underwent taxane-based neoadjuvant chemotherapy (NCT) to further verify the predictive value of the signature. In both the training and validation sets, the integrated signature had better prognostic value than clinicopathologic parameters. We also confirmed the interaction between the administration of taxane-based NCT and different risk groups. In the NCT cohort, patients in the low-risk group were more likely to achieve pathologic complete remission after taxane-based NCT (P = 0.014). Functionally, we showed that HIF1A-AS2 and AK124454 promoted cell proliferation and invasion in TNBC cells and contributed there to paclitaxel resistance. Overall, our results established an integrated mRNA-lncRNA signature as a reliable tool to predict tumor recurrence and the benefit of taxane chemotherapy in TNBC, warranting further investigation in larger populations to help frame individualized treatments for TNBC patients. Cancer Res; 76(8); 2105–14. ©2016 AACR.
A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study
Authors: Cooper Todd M. , Cassar Jeannette , Eckroth Elena , Malvar Jemily , Sposto Richard , Gaynon Paul , Chang Bill H. , Gore Lia , August Keith , Pollard Jessica A. , DuBois Steven G. , Silverman Lewis B. , Oesterheld Javier , Gammon Guy , Magoon Daniel , Annesley Colleen , Brown Patrick A.
Published: February 2016

Purpose: To determine a safe and biologically active dose of quizartinib (AC220), a potent and selective class III receptor tyrosine kinase (RTK) FLT3 inhibitor, in combination with salvage chemotherapy in children with relapsed acute leukemia.

Experimental Design: Quizartinib was administered orally to children with relapsed AML or MLL-rearranged ALL following 5 days of high-dose cytarabine and etoposide (AE). A 3+3 dose escalation design was used to identify a safe and biologically active dose. Plasma inhibitory assay (PIA) testing was performed weekly to determine biologic activity.

Results: Toxicities were consistent with intensive relapsed leukemia regimens. One of 6 patients experienced a dose-limiting toxicity (DLT) at 40 mg/m2/day (elevated lipase) and 1 of 9 had a DLT (hyperbilirubinemia) at the highest tested dose of 60 mg/m2/day. Of 17 response evaluable patients, 2 had complete response (CR), 1 complete response without platelet recovery (CRp), 1 complete response with incomplete neutrophil and platelet recovery (CRi), 10 stable disease (SD), and 3 progressive disease (PD). Of 7 FLT3-ITD patients, 1 achieved CR, 1 CRp, 1 Cri, and 4 SD. FLT3-ITD patients, but not FLT3 wild-type (WT) patients, had significantly lower blast counts post-quizartinib. FLT3 phosphorylation was completely inhibited in all patients.

Conclusions: Quizartinib plus intensive chemotherapy is well tolerated at 60 mg/m2/day with near complete inhibition of FLT3 phosphorylation in all patients. The favorable toxicity profile, pharmacodynamic activity, and encouraging response rates warrant further testing of quizartinib in children with FLT3-ITD AML. Clin Cancer Res; 22(16); 4014–22. ©2016 AACR.
Low-Dose Histone Deacetylase Inhibitor Treatment Leads to Tumor Growth Arrest and Multi-Lineage Differentiation of Malignant Rhabdoid Tumors
Authors: Muscat Andrea , Popovski Dean , Jayasekara W. Samantha N. , Rossello Fernando J. , Ferguson Melissa , Marini Kieren D. , Alamgeer Muhammad , Algar Elizabeth M. , Downie Peter , Watkins D. Neil , Cain Jason E. , Ashley David M.
Published: February 2016

Purpose: Malignant rhabdoid tumor (MRT) and atypical teratoid rhabdoid tumors (ATRT) are rare aggressive undifferentiated tumors primarily affecting the kidney and CNS of infants and young children. MRT are almost exclusively characterized by homozygous deletion or inactivation of the chromatin remodeling gene SMARCB1. SMARCB1 protein loss leads to direct impairment of chromatin remodeling and we have previously reported a role for this protein in histone acetylation. This provided the rationale for investigating the therapeutic potential of histone deactylase inhibitors (HDACi) in MRT.

Experimental Design: Whereas previously HDACis have been used at doses and schedules that induce cytotoxicity, in the current studies we have tested the hypothesis, both in vitro and in vivo, that sustained treatment of human MRT with low-dose HDACi can lead to sustained cell growth arrest and differentiation.

Results: Sustained low-dose panobinostat (LBH589) treatment led to changes in cellular morphology associated with a marked increase in the induction of neural, renal, and osteoblast differentiation pathways. Genome-wide transcriptional profiling highlighted differential gene expression supporting multilineage differentiation. Using mouse xenograft models, sustained low-dose LBH589 treatment caused tumor growth arrest associated with tumor calcification detectable by X-ray imaging. Histological analysis of LBH589-treated tumors revealed significant regions of ossification, confirmed by Alizarin Red staining. Immunohistochemical analysis showed increased TUJ1 and PAX2 staining suggestive of neuronal and renal differentiation, respectively.

Conclusions: Low-dose HDACi treatment can terminally differentiate MRT tumor cells and reduce their ability to self-renew. The use of low-dose HDACi as a novel therapeutic approach warrants further investigation. Clin Cancer Res; 22(14); 3560–70. ©2016 AACR.
High Levels of Antibody that Neutralize B-cell Infection of Epstein–Barr Virus and that Bind EBV gp350 Are Associated with a Lower Risk of Nasopharyngeal Carcinoma
Authors: Coghill Anna E. , Bu Wei , Nguyen Hanh , Hsu Wan-Lun , Yu Kelly J. , Lou Pei-Jen , Wang Cheng-Ping , Chen Chien-Jen , Hildesheim Allan , Cohen Jeffrey I.
Published: February 2016

Purpose: Elevated IgA antibodies indicative of ongoing exposure to Epstein–Barr virus (EBV) are high-risk biomarkers for nasopharyngeal carcinoma (NPC), an EBV-related epithelial tumor. However, protective biomarkers that limit exposure to the virus have not been defined. We evaluated whether antibodies that can neutralize EBV infection by targeting glycoproteins involved in viral cell entry, including EBV vaccine candidate glycoprotein 350 (gp350), were associated with lower NPC risk.

Experimental Design: In a prospective cohort of 2,557 individuals from 358 high-risk NPC multiplex families in Taiwan, we identified 21 incident NPC cases and 50 disease-free controls. To complement data from high-risk families, we further identified 30 prevalent NPC cases and 50 healthy controls from the general Taiwanese population. We quantified EBV-neutralizing antibody, antibodies against EBV glycoproteins involved in B-cell and epithelial cell entry, and anti-EBNA1 IgA, a high-risk NPC biomarker.

Results: EBV-neutralizing antibodies blocking B-cell infection and anti-gp350 antibodies were present at significantly higher levels in disease-free controls compared with incident NPC cases (P < 0.03). Family members with both low EBV-neutralizing potential and elevated EBNA1 IgA had a 7-fold increased risk of NPC (95% CI, 1.9–28.7). Neutralizing antibodies against epithelial cell infection did not differ between incident cases and disease-free controls. Anti-glycoprotein antibody levels measured at diagnosis (prevalent NPC) were significantly higher than levels measured prior to diagnosis (P < 0.01).

Conclusions: Elevated titers of EBV-neutralizing antibody and anti-gp350 antibody were low-risk biomarkers for NPC. These data suggest that a vaccine that induces potent EBV gp350 and B-cell–neutralizing antibodies could reduce the risk of EBV-related cancers such as NPC. Clin Cancer Res; 22(14); 3451–7. ©2016 AACR.
Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer
Authors: Baselga José , Lewis Phillips Gail D. , Verma Sunil , Ro Jungsil , Huober Jens , Guardino Alice E. , Samant Meghna K. , Olsen Steve , de Haas Sanne L. , Pegram Mark D.
Published: February 2016

Purpose: HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody–drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study.

Experimental Design: Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations.

Results: Longer progression-free survival (PFS) and overall survival (OS) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups. PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib–treated patients, but not in T-DM1–treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations.

Conclusions: Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755–63. ©2016 AACR.
Everything Old Is New Again: Using Nelfinavir to Radiosensitize Rectal Cancer
Authors: Meyn Raymond E. , Krishnan Sunil , Skinner Heath D.
Published: February 2016

Repurposing agents approved for other indications to radiosensitize tumors may be advantageous. The study by Hill and colleagues utilizes nelfinavir, an HIV protease inhibitor (PI), in combination with radiotherapy in rectal cancer in a prospective study. This combination may improve tumor perfusion and regression compared with radiotherapy alone. Clin Cancer Res; 22(8); 1834–6. ©2016 AACR.

See related article by Hill et al., p. 1922
Therapeutic Guide for mTOuRing through the Braided Kidney Cancer Genomic River
Authors: Voss Martin H. , Hsieh James J.
Published: February 2016

mTORC1 inhibitors were first approved for the use in metastatic kidney cancer. However, observed treatment benefit was highly heterogeneous among patients. Through case-based cancer genomic sequencing of therapeutic outliers, we can begin to appreciate the convergent evolution of given cancer pathways/phenotypes beyond genes in kidney cancer, like a braided river. Clin Cancer Res; 22(10); 2320–2. ©2016 AACR.

See related article by Kwiatkowski et al., p. 2445
In Vitro and In Vivo Studies of a New Class of Anticancer Molecules for Targeted Radiotherapy of Cancer
Authors: Wang Chun-Rong , Mahmood Javed , Zhang Qin-Rong , Vedadi Ali , Warrington Jenny , Ou Ning , Bristow Robert G. , Jaffray David A. , Lu Qing-Bin
Published: February 2016

There is a compelling need to develop anticancer therapies that target cancer cells and tissues. Arising from innovative femtomedicine studies, a new class of non–platinum-based halogenated molecules (called FMD molecules) that selectively kill cancer cells and protect normal cells in treatments of multiple cancers has been discovered. This article reports the first observation of the radiosensitizing effects of such compounds in combination with ionizing radiation for targeted radiotherapy of a variety of cancers. We present in vitro and in vivo studies focused on combination with radiotherapy of cervical, ovarian, head and neck, and lung cancers. Our results demonstrate that treatments of various cancer cells in vitro and in vivo mouse xenograft models with such compounds led to enhanced efficiencies in radiotherapy, while the compounds themselves induced no or little radiotoxicity toward normal cells or tissues. These compounds are therefore effective radiosensitizers that can be translated into clinical trials for targeted radiotherapy of multiple types of cancer. This study also shows the potential of femtomedicine to bring breakthroughs in understanding fundamental biologic processes and to accelerate the discovery of novel drugs for effective treatment or prevention of a variety of cancers. Mol Cancer Ther; 15(4); 640–50. ©2016 AACR.
β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation
Authors: Kallifatidis Georgios , Munoz Daniel , Singh Rajendra Kumar , Salazar Nicole , Hoy James J. , Lokeshwar Bal L.
Published: February 2016

The atypical 7-transmembrane chemokine receptor, CXCR7, transactivates the EGFR leading to increased tumor growth in several tumor types. However, the molecular mechanism of CXCR7 ligand–independent EGFR transactivation is unknown. We used cDNA knock-in, RNAi and analysis of mitogenic signaling components in both normal prostate epithelial cells and prostate cancer cells to decipher the proliferation-inducing mechanism of the CXCR7–EGFR interaction. The data demonstrate that CXCR7-induced EGFR transactivation is independent of both the release of cryptic EGFR ligands (e.g., AREG/amphiregulin) and G-protein–coupled receptor signaling. An alternate signaling mechanism involving β-arrestin-2 (ARRB2/β-AR2) was examined by manipulating the levels of β-AR2 and analyzing changes in LNCaP cell growth and phosphorylation of EGFR, ERK1/2, Src, and Akt. Depletion of β-AR2 in LNCaP cells increased proliferation/colony formation and significantly increased activation of Src, phosphorylation of EGFR at Tyr-1110, and phosphorylation/activation of ERK1/2 compared with that with control shRNA. Moreover, β-AR2 depletion downregulated the proliferation suppressor p21. Stimulation of β-AR2–expressing cells with EGF resulted in rapid nuclear translocation of phosphorylated/activated EGFR. Downregulation of β-AR2 enhanced this nuclear translocation. These results demonstrate that β-AR2 is a negative regulator of CXCR7/Src/EGFR–mediated mitogenic signaling.

Implications: This study reveals that β-AR2 functions as a tumor suppressor, underscoring its clinical importance in regulating CXCR7/EGFR–mediated tumor cell proliferation. Mol Cancer Res; 14(5); 493–503. ©2016 AACR.
Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti–PD-L1 Immune Checkpoint Inhibitor
Authors: Vandeveer Amanda J. , Fallon Jonathan K. , Tighe Robert , Sabzevari Helen , Schlom Jeffrey , Greiner John W.
Published: February 2016

Bacillus Calmette–Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, nonmetastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49luc), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49luc murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, nonmetastatic urothelial carcinomas. MB49luc bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P < 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. Cancer Immunol Res; 4(5); 452–62. ©2016 AACR.
Cardiac Resynchronization Therapy
Authors: Sridhar Arun Raghav Mahankali , Yarlagadda Vivek , Parasa Sravanthi , Reddy Yeruva Madhu , Patel Dhavalkumar , Lakkireddy Dhanunjaya , Wilkoff Bruce L. , Dawn Buddhadeb
Published: February 2016

Background—

The use of cardiac resynchronization therapy (CRT) has increased significantly since its initial approval in 2001 for use in patients with advanced heart failure. However, trends in utilization of CRT have not been systematically characterized.

Methods and Results—

We used the Nationwide Inpatient Sample database to identify all patients with CRT implantation during 2002 to 2010. The overall trends in CRT device implantation, patient characteristics, and outcomes were examined in detail and compared among demographic subgroups. During 2002 to 2010, a total of 374 202 CRT procedures were recorded. Significant and persistent gender and racial disparities favoring men (71.4%) and white (79.6%), respectively, were noted in all years. The highest number of CRT devices were implanted in the 65- to 84-year age group (64.6%), with significant increase in number of CRT implants in older patients ≥85 years over the years (
P
=0.02). The CRT-associated in-hospital mortality improved from 1.08% in 2003 to 0.70% in 2010 (
P
=0.03). The correlates of higher mortality included males (0.93% versus 0.71% in females;
P
=0.04) and older age (age ≥85 years had 1.5% mortality versus 0.8% for age <85 year;
P
<0.001). The mean hospital length of stay for CRT decreased, while mean CRT-associated hospital charges increased progressively over the years. Factors associated with higher charges were gender (males>females), older age, and greater comorbidities.

Conclusions—

CRT implantation is a relatively safe procedure that has become safer in higher risk patients. However, significant disparities in CRT utilization exist in certain demographic subgroups, and these disparities have persisted across the years.