bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 purposeBrain 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 methodsConsecutive 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.Results22 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.ConclusionsOur 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

ObjectivesTo determine the degree of risk factor control, the clinical symptoms and the therapeutic management of patients with a history of previous myocardial infarction.MethodsCross-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.ResultsWe 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.ConclusionsLDL 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.
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

Abstract
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.
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

Abstract
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

AbstractHoming 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &lt; 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 &lt; 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.