bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphisms of Homologous RecombinationRAD51,RAD51B,XRCC2, andXRCC3Genes and the Risk of Prostate Cancer
Authors: Nowacka-Zawisza Maria , Wiśnik Ewelina , Wasilewski Andrzej , Skowrońska Milena , Forma Ewa , Bryś Magdalena , Różański Waldemar , Krajewska Wanda M.
Published: August 2015

Genetic polymorphisms in DNA repair genes may induce individual variations in DNA repair capacity, which may in turn contribute to the risk of cancer developing. Homologous recombination repair (HRR) plays a critical role in maintaining chromosomal integrity and protecting against carcinogenic factors. The aim of the present study was to evaluate the relationship between prostate cancer risk and the presence of single nucleotide polymorphisms (SNPs) in the genes involved in HRR, that is,RAD51(rs1801320 and rs1801321),RAD51B(rs10483813 and rs3784099),XRCC2(rs3218536), andXRCC3(rs861539). Polymorphisms were analyzed by PCR-RFLP and Real-Time PCR in 101 patients with prostate adenocarcinoma and 216 age- and sex-matched controls. A significant relationship was detected between theRAD51gene rs1801320 polymorphism and increased prostate cancer risk. Our results indicate that theRAD51gene rs1801320 polymorphism may contribute to prostate cancer susceptibility in Poland.
Effects of Nanoscale Carbon Black Modified by HNO3on Immobilization and Phytoavailability of Ni in Contaminated Soil
Authors: Cheng Jiemin , Yu Lei , Li Tong , Liu Yuzhen , Lu Chengxiu , Li Tingting , Wang Hanwei
Published: August 2015

A surface-modified nanoscale carbon black (MCB) as Ni adsorbent in contaminated soil was prepared by oxidizing the carbon black with 65% HNO3. The surface properties of the adsorbent were characterized by zeta potential analysis, scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIRs). Batch experiments were conducted to evaluate the improvement of Ni2+adsorption by MCB. Greenhouse cultivation experiments were conducted to examine the effect of MCB on the DTPA-extractable Ni2+in soil, Ni2+uptake of ryegrass shoot, and growth of ryegrass. Results indicated that MCB had much lower negative zeta potential, more functional groups for exchange and complexation of cation, and more heterogeneous pores and cavities for the adsorption of cation than the unmodified parent one (CB). MCB showed enhanced sorption capacity for Ni (qmax, 49.02 mg·g−1) compared with CB (qmax, 39.22 mg·g−1). Greenhouse cultivation experiment results showed that the biomass of ryegrass shoot and the Ni uptake of the ryegrass shoot were significantly increased and the concentrations of DTPA-extractable Ni in soil were significantly decreased with the increasing of MCB amount. It is clear from this work that the MCB had good adsorption properties for the Ni and could be applied in the in situ immobilization and remediation of heavy metal contaminated saline-alkali soils.
Survey of Security Technologies on Wireless Sensor Networks
Authors: Yang Qiuwei , Zhu Xiaogang , Fu Hongjuan , Che Xiqiang
Published: August 2015

Because of their low cost and adaptability, wireless sensor networks are widely used in civil, military, and commercial fields and other fields. However, since the sensor node in the calculation of the capacity, battery capacity, and storage capacity are restricted by the limitations and inherent characteristics of the sensor networks, compared to traditional networks, which makes wireless sensor networks face more security threats. This paper summarized research progress of sensor network security issues as three aspects, key management, authentication, and secure routing, analyzed and commented on these results advantages and disadvantages and pointed out the future direction of the hot research field.
Augmented Reality: A Brand New Challenge for the Assessment and Treatment of Psychological Disorders
Authors: Chicchi Giglioli Irene Alice , Pallavicini Federica , Pedroli Elisa , Serino Silvia , Riva Giuseppe
Published: August 2015

Augmented Reality is a new technological system that allows introducing virtual contents in the real world in order to run in the same representation and, in real time, enhancing the user’s sensory perception of reality. From another point of view, Augmented Reality can be defined as a set of techniques and tools that add information to the physical reality. To date, Augmented Reality has been used in many fields, such as medicine, entertainment, maintenance, architecture, education, and cognitive and motor rehabilitation but very few studies and applications of AR exist in clinical psychology. In the treatment of psychological disorders, Augmented Reality has given preliminary evidence to be a useful tool due to its adaptability to the patient needs and therapeutic purposes and interactivity. Another relevant factor is the quality of the user’s experience in the Augmented Reality system determined from emotional engagement and sense of presence. This experience could increase the AR ecological validity in the treatment of psychological disorders. This paper reviews the recent studies on the use of Augmented Reality in the evaluation and treatment of psychological disorders, focusing on current uses of this technology and on the specific features that delineate Augmented Reality a new technique useful for psychology.
Morphophysiological Behavior and Cambial Activity in Seedlings of Two Amazonian Tree Species under Shade
Authors: Lopes Monyck Jeane dos Santos , Dias-Filho Moacyr Bernardino , Menezes Neto Marco Antônio , Cruz Eniel David
Published: August 2015

Variations in light intensity can lead to important anatomical and morphophysiological changes in plants. Aiming to increase knowledge about the Amazonian tree species, this study examines the influence of shade on the cambial activity and development ofParkia gigantocarpaDucke andSchizolobium parahybavar.amazonicum(Huber ex Ducke) Barneby seedlings. Seedlings of the two species were grown in a nursery under four shade intensities (treatments): full sun, low, moderate, and high shade (resp., 0%, 23%, 67%, and 73% of shade, or 2000, 1540, 660, and 540 µmol·m−2·s−1) obtained with polyethylene screens. We measured plant height, stem diameter, biomass production, stomatal conductance (gs), transpiration (E), photosynthesis (A), and cambial activity (CA) (xylem, cambium, and phloem). Also, we calculated the Dickson Quality Index (DQI). The highest values of biomass production,gs,  E, A, and DQI, were found under full sun, inP. gigantocarpa, and under low shade intensity inS. parahyba. In both species high shade intensity reduced CA. We concluded that the CA and the physiological and morphological attributes work together, explaining the radial growth and increasing seedlings quality, which optimized efficient seedling production under full sun, inP. gigantocarpa, and under low shade intensity inS. parahyba.
Serum Indicators Reflecting Gastric Function May Also Correlate with Other Extragastric Diseases
Authors: Gong Yuehua , Wang Wei , Li Yi , Yuan Yuan
Published: August 2015

Aim. Serological indicators of organ function can reveal intrinsic links between different organs. The present study aimed to determine the correlations of serum indicators for gastric and extragastric function.Methods. A total of 823 individuals were enrolled. Data on indicators reflecting blood lipids, blood glucose, indexes of stomach, kidney, liver, and thyroid function, andH. pyloriIgG antibody level were collected.Results. As creatine (Cr) levels increased, PGI (pepsinogen I), PGII concentrations, and PGI/II ratio increased monotonically from 79.7 to 105.15 µg/L, 6.5 to 8.4 µg/L, and 11.97 to 12.27, respectively (P<0.05). As thyroid peroxidase antibody (TPOAb) levels increased, PGI level decreased from 100.85 to 84 µg/L (P<0.05) and as thyroid stimulating hormone (TSH) increased, PGI/II ratio increased monotonically from 11.54 to 12.68 (P<0.05). As triglyceride (TG) levels increased, gastrin 17 (G17) concentrations increased monotonically from 1.73 to 2.7 pmol/L (P<0.05). As serum glucose and glycated hemoglobin (HbA1C) increased, PGI/II concentrations increased monotonically from 11.98 to 12.67 and 9.7 to 13.54 (P<0.05), respectively.Conclusions. Serum PG and G17 levels were associated with blood glucose and lipids, kidney function, and thyroid function but not with liver function. Serum indicators reflecting gastric function may correlate not only with primary diseases, but also with other extragastric diseases.
Data Collection for Time-Critical Applications in the Low-Duty-Cycle Wireless Sensor Networks
Authors: Luo Shuyun , Sun Yongmei , Ji Yuefeng
Published: August 2015

In low-duty-cycle wireless sensor networks, wireless nodes usually have two states: active state and dormant state. The necessary condition for a successful wireless transmission is that both the sender and the receiver are awake. In this paper, we study the problem: How fast can raw data be collected from all source nodes to a sink in low-duty-cycle WSNs with general topology? Both the lower and upper tight bounds are given for this problem. We use TDMA scheduling on the same frequency channel and present centralized and distributed fast data collection algorithms to find an optimal solution in polynomial time when no interfering links happen. If interfering links happen, multichannel scheduling is introduced to eliminate them. We next propose a novel Receiver-based Channel and Time Scheduling (RCTS) algorithm to obtain the optimal solution. Based on real trace, extensive simulations are conducted and the results show that the proposed RCTS algorithm is significantly more efficient than the link schedule on one channel and achieves the lower bound. We also evaluate the proposed data collection algorithms and find that RCTS is time-efficient and suffices to eliminate most of the interference in both indoor and outdoor environment for moderate size networks.
Application of a Gastroduodenal Artery Graft for Reconstruction of the Hepatic Artery during Radical Resection of Hilar Cholangiocarcinoma
Authors: Liang Yurong , Wang Jing , Shi Xianjie , Dong Jiahong , Gu Wanqing
Published: August 2015

This paper was designed to evaluate a novel surgical procedure of using a gastroduodenal artery graft for reconstruction of the hepatic artery during radical resection of hilar cholangiocarcinoma, which is citation-free and self-contained. In this paper we retrospectively analyzed the clinical data, surgical procedure, and follow-up results in nine patients who underwent hepatic artery reconstruction using a gastroduodenal artery graft during their radical resection of hilar cholangiocarcinoma and no artery thrombosis or other surgical complications were found after operation with minimum follow-up duration of three months. We recommended that a gastroduodenal artery graft was shown to be a good choice for hepatic artery resection after radical resection of hilar cholangiocarcinoma.
An Effective and Novel Neural Network Ensemble for Shift Pattern Detection in Control Charts
Authors: Barghash Mahmoud
Published: August 2015

Pattern recognition in control charts is critical to make a balance between discovering faults as early as possible and reducing the number of false alarms. This work is devoted to designing a multistage neural network ensemble that achieves this balance which reduces rework and scrape without reducing productivity. The ensemble under focus is composed of a series of neural network stages and a series of decision points. Initially, this work compared using multidecision points and single-decision point on the performance of the ANN which showed that multidecision points are highly preferable to single-decision points. This work also tested the effect of population percentages on the ANN and used this to optimize the ANN’s performance. Also this work used optimized and nonoptimized ANNs in an ensemble and proved that using nonoptimized ANN may reduce the performance of the ensemble. The ensemble that used only optimized ANNs has improved performance over individual ANNs and three-sigma level rule. In that respect using the designed ensemble can help in reducing the number of false stops and increasing productivity. It also can be used to discover even small shifts in the mean as early as possible.
Security Requirements for Multimedia Archives
Authors: Park Sang Bae
Published: August 2015

With the explosive growth of various multimedia contents, digital archives are used to store those contents accordingly. In contrast to the traditional storage systems in which data lifetime is measured in months or years, data lifetime in the archive is measured in decades. This longevity of contents causes new security issues that threat the archive systems. In this paper, we discuss these new security issues in perspective. And we suggest some security requirements for digital archives.
Synthesis and Electrochemical Performance of Graphene Wrapped SnxTi1−xO2 Nanoparticles as an Anode Material for Li‐Ion Batteries
Authors: Xin Xing , Zhou Xufeng , Shen Tao , Liu Zhaoping
Published: August 2015

Ever‐growing development of Li‐ion battery has urged the exploitation of new materials as electrodes. Here, SnxTi1−xO2 solid‐solution nanomaterials were prepared by aqueous solution method. The morphology, structures, and electrochemical performance of SnxTi1−xO2 nanoparticles were systematically investigated. The results indicate that Ti atom can replace the Sn atom to enter the lattice of SnO2 to form substitutional solid‐solution compounds. The capacity of the solid solution decreases while the stability is improved with the increasing of the Ti content. Solid solution with x of 0.7 exhibits the optimal electrochemical performance. The Sn0.7Ti0.3O2 was further modified by highly conductive graphene to enhance its relatively low electrical conductivity. The Sn0.7Ti0.3O2/graphene composite exhibits much improved rate performance, indicating that the SnxTi1−xO2 solid solution can be used as a potential anode material for Li‐ion batteries.
Mediators, Receptors, and Signalling Pathways in the Anti-Inflammatory and Antihyperalgesic Effects of Acupuncture
Authors: McDonald John L. , Cripps Allan W. , Smith Peter K.
Published: August 2015

Acupuncture has been used for millennia to treat allergic diseases including both intermittent rhinitis and persistent rhinitis. Besides the research on the efficacy and safety of acupuncture treatment for allergic rhinitis, research has also investigated how acupuncture might modulate immune function to exert anti-inflammatory effects. A proposed model has previously hypothesized that acupuncture might downregulate proinflammatory neuropeptides, proinflammatory cytokines, and neurotrophins, modulating transient receptor potential vallinoid (TRPV1), a G-protein coupled receptor which plays a central role in allergic rhinitis. Recent research has been largely supportive of this model. New advances in research include the discovery of a novel cholinergic anti-inflammatory pathway activated by acupuncture. A chemokine-mediated proliferation of opioid-containing macrophages in inflamed tissues, in response to acupuncture, has also been demonstrated for the first time. Further research on the complex cross talk between receptors during inflammation is also helping to elucidate the mediators and signalling pathways activated by acupuncture.
Two Rare Cases of Hepatocellular Carcinoma after Kasai Procedure for Biliary Atresia: A Recommendation for Close Follow-Up
Authors: Hirzel Alicia C. , Madrazo Beatrice , Rojas Claudia P.
Published: August 2015

The instigation of the Kasai procedure in infants who are born with biliary atresia has led to increased survival in this population for over half a century. The many complications that arise as a result of biliary atresia led to an early death for most patients. However, the Kasai procedure is not without its own impediments. Among them is the development of hepatocellular carcinoma. We present two cases of hepatocellular carcinoma, after Kasai procedure, from two different age groups, as a recommendation that these patients should be even more closely monitored. Furthermore, if they are in need of transplant, we recommend that the explanted livers be carefully examined, as the tumor may not have been diagnosed preoperatively.
Computational Psychometrics in Communication and Implications in Decision Making
Authors: Cipresso Pietro , Villani Daniela , Repetto Claudia , Bosone Lucia , Balgera Anna , Mauri Maurizio , Villamira Marco , Antonietti Alessandro , Riva Giuseppe
Published: August 2015

Recent investigations emphasized the role of communication features on behavioral trust and reciprocity in economic decision making but no studies have been focused on the effect of communication on affective states in such a context. Thanks to advanced methods of computational psychometrics, in this study, affective states were deeply examined using simultaneous and synchronized recordings of gazes and psychophysiological signals in 28 female students during an investment game. Results showed that participants experienced different affective states according to the type of communication (personal versus impersonal). In particular, participants involved in personal communication felt more relaxed than participants involved in impersonal communication. Moreover, personal communication influenced reciprocity and participants’ perceptions about trust and reciprocity. Findings were interpreted in the light of the Arousal/Valence Model and self-disclosure process.
Concordance of Hypermethylated DNA and the Tumor Markers CA 15-3, CEA, and TPA in Serum during Monitoring of Patients with Advanced Breast Cancer
Authors: Kristiansen Søren , Jørgensen Lars Mønster , Hansen Morten Høgh , Nielsen Dorte , Sölétormos György
Published: August 2015

The serological protein tumor markers CA 15-3, CEA, and TPA are frequently used to monitor tumor burden among metastatic breast cancer patients. Breast cancer is associated with global DNA hypomethylation and hypermethylation of some promoter regions. No monitoring study has yet investigated the interrelationship between protein tumor markers, the global DNA hypomethylation, and hypermethylated genes in serum from patients with advanced disease. Twenty-nine patients with histologically proven advanced breast cancer received first-line chemotherapy with epirubicin. Samples were collected prior to each treatment and prospectively analyzed for CA 15-3, CEA, and TPA. The same samples were retrospectively analyzed for the concentration of hypermethylatedRASSF1Aand for global DNA hypomethylation usingLINE-1. Among patients with elevated concentrations of the protein markers, concordance could be observed between serial changes of the hypermethylatedRASSF1Agene and the protein markers. Among patients with lower concentrations,RASSF1Acould only be detected periodically. There was discordance between changes of the hypomethylatedLINE-1as compared to the protein markers. Circulating hypermethylatedRASSF1Aand protein markers may have similar kinetics during monitoring of tumor burden. Further investigations are needed to determine whether any of the hypermethylated DNA genes may provide predictive information during monitoring.
Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages
Authors: Frankenberger Casey , Rabe Daniel , Bainer Russell , Sankarasharma Devipriya , Chada Kiran , Krausz Thomas , Gilad Yoav , Becker Lev , Rosner Marsha Rich
Published: August 2015

Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. TNBC is characterized by reduced expression of metastasis suppressors such as Raf kinase inhibitory protein (RKIP), which inhibits tumor invasiveness. Mechanisms by which metastasis suppressors alter tumor cells are well characterized; however, their ability to regulate the tumor microenvironment and the importance of such regulation to metastasis suppression are incompletely understood. Here, we use species-specific RNA sequencing to show that RKIP expression in tumors markedly reduces the number and metastatic potential of infiltrating tumor-associated macrophages (TAM). TAMs isolated from nonmetastatic RKIP+ tumors, relative to metastatic RKIP− tumors, exhibit a reduced ability to drive tumor cell invasion and decreased secretion of prometastatic factors, including PRGN, and shed TNFR2. RKIP regulates TAM recruitment by blocking HMGA2, resulting in reduced expression of numerous macrophage chemotactic factors, including CCL5. CCL5 overexpression in RKIP+ tumors restores recruitment of prometastatic TAMs and intravasation, whereas treatment with the CCL5 receptor antagonist Maraviroc reduces TAM infiltration. These results highlight the importance of RKIP as a regulator of TAM recruitment through chemokines such as CCL5. The clinical significance of these interactions is underscored by our demonstration that a signature comprised of RKIP signaling and prometastatic TAM factors strikingly separates TNBC patients based on survival outcome. Collectively, our findings identify TAMs as a previously unsuspected mechanism by which the metastasis-suppressor RKIP regulates tumor invasiveness, and further suggest that TNBC patients with decreased RKIP activity and increased TAM infiltration may respond to macrophage-based therapeutics. Cancer Res; 75(19); 4063–73. ©2015 AACR.
A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis
Authors: Remy Elisabeth , Rebouissou Sandra , Chaouiya Claudine , Zinovyev Andrei , Radvanyi François , Calzone Laurence
Published: August 2015

Relationships between genetic alterations, such as co-occurrence or mutual exclusivity, are often observed in cancer, where their understanding may provide new insights into etiology and clinical management. In this study, we combined statistical analyses and computational modeling to explain patterns of genetic alterations seen in 178 patients with bladder tumors (either muscle-invasive or non–muscle-invasive). A statistical analysis on frequently altered genes identified pair associations, including co-occurrence or mutual exclusivity. Focusing on genetic alterations of protein-coding genes involved in growth factor receptor signaling, cell cycle, and apoptosis entry, we complemented this analysis with a literature search to focus on nine pairs of genetic alterations of our dataset, with subsequent verification in three other datasets available publicly. To understand the reasons and contexts of these patterns of associations while accounting for the dynamics of associated signaling pathways, we built a logical model. This model was validated first on published mutant mice data, then used to study patterns and to draw conclusions on counter-intuitive observations, allowing one to formulate predictions about conditions where combining genetic alterations benefits tumorigenesis. For example, while CDKN2A homozygous deletions occur in a context of FGFR3-activating mutations, our model suggests that additional PIK3CA mutation or p21CIP deletion would greatly favor invasiveness. Furthermore, the model sheds light on the temporal orders of gene alterations, for example, showing how mutual exclusivity of FGFR3 and TP53 mutations is interpretable if FGFR3 is mutated first. Overall, our work shows how to predict combinations of the major gene alterations leading to invasiveness through two main progression pathways in bladder cancer. Cancer Res; 75(19); 4042–52. ©2015 AACR.
Transcriptomic Profiling of Sequential Tumors from Breast Cancer Patients Provides a Global View of Metastatic Expression Changes Following Endocrine Therapy
Authors: McBryan Jean , Fagan Ailís , McCartan Damian , Bane Fiona T. , Varešlija Damir , Cocchiglia Sinéad , Byrne Christopher , Bolger Jarlath , McIlroy Marie , Hudson Lance , Tibbitts Paul , Ó Gaora Peadar , Hill Arnold D. , Young Leonie S.
Published: August 2015

Purpose: Disease recurrence is a common problem in breast cancer and yet the mechanisms enabling tumor cells to evade therapy and colonize distant organs remain unclear. We sought to characterize global expression changes occurring with metastatic disease progression in the endocrine-resistant setting.

Experimental Design: Here, for the first time, RNAsequencing has been performed on matched primary, nodal, and liver metastatic tumors from tamoxifen-treated patients following disease progression. Expression of genes commonly elevated in the metastases of sequenced patients was subsequently examined in an extended matched patient cohort with metastatic disease from multiple sites. The impact of tamoxifen treatment on endocrine-resistant tumors in vivo was investigated in a xenograft model.

Results: The extent of patient heterogeneity at the gene level was striking. Less than 3% of the genes differentially expressed between sequential tumors were common to all patients. Larger divergence was observed between primary and liver tumors than between primary and nodal tumors, reflecting both the latency to disease progression and the genetic impact of intervening therapy. Furthermore, an endocrine-resistant in vivo mouse model demonstrated that tamoxifen treatment has the potential to drive disease progression and establish distant metastatic disease. Common functional pathways altered during metastatic, endocrine-resistant progression included extracellular matrix receptor interactions and focal adhesions.

Conclusions: This novel global analysis highlights the influence of primary tumor biology in determining the transcriptomic profile of metastatic tumors, as well as the need for adaptations in cell–cell communications to facilitate successful tumor cell colonization of distant host organs. Clin Cancer Res; 21(23); 5371–9. ©2015 AACR.
CCR 20th Anniversary Commentary: A Genetic Mechanism of Imatinib Resistance in Gastrointestinal Stromal Tumor—Where Are We a Decade Later?
Authors: Antonescu Cristina R. , DeMatteo Ronald P.
Published: August 2015

In the June 1, 2005, issue of Clinical Cancer Research, Antonescu and colleagues defined second-site KIT mutations in gastrointestinal stromal tumor (GIST) as the leading mechanism of acquired resistance to imatinib. Secondary mutations were detectable mainly in KIT exon 11 mutant GISTs after prolonged initial clinical responses. These findings played a critical role in designing the next generation of tyrosine kinase inhibitors. Clin Cancer Res; 21(15); 3363–5. ©2015 AACR.

See related article by Antonescu et al., Clin Cancer Res 2005;11(11) June 1, 2005;4182–90
Autocrine Signaling by Wnt-5a Deregulates Chemotaxis of Leukemic Cells and Predicts Clinical Outcome in Chronic Lymphocytic Leukemia
Authors: Janovska Pavlina , Poppova Lucie , Plevova Karla , Plesingerova Hana , Behal Martin , Kaucka Marketa , Ovesna Petra , Hlozkova Michaela , Borsky Marek , Stehlikova Olga , Brychtova Yvona , Doubek Michael , Machalova Michaela , Baskar Sivasubramanian , Kozubik Alois , Pospisilova Sarka , Pavlova Sarka , Bryja Vitezslav
Published: August 2015

Purpose: ROR1, a receptor in the noncanonical Wnt/planar cell polarity (PCP) pathway, is upregulated in malignant B cells of chronic lymphocytic leukemia (CLL) patients. It has been shown that the Wnt/PCP pathway drives pathogenesis of CLL, but which factors activate the ROR1 and PCP pathway in CLL cells remains unclear.

Experimental Design: B lymphocytes from the peripheral blood of CLL patients were negatively separated using RosetteSep (StemCell) and gradient density centrifugation. Relative expression of WNT5A, WNT5B, and ROR1 was assessed by quantitative real-time PCR. Protein levels, protein interaction, and downstream signaling were analyzed by immunoprecipitation and Western blotting. Migration capacity of primary CLL cells was analyzed by the Transwell migration assay.

Results: By analyzing the expression in 137 previously untreated CLL patients, we demonstrate that WNT5A and WNT5B genes show dramatically (five orders of magnitude) varying expression in CLL cells. High WNT5A and WNT5B expression strongly associates with unmutated IGHV and shortened time to first treatment. In addition, WNT5A levels associate, independent of IGHV status, with the clinically worst CLL subgroups characterized by dysfunctional p53 and mutated SF3B1. We provide functional evidence that WNT5A-positive primary CLL cells have increased motility and attenuated chemotaxis toward CXCL12 and CCL19 that can be overcome by inhibitors of Wnt/PCP signaling.

Conclusions: These observations identify Wnt-5a as the crucial regulator of ROR1 activity in CLL and suggest that the autocrine Wnt-5a signaling pathway allows CLL cells to overcome natural microenvironmental regulation. Clin Cancer Res; 22(2); 459–69. ©2015 AACR.
HAGE in Triple-Negative Breast Cancer Is a Novel Prognostic, Predictive, and Actionable Biomarker: A Transcriptomic and Protein Expression Analysis
Authors: Abdel-Fatah Tarek M.A. , McArdle Stephanie E.B. , Agarwal Devika , Moseley Paul M. , Green Andrew R. , Ball Graham R. , Pockley A. Graham , Ellis Ian O. , Rees Robert C. , Chan Stephen Y.T.
Published: August 2015

Purpose: The expression of HAGE as a novel prognostic and predictive tool was assessed in 1,079 triple-negative breast cancers (TNBC).

Experimental Design: HAGE protein expression was investigated in an early primary TNBC (EP-TNBC; n = 520) cohort who received adjuvant chemotherapy (ACT) and in a locally advanced primary TNBC cohort who received anthracycline combination Neo-ACT (n = 110; AC-Neo-ACT). HAGE-mRNA expression was evaluated in the METABRIC-TNBC cohort (n = 311) who received ACT and in a cohort of patients with TNBC who received doxorubicin/cyclophosphamide Neo-ACT, followed by 1:1 randomization to ixabepilone (n = 68) or paclitaxel (n = 64) as part of a phase II clinical trial. Furthermore, a cohort of 128 tumors with integrated HAGE gene copy number changes, mRNA, and protein levels were analyzed.

Results: In patients with EP-TNBC, who were chemotherapy-naïve, high HAGE protein expression (HAGE+) was associated with a higher risk of death [HR, 1.3; 95% confidence interval (CI), 1.2–1.5; P = 0.000005] when compared with HAGE− cases. Patients who received ACT and expressed mRNA-HAGE+ were at a lower risk of death than those who were mRNA–HAGE− (P = 0.004). The expression of HAGE was linked to the presence of tumor-infiltrating lymphocytes (TIL), and both features were found to be independent predictors for pathologic complete response (pCR, P < 0.001) and associated with prolonged survival (P < 0.01), following AC-Neo-ACT. In patients with residual disease, HAGE+ had a 2-fold death risk increase (P = 0.018) compared with HAGE−.

Conclusions: HAGE expression is a potential prognostic marker and a predictor of response to anthracycline treatment in TNBC. A prospective clinical trial to examine the therapeutic value of HAGE for TNBC cases is warranted. Clin Cancer Res; 22(4); 905–14. ©2015 AACR.
Glycogen Synthase Kinase 3 Beta Predicts Survival in Resected Adenocarcinoma of the Pancreas
Authors: Ben-Josef Edgar , George Asha , Regine William F. , Abrams Ross , Morgan Meredith , Thomas Dafydd , Schaefer Paul L. , DiPetrillo Thomas A. , Fromm Mitchel , Small William , Narayan Samir , Winter Kathryn , Griffith Kent A. , Guha Chandan , Williams Terence M.
Published: August 2015

Purpose: GSK3β is a protein kinase that can suppress a number of key oncoproteins. We have previously shown in preclinical models of pancreatic ductal adenocarcinoma (PDAC) that inhibition of GSK3β causes stabilization and nuclear translocation of β-catenin, poor differentiation, proliferation, and resistance to radiation. The objective of this study was to determine its utility as a biomarker of clinical outcomes.

Experimental Design: Automated Quantitative Immunofluorescence Analysis (AQUA) of GSK3β was performed on a tissue microarray with samples from 163 patients treated on RTOG 9704. On the basis of findings in an exploratory cohort, GSK3β was analyzed as a categorical variable using its upper quartile (>Q3) as a cut point. Overall survival (OS) and disease-free survival (DFS) were estimated with the Kaplan–Meier method, and GSK3β groupings were compared using the log-rank test. Univariable and multivariable Cox proportional hazards models were used to determine associations between GSK3β and OS/DFS.

Results: The 3-year OS rates for GSK3β≤Q3 versus GSK3β >Q3 were 16% (95% confidence intervals; CI, 10%–23%) and 30% (95% CI, 17%–44%), respectively, P = 0.0082. The 3-year DFS rates were 9% (95% CI, 5%–15%) and 20% (95% CI, 9%–33%) respectively, P value = 0.0081. On multivariable analysis, GSK3β was a significant predictor of OS. Patients with GSK3β >Q3 had a 46% reduced risk of dying of pancreatic cancer (HR, 0.54; 95% CI, 0.31–0.96, P value = 0.034). The HR for DFS was 0.65 (95% CI, 0.39–1.07; P value = 0.092).

Conclusions: GSK3β expression is a strong prognosticator in PDAC, independent of other known factors such as tumor (T) stage, nodal status, surgical margins and CA19-9. Clin Cancer Res; 21(24); 5612–8. ©2015 AACR.
Abstract 3914: IGF-II causes translocation of estrogen receptor beta to the mitochondria in triple negative breast cancer cell lines
Authors: O'Bannon-Joseph Chane' , DeLeon Daisy D. ,   Center for Health Disparities and Molecular Medicine
Published: August 2015

Breast cancer is the most frequently diagnosed cancer and is the leading cause of death among women worldwide. Breast cancer is classified by the presence or absence of the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). Triple negative breast cancers (TNBCs) lack all 3 receptors and account for approximately 15-20% of all breast cancers. Due to lack of targeted treatments TNBCs become aggressive and can metastasize to other parts of the body. The insulin-like growth factor-II (IGF-II) has an important role in fetal and cancer development. IGF-II signals through the IGF-I receptor (IGF-IR), insulin receptor (Ins-R), and has been associated in cross-talk with the estrogen receptors alpha and beta (ERα, ERß). Our lab has demonstrated that IGF-II activates the translocation of estrogen receptor alpha (ER-α) and estrogen receptor beta (ER-β) in the absence of the estrogen ligand. When co-expressed, ER-β counteracts the proliferative function of ER-α, however the role of ER-β in ER-α negative breast cancers is unclear. Although TNBC accounts for 20% of all BC, 50-90% of all TNBC express high levels of ER-β. Triple negative breast cancer can be more aggressive and difficult to treat. Also, the cancer is more likely to spread and recur. With the elevated levels of expression of the ER-β found in TNBC our lab demonstrated through western blotting and confocal microscopy that not only did treatment with IGF-II increase the expression of ER-β in both ER positive (MCF-7) and TNBC cell lines (CRL-231, 2335, and HS578-T) but it also stimulated translocation predominantly to the mitochondria in the TNBC cell lines. The presence of ER-β in the mitochondria suggests a need for further study on the action of ER-β in the mitochondria of all BC cell lines, especially TNBC cell lines.

Citation Format: Chane' O'Bannon-Joseph, Daisy D. DeLeon, Center for Health Disparities and Molecular Medicine. IGF-II causes translocation of estrogen receptor beta to the mitochondria in triple negative breast cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3914. doi:10.1158/1538-7445.AM2015-3914
Abstract 4606: Fine mapping of 64 prostate cancer GWAS regions identifies multiple novel association signals
Authors: Kote-Jarai Zsofia , Al Olama Ali Amin , Dadaev Tokhir , Hazelett Dennis , Li Qiuyan , Leongamornlert Daniel , Saunders Ed , Feedman Matthew , Conti David , Easton Douglas , Coetzee Gerhard , Eeles Rosalind ,   The PRACTICAL Consortium
Published: August 2015

Genome-wide association studies (GWAS) have identified 100 common prostate cancer (PrCa) susceptibility loci to date. We performed comprehensive fine-mapping of 64 GWAS regions using genotyping and imputation to a 1000 Genomes reference panel for 25,779 PrCa cases and 26,218 controls of European ancestry from the PRACTICAL Consortium and two UK GWAS studies. In order to identify independent variants associated to PrCa, SNPs significant at P ≤10-4 were included in a stepwise logistic regression (SLR). Where the initial SLR identified multiple independent SNPs in a region, we re-analysed the region conditioning on the top hit. The adjusted results were subsequently trimmed using a P-value cut-off of ≤10-5 and a second SLR performed to identify independently significant index SNPs. We observed a single independent signal at 39 regions, with a novel, more significantly associated index SNP at 35 of these. Amongst these, we confirmed association in the European population for 2 loci previously reported in Asian GWAS. At 16 regions there was evidence for multiple independent signals, 14 of these contain newly identified additional significant associations. Functional annotation using data from ENCODE filtered for PrCa cell lines showed enrichment for overlap with bio-features within the fine-mapped SNP set and eQTL analysis identified novel candidate genes regulated by SNPs discovered in this study. Furthermore, we observed a 7% (from 32%-to 39%) improvement in the estimated proportion of familial relative risk explained through these refined and newly identified genetic variants. This study demonstrates the utility of fine-mapping, in silico functional annotation and eQTL approaches to narrow down the number of candidate functional variants. In addition, since a greater proportion of GWAS loci contained multiple independent risk variants than previously appreciated; this may explain a proportion of the missing heritability of complex diseases.

Citation Format: Zsofia Kote-Jarai, Ali Amin Al Olama, Tokhir Dadaev, Dennis Hazelett, Qiuyan Li, Daniel Leongamornlert, Ed Saunders, Matthew Feedman, David Conti, Douglas Easton, Gerhard Coetzee, Rosalind Eeles, The PRACTICAL Consortium. Fine mapping of 64 prostate cancer GWAS regions identifies multiple novel association signals. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4606. doi:10.1158/1538-7445.AM2015-4606
ERBB2 Emerges as a New Target for Colorectal Cancer
Authors: Pectasides Eirini , Bass Adam J.
Published: August 2015

Summary: ERBB2 mutations and amplifications are present in 7% of colorectal cancers. The presence of these alterations may be a marker of resistance to anti-EGFR therapy and, more importantly, could help identify patients who would benefit from ERBB2-directed therapy. Cancer Discov; 5(8); 799–801. ©2015 AACR.

See related article by Kavuri et al., p. 832.
Clonal Evolution: Multiregion Sequencing of Esophageal Adenocarcinoma Before and After Chemotherapy
Authors: Devarakonda Siddhartha , Govindan Ramaswamy
Published: August 2015

Summary: It is possible to decipher the clonal architecture of a tumor and the sequence in which cancer clones acquire genomic alterations through multiregion sequencing (M-seq). Serial evaluation of tumor specimens through M-seq can provide valuable information on the molecular basis of resistance to therapy. Cancer Discov; 5(8); 796–8. ©2015 AACR.

See related article by Murugaesu et al., p. 821.
MET Receptor Juxtamembrane Exon 14 Alternative Spliced Variant: Novel Cancer Genomic Predictive Biomarker
Authors: Ma Patrick C.
Published: August 2015

Clinical studies on MET-targeting cancer therapeutics have yielded mixed results in recent years, and MET-relevant predictive biomarkers remain elusive. New studies now reveal METex14 alternative splicing aberrations to represent potential predictive cancer genomic biomarker, hence renewing optimism and directions in the quest for optimized MET-targeting personalized cancer therapy. Cancer Discov; 5(8); 802–5. ©2015 AACR.

See related article by Paik et al., p. 842.

See related article by Frampton et al., p. 850.
Expression of Antioxidant Genes in the Mouse Cochlea and Brain in Salicylate-Induced Tinnitus and Effect of Treatment with Spirulina platensis Water Extract
Authors: Hwang Juen-Haur , Chang Nian-Cih , Chen Jin-Cherng , Chan Yin-Ching
Published: August 2015

Salicylate increased manganese-superoxide dismutase (Mn-SOD) gene expression, but decreased catalase (CAT) gene expression in the cochlea and various brain regions of mice with tinnitus. Spirulinaplatensis water extract reduced salicylate-induced overexpression of the Mn-SOD gene, but increased salicylate-induced downregulation of the CAT gene. With the exception of significantly increased SOD activity in the brainstem and inferior colliculus of the Spirulina group, SOD and CAT enzyme activities did not differ among the three groups. The tinnitus group had higher malondialdehyde (MDA) levels than the control group in the temporal and the frontal lobes. S.platensis water extract reduced salicylate-induced elevations of MDA levels in many brain areas. We proposed that altered expression of antioxidant genes may reflect states of oxidative stress associated with tinnitus.
Martorell's Ulcer: Diagnostic and Therapeutic Challenge
Authors: Pinto Ana Paula Frade Lima , Silva Jr. Nelson Araújo , Osorio Carolina Teixeira , Rivera Lina Maria , Carneiro Sueli , Ramos-e-Silva Marcia , Bica Blanca Elena Rios Gomes
Published: August 2015

Martorell's ulcer is an uncommon ischemic and extremely painful lesion located in the distal portion of the lower limb, resulting from severe systemic and poorly controlled hypertension. It is common in women between 50 and 70 years of age. The diagnosis is clinical and mostly belated, following exclusion of other causes. The response to treatment takes time and is unsatisfactory. A combination of several drugs associated with surgery may be required for wound healing. The authors present a case of Martorell's hypertensive ulcer, with emphasis on the diagnostic and therapeutic difficulties.
Severe Pulmonary Hypertension Associated with COPD: Hemodynamic Improvement with Specific Therapy
Authors: Girard Anne , Jouneau Stephane , Chabanne Céline , Khouatra Chahéra , Lannes Morgane , Traclet Julie , Turquier Ségolène , Delaval P. , Cordier J.-F. , Cottin Vincent
Published: August 2015

Background: There is no recommendation for treating pulmonary hypertension (PH) when associated with chronic obstructive pulmonary disease (COPD). Objective: To evaluate the effect of PH-specific therapy in patients with COPD. Methods: All successive patients with severe PH [mean pulmonary arterial pressure (mPAP) ≥35 mm Hg] and COPD, who received specific PH medication and who underwent right heart catheterization at baseline and after 3-12 months of treatment, were analyzed from a prospective database. Results: Twenty-six patients were included with a median follow-up of 14 months. Mean forced expiratory volume in 1 s was 57 ± 20% of predicted, and mean forced expiratory volume in 1 s/forced vital capacity was 47 ± 12%. Dyspnea was New York Health Association classification stage (NYHA) II in 15%, NYHA III in 81% and NYHA IV in 4%. First-line treatments were endothelin receptor antagonists in 11 patients, phosphodiesterase-5 inhibitors in 11 patients, calcium blocker in 1 patient, combination therapy in 3 patients including 2 with a prostanoid. After 6 ± 3 months, pulmonary vascular resistance decreased from 8.5 ± 3 to 6.6 ± 2 Wood units (p < 0.001), with significant improvement of cardiac index from 2.44 ± 0.43 to 2.68 ± 0.63 liters × min × m-2 (p = 0.015) and mPAP from 48 ± 9 to 42 ± 10 mm Hg (p = 0.008). There was no significant difference in dyspnea, 6-min walking distance, echocardiographic parameters or N-terminal pro-brain natriuretic peptide levels. There was no significant difference in arterial oxygen saturation after 3-12 months of treatment. Conclusions: Specific PH medications may improve hemodynamic parameters in COPD patients with severe PH. Appropriate prospective randomized studies are needed to evaluate the potential long-term clinical benefit of treatment.
Atypical Clinical Presentation of Xeroderma Pigmentosum in a Patient Harboring a Novel Missense Mutation in the XPC Gene: The Importance of Clinical Suspicion
Authors: Meneses Marina , Chavez-Bourgeois Marion , Badenas Celia , Villablanca Salvador , Aguilera Paula , Bennàssar Antoni , Alos Llucia , Puig Susana , Malvehy Josep , Carrera Cristina
Published: August 2015

Background: Xeroderma pigmentosum (XP) is a genodermatosis caused by abnormal DNA repair. XP complementation group C (XPC) is the most frequent type in Mediterranean countries. We describe a case with a novel mutation in the XPC gene. Case: A healthy Caucasian male patient was diagnosed with multiple primary melanomas. Digital follow-up and molecular studies were carried out. Results: During digital follow-up 8 more additional melanomas were diagnosed. Molecular studies did not identify mutations in CDKN2A, CDK4 or MITF genes. Two heterozygous mutations in the XPC gene were detected: c.2287delC (p.Leu763Cysfs*4) frameshift and c.2212A>G (p.Thr738Ala) missense mutations. Conclusion: The p.Thr738Ala missense mutation has not been previously described. Missense mutations in the XPC gene may allow partial functionality that could explain this unusual late onset XP. Atypical clinical presentation of XPC could be misdiagnosed when genetic aberrations allow partial DNA repair capacity.
Use of Plastic Needles for Early Arteriovenous Fistula Cannulation
Authors: Letachowicz Krzysztof , Kusztal Mariusz , Gołębiowski Tomasz , Letachowicz Waldemar , Weyde Wacław , Klinger Marian
Published: August 2015

Background: The native arteriovenous fistula (AVF) needs maturation before it can be used. Needling done before time may result in haematoma formation, miscannulation or even access loss. Methods: This retrospective study included 20 patients with AVFs punctured with fluoroplastic dialysis catheters within 30 days after access creation and 19 historical controls. Results: The time to first puncture was 2-29 days for the study group and 1-26 days for the control group. The incidences of haematoma were 16.7 and 48 per 1,000 dialysis sessions for plastic and metal needles, respectively. Estimated primary functional fistula survival at 3, 6 and 12 months were 95, 90 and 74% for the study group and 79, 67 and 60% for the control group (p = 0.106), respectively. Conclusions: Use of plastic needles enables safe AVF cannulation. If applied judiciously, it can minimize or even avoid catheter use.
Renal Tumor in Pregnancy: A Case Report and Review of the Literature
Authors: Berczi Csaba , Flasko Tibor
Published: August 2015

The authors present their renal tumor cases observed during pregnancy and review the literature related to this topic. Between January 1, 2000 and January 1, 2015, altogether 3 patients were treated for renal tumor during pregnancy. Two of them had surgery performed during pregnancy, while in the other, premature birth of the baby preceded surgery. In the first case, a laparoscopic tumor resection was performed in the 29th week of the patient's pregnancy. In the second case, a transperitoneal radical nephrectomy was carried out during the 10th week of pregnancy. In the case of the third patient, a caesarean section was performed during the 32nd week of gestation, and then followed later by surgery for the metastatic renal tumor. However, the tumor was found to be inoperable.