bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Precipitated Calcium Carbonate/Polylactic Acid and Halloysite/Polylactic Acid Nanocomposites
Authors: Shi Xuetao , Zhang Guangcheng , Siligardi Cristina , Ori Guido , Lazzeri Andrea
Published: February 2015

PLA nanocomposites with stearate coated precipitated calcium carbonate (PCC) and halloysite natural nanotubes (HNT) were prepared by melt extrusion. The crystallization behavior, mechanical properties, thermal dynamical mechanical analysis (DMTA), and the morphology of the PCC/PLA, HNT/PLA, and HNT/PCC/PLA composites were discussed. Compared to halloysite nanotubes, PCC nanoparticles showed a better nucleating effect, which decreased both the glass transition and cold crystallization temperatures. The tensile performance of PLA composites showed that the addition of inorganic nanofillers increased Young’s modulus but decreased tensile strength. More interestingly, PLA composites with PCC particles exhibited an effectively increased elongation at break with respect to pure PLA, while HNT/PLA showed a decreased ultimate deformation of composites. DMTA results indicated that PLA composites had a similar storage modulus at temperatures below the glass transition and the addition of nanofillers into PLA caused Tg to shift to lower temperatures by about 3°C. The morphological analysis of fractures surface of PLA nanocomposites showed good dispersion of nanofillers, formation of microvoids, and larger plastic deformation of the PLA matrix when the PCC particles were added, while a strong aggregation was noticed in composites with HNT nanofillers, which has been attributed to a nonoptimal surface coating.
A Secure Storage System for Sensitive Data Protection Based on Mobile Virtualization
Authors: Park Su-Wan , Lim JaeDeok , Kim Jeong Nyeo
Published: February 2015

Recently, the development of smart phones has been reported the number of security vulnerabilities. Although these smart phones have a concept of Sandbox for the security, sensitive personal information has been still exposed by internal data exchange or root privilege acquisition. In this paper, we propose a system framework for secure storage of sensitive data in smartphone. The system is divided into general domain (GD) and secure domain (SD) in mobile device utilizing domain separation technique of virtualization, and SD provides a secure execution environment to protect sensitive data and secure services. In addition, our system introduces the secure functions such as authentication/access control, and encryption/key management and secures filesystem to be run in SD and addresses a detailed secure filesystem as a key function for secure storage. Lastly, the experiments are conducted to measure the performance overhead imposed by security features in SD and by overall system with interdomain communication from GD to SD. These experiment results show suitability of our system and suggest applicability of various secure functions which can be applied in our secure storage system.
Stochastic Search Algorithms for Identification, Optimization, and Training of Artificial Neural Networks
Authors: Nikolic Kostantin P.
Published: February 2015

This paper presents certain stochastic search algorithms (SSA) suitable for effective identification, optimization, and training of artificial neural networks (ANN). The modified algorithm of nonlinear stochastic search (MN-SDS) has been introduced by the author. Its basic objectives are to improve convergence property of the source defined nonlinear stochastic search (N-SDS) method as per Professor Rastrigin. Having in mind vast range of possible algorithms and procedures a so-called method of stochastic direct search (SDS) has been practiced (in the literature is called stochastic local search-SLS). The MN-SDS convergence property is rather advancing over N-SDS; namely it has even better convergence over range of gradient procedures of optimization. The SDS, that is, SLS, has not been practiced enough in the process of identification, optimization, and training of ANN. Their efficiency in some cases of pure nonlinear systems makes them suitable for optimization and training of ANN. The presented examples illustrate only partially operatively end efficiency of SDS, that is, MN-SDS. For comparative method backpropagation error (BPE)
method was used.
The Effect of Welding Residual Stress for Making Artificial Stress Corrosion Crack in the STS 304 Pipe
Authors: Kim Jae-Seong , Lee Bo-Young , Hwang Woong-Gi , Kang Sung-Sik
Published: March 2015

The stress corrosion crack is one of the fracture phenomena for the major structure components in nuclear power plant. During the operation of a power plant, stress corrosion cracks are initiated and grown especially in dissimilar weldment of primary loop components. In particular, stress corrosion crack usually occurs when the following three factors exist at the same time: susceptible material, corrosive environment, and tensile stress (residual stress included). Thus, residual stress becomes a critical factor for stress corrosion crack when it is difficult to improve the material corrosivity of the components and their environment under operating conditions. In this study, stress corrosion cracks were artificially produced on STS 304 pipe itself by control of welding residual stress. We used the instrumented indentation technique and 3D FEM analysis (using ANSYS 12) to evaluate the residual stress values in the GTAW area. We used the custom-made device for fabricating the stress corrosion crack in the inner STS 304 pipe wall. As the result of both FEM analysis and experiment, the stress corrosion crack was quickly generated and could be reproduced, and it could be controlled by welding residual stress.
Survival of Mexican Children with Acute Myeloid Leukaemia Who Received Early Intensification Chemotherapy and an Autologous Transplant
Authors: Jiménez-Hernández Elva , Dueñas-González María Teresa , Arellano-Galindo José , Medrano-Ortíz-De-Zárate María Elena , Bekker-Méndez Vilma Carolina , Berges-García Adolfina , Solís-Labastida Karina , Sánchez-Jara Berenice , Tiznado-García Héctor Manuel , Jaimes-Reyes Ethel Zulie , García-Jiménez Xochiketzalli , Espinoza-Hernández Laura , Núñez-Villegas Nora Nancy , Franco-Ornelas Sergio , Pérez-Casillas Ruy Xavier , Martínez Villegas Octavio , Palomares Teresa Marin , Mejía-Aranguré Juan Manuel
Published: March 2015

Background. In Mexico and other developing countries, few reports of the survival of children with acute leukaemia exist.Objective. We aimed at comparing the disease-free survival of children with acute myeloid leukaemia who, in addition to being treated with the Latin American protocol of chemotherapy and an autologous transplant, either underwent early intensified chemotherapy or did not undergo such treatment.Procedure. This was a cohort study with a historical control group, forty patients, less than 16 years old. Group A (20 patients), diagnosed in the period 2005–2007, was treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy: high doses of cytarabine and mitoxantrone. Group B (20 patients), diagnosed in the period 1999–2004, was treated as Group A, but without the early intensified chemotherapy.Results. Relapse-free survival for Group A was 90% whereas that for Group B it was 60% (P=0.041). Overall survival for Group A (18, 90%) was higher than that for Group B (60%). Complete remission continued for two years of follow-up.Conclusions. Relapse-free survival for paediatric patients treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy was higher than that for those who did not receive early intensified chemotherapy.
Cerebellar Transcranial Direct Current Stimulation Effects on Saccade Adaptation
Authors: Avila Eric , van der Geest Jos N. , Kengne Kamga Sandra , Verhage M. Claire , Donchin Opher , Frens Maarten A.
Published: March 2015

Saccade adaptation is a cerebellar-mediated type of motor learning in which the oculomotor system is exposed to repetitive errors. Different types of saccade adaptations are thought to involve distinct underlying cerebellar mechanisms. Transcranial direct current stimulation (tDCS) induces changes in neuronal excitability in a polarity-specific manner and offers a modulatory, noninvasive, functional insight into the learning aspects of different brain regions. We aimed to modulate the cerebellar influence on saccade gains during adaptation using tDCS. Subjects performed an inward (n=10) or outward (n=10) saccade adaptation experiment (25% intrasaccadic target step) while receiving 1.5 mA of anodal cerebellar tDCS delivered by a small contact electrode. Compared to sham stimulation, tDCS increased learning of saccadic inward adaptation but did not affect learning of outward adaptation. This may imply that plasticity mechanisms in the cerebellum are different between inward and outward adaptation. TDCS could have influenced specific cerebellar areas that contribute to inward but not outward adaptation. We conclude that tDCS can be used as a neuromodulatory technique to alter cerebellar oculomotor output, arguably by engaging wider cerebellar areas and increasing the available resources for learning.
Akt–Girdin Signaling in Cancer-Associated Fibroblasts Contributes to Tumor Progression
Authors: Yamamura Yumiko , Asai Naoya , Enomoto Atsushi , Kato Takuya , Mii Shinji , Kondo Yuji , Ushida Kaori , Niimi Kaoru , Tsunoda Nobuyuki , Nagino Masato , Ichihara Shu , Furukawa Koichi , Maeda Kengo , Murohara Toyoaki , Takahashi Masahide
Published: March 2015

PI3K–Akt signaling is critical for the development, progression, and metastasis of malignant tumors, but its role in the tumor microenvironment has been relatively little studied. Here, we report that the Akt substrate Girdin, an actin-binding protein that regulates cell migration, is expressed and activated by Akt phosphorylation in cancer-associated fibroblasts (CAF) and blood vessels within the tumor microenvironment. Lewis lung tumors grafted into mice defective in Akt-mediated Girdin phosphorylation (SA transgenic mice) exhibited a decrease in both CAF infiltration and tumor growth, compared with wild-type (WT) host control animals. Contrasting with the findings of other studies, we found that Akt-dependent phosphorylation of Girdin was not a rate-limiting step in the growth of endothelial cells. In addition, Lewis lung tumors displayed limited outgrowth when cotransplanted with CAF derived from tumor-bearing SA transgenic mice, compared with CAF derived from tumor-bearing WT mice. Collectively, our results revealed a role for Akt-mediated Girdin phosphorylation in CAF during tumor progression, highlighting the need to inhibit Akt function in both tumor cells and cells that comprise the tumor microenvironment. Cancer Res; 75(5); 813–23. ©2015 AACR.
RIP1 Kinase Is an Oncogenic Driver in Melanoma
Authors: Liu Xiao Ying , Lai Fritz , Yan Xu Guang , Jiang Chen Chen , Guo Su Tang , Wang Chun Yan , Croft Amanda , Tseng Hsin-Yi , Wilmott James S. , Scolyer Richard A. , Jin Lei , Zhang Xu Dong
Published: February 2015

Although many studies have uncovered an important role for the receptor-binding protein kinase RIP1 in controlling cell death signaling, its possible contributions to cancer pathogenesis have been little explored. Here, we report that RIP1 functions as an oncogenic driver in human melanoma. Although RIP1 was commonly upregulated in melanoma, RIP1 silencing inhibited melanoma cell proliferation in vitro and retarded the growth of melanoma xenografts in vivo. Conversely, while inducing apoptosis in a small proportion of melanoma cells, RIP1 overexpression enhanced proliferation in the remaining cells. Mechanistic investigations revealed that the proliferative effects of RIP1 overexpression were mediated by NF-κB activation. Strikingly, ectopic expression of RIP1 enhanced the proliferation of primary melanocytes, triggering their anchorage-independent cell growth in an NF-κB–dependent manner. We identified DNA copy-number gain and constitutive ubiquitination by a TNFα autocrine loop mechanism as two mechanisms of RIP1 upregulation in human melanomas. Collectively, our findings define RIP1 as an oncogenic driver in melanoma, with potential implications for targeting its NF-κB–dependent activation mechanism as a novel approach to treat this disease. Cancer Res; 75(8); 1736–48. ©2015 AACR.
“(Not) All (Dead) Things Share the Same Breath”: Identification of Cell Death Mechanisms in Anticancer Therapy
Authors: Rello-Varona Santiago , Herrero-Martín David , López-Alemany Roser , Muñoz-Pinedo Cristina , Tirado Oscar M.
Published: February 2015

During the last decades, the knowledge of cell death mechanisms involved in anticancer therapy has grown exponentially. However, in many studies, cell death is still described in an incomplete manner. The frequent use of indirect proliferation assays, unspecific probes, or bulk analyses leads too often to misunderstandings regarding cell death events. There is a trend to focus on molecular or genetic regulations of cell demise without a proper characterization of the phenotype that is the object of this study. Sometimes, cancer researchers can feel overwhelmed or confused when faced with such a corpus of detailed insights, nomenclature rules, and debates about the accuracy of a particular probe or assay. On the basis of the information available, we propose a simple guide to distinguish forms of cell death in experimental settings using cancer cell lines. Cancer Res; 75(6); 913–7. ©2015 AACR.
PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients
Authors: de la Rochefordiere Anne , Kamal Maud , Floquet Anne , Thomas Laurence , Petrow Peter , Petit Thierry , Pop Marius , Fabbro Michel , Kerr Christine , Joly Florence , Sevin Emmanuel , Maillard Sophie , Curé Hervé , Weber Béatrice , Brunaud Claire , Minsat Mathieu , Gonzague Laurence , Berton-Rigaud Dominique , Aumont Maud , Gladieff Laurence , Peignaux Karine , Bernard Virginie , Leroy Quentin , Bieche Ivan , Margogne Audrey , Nadan AnaTereza , Fourchotte Virginie , Diallo Alhassane , Asselain Benard , Plancher Corine , Armanet Sébastien , Beuzeboc Philippe , Scholl Suzy M.
Published: February 2015

Purpose: EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis.

Experimental Design: This randomized phase II trial enrolled 78 FIGO stage IB2–IIIB cervical cancer patients to either cisplatin-based radiochemotherapy alone (arm B, n = 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n = 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients.

Results: Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P = 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P = 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P = 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18).

Conclusions: Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups. Clin Cancer Res; 21(11); 2530–7. ©2015 AACR.
Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib
Authors: Gainor Justin F. , Tan Daniel S.W. , De Pas Tomasso , Solomon Benjamin J. , Ahmad Aziah , Lazzari Chiara , de Marinis Filippo , Spitaleri Gianluca , Schultz Katherine , Friboulet Luc , Yeap Beow Y. , Engelman Jeffrey A. , Shaw Alice T.
Published: February 2015

Purpose: Anaplastic lymphoma kinase (ALK) rearrangements are important therapeutic targets in non–small cell lung cancer (NSCLC) that confer sensitivity to the ALK inhibitors crizotinib and ceritinib. To determine the outcome of sequential treatment with crizotinb and ceritinib, we retrospectively evaluated a cohort of ALK-positive patients treated with both agents.

Experimental Design: We identified 73 ALK-positive NSCLC patients treated with crizotinib followed by ceritinib at four institutions. Medical records were reviewed to determine overall survival (OS) and progression-free survival (PFS) on crizotinib and ceritinib.

Results: Among 73 ALK-positive patients, the median PFS (mPFS) on crizotinib was 8.2 months [95% confidence interval (CI), 7.4–10.6]. The median interval from crizotinib discontinuation to initiation of ceritinib was 25 days (range, 1–694). The mPFS on ceritinib was 7.8 months (6.5–9.1). Among 53 patients with no interval therapies between crizotinib and ceritinib, the mPFS on ceritinib was similar at 7.8 months (5.4–9.8). The median combined PFS for sequential treatment with crizotinib and ceritinib was 17.4 months (15.5–19.4). Among 23 patients who underwent post-crizotinib/pre-ceritinib biopsies, there was no difference in PFS on ceritinib between patients with or without ALK resistance mutations (mPFS 5.8 vs. 6.5 months, respectively; P = 0.510). In the overall study population, median OS was 49.4 months (35.5–63.1).

Conclusions: Ceritinib has significant antitumor activity in ALK-positive NSCLC—even when crizotinib immediately precedes treatment with ceritinib (median combined PFS 17.0 months). Additional studies are necessary to further define the impact of specific ALK resistance mutations on duration of response to ceritinib. Clin Cancer Res; 21(12); 2745–52. ©2015 AACR.
Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus
Authors: Huynh Hung , Hao Huai-Xiang , Chan Stephen L. , Chen David , Ong Richard , Soo Khee Chee , Pochanard Panisa , Yang David , Ruddy David , Liu Manway , Derti Adnan , Balak Marissa N. , Palmer Michael R. , Wang Yan , Lee Benjamin H. , Sellami Dalila , Zhu Andrew X. , Schlegel Robert , Huang Alan
Published: February 2015

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV+ HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. Mol Cancer Ther; 14(5); 1224–35. ©2015 AACR.
Detection of Tumor Suppressor Genes in Cancer Development by a Novel shRNA-Based Method
Authors: von Burstin Johannes , Diersch Sandra , Schneider Günter , Reichert Maximilian , Rustgi Anil K. , Schmid Roland M.
Published: February 2015

Pancreatic cancer is one of the deadliest cancers with poor survival rates and limited therapeutic options. To improve the understanding of this disease's biology, a prerequisite for the generation of novel therapeutics, new platforms for rapid and efficient genetic and therapeutic screening are needed. Therefore, a combined in vitro/in vivo hybrid shRNA assay was developed using isolated murine primary pancreatic ductal cells (PDCs), in which oncogenic KrasG12D could be activated in vitro by genomic recombination through 4OH-tamoxifen–induced nuclear translocation of Cre-ERT2 expressed under control of the ROSA26 promoter. Further genetic manipulation was achieved through selective and stable RNAi against the tumor suppressors p16Ink4a (CDKN2A) or Trp53 (TP53) using lentiviral gene delivery. Treatment of PDCs with 4OH-tamoxifen increased phosphorylation of ERK downstream of KRAS, and subsequent lentiviral transduction resulted in sustained target gene repression. Double-mutant PDCs were then reintroduced into the pancreata of NOD-SCID-gamma (NSG) mice and monitored for tumor growth. Orthotopic implantation of PDCs carrying the activated KrasG12D-allele and shRNA against p16Ink4a or Trp53 resulted in tumor growth, metastasis, and reduced survival of NSG mice. In contrast, KrasG12D alone was not sufficient to induce tumor growth.

Implications: The combinatory in vitro/in vivo approach described in this study allows for rapid and efficient identification of genes involved in carcinogenesis and opens new avenues for the development of therapeutic strategies to improve cancer treatment. Mol Cancer Res; 13(5); 863–9. ©2015 AACR.
Integrating Different Aspects of Resting Brain Activity: A Review of Electroencephalographic Signatures in Resting State Networks Derived from Functional Magnetic Resonance Imaging
Authors: Nishida Keiichiro , Razavi Nadja , Jann Kay , Yoshimura Masafumi , Dierks Thomas , Kinoshita Toshihiko , Koenig Thomas
Published: March 2015

Electroencephalography (EEG) is an established measure in the field of brain resting state with a range of quantitative methods (qEEG) that yield unique information about neuronal activation and synchronization. Meanwhile, in the last decade, functional magnetic resonance imaging (fMRI) studies have revealed the existence of more than a dozen resting state networks (RSNs), and combined qEEG and fMRI have allowed us to gain understanding about the relationship of qEEG and fMRI-RSNs. However, the overall picture is less clear because there is no a priori hypothesis about which EEG features correspond well to fMRI-RSNs. We reviewed the associations of several types of qEEG features to four RSNs considered as neurocognitive systems central for higher brain processes: the default mode network, dorsal and ventral frontoparietal networks, and the salience network. We could identify 12 papers correlating qEEG and RSNs in adult human subjects and employing a simultaneous design under a no-task resting state condition. A systematic overview investigates which qEEG features replicably relate to the chosen RSNs. This review article leads to the conclusion that spatially delimited θ and whole/local α may be the most promising measures, but the time domain methods add important additional information.
Topographic Analysis of Electroencephalographic Changes during Photic Driving Responses in Patients with Migraine
Authors: Takashima Ryotaro , Tanaka Hideaki , Kimoto Kazuhito , Watanabe Yuka , Hirata Koichi
Published: March 2015

Objective: Migraineurs demonstrate abnormal information processing such as photic hypersensitivity. The photic driving response to photic stimulation (PS) is a reaction to the visual stimulation of electroencephalography (EEG). Both the photic driving response and photic hypersensitivity appear during light stimulation. We considered that evaluation of a migraineur's photic driving response may help to elucidate the mechanism of the migraineur's sensitive condition. Our study aimed to investigate EEG photic driving responses with a source-localizing method. Methods: We recorded spontaneous resting EEG with eyes closed from 20 electrodes on the scalp during the interictal phase. After recording, each PS was separately selected. We also analyzed EEG by fast Fourier transform and observed the spectrum frequency peaks and topographies in response to PS. Results: The photic driving response could be observed at a flashing rate of >15 Hz. Patients with photic hypersensitivity tended to show more photic driving regardless of the migraine subtype. Moreover, in topographies, their activated areas were shifted anteriorly from fundamental driving to harmonic driving for each photic frequency. This anterior shift was more evident with a longer duration of illness, although no significant differences were seen between migraine subtypes. The global field power value had a positive correlation with the duration of illness. Conclusion: Photic hypersensitivity and photic driving responses were increased in migraineurs. Photic hypersensitivity might result in sensitization of the limbic system.
p16 Gene Transfer Induces Centrosome Amplification and Abnormal Nucleation Associated with Survivin Downregulation in Glioma Cells
Authors: Takayasu Takeshi , Hama Seiji , Yamasaki Fumiyuki , Saito Taiichi , Watanabe Yosuke , Nosaka Ryo , Sugiyama Kazuhiko , Kurisu Kaoru
Published: March 2015

Objective: In human glioma cells, p16 gene transfer induced G1/S arrest, increased radiosensitivity and abnormal nucleation (especially bi- and multinucleation). Survivin suppression caused G2/M arrest, radiosensitization and an increase in aneuploidy accompanied by centrosome amplification. Abnormal nucleation and aneuploidy represent chromosome instability (CIN), and it is well known that centrosome amplification leads to CIN. However, little has been reported that suggests that transferring p16 causes centrosome overduplication during the G1/S phase. Methods: The p16 gene was transferred into p16-null human glioma cell lines (U251MG and D54MG) using adenovirus with or without irradiation. Centrosome amplification was evaluated by immunofluorescence. We also investigated the DNA replication licensing factor CDT1, its inhibitor geminin and survivin expression as regulators of chromosomal segregation. Results: p16 gene transfer with radiation initiated the greatest degree of centrosome overduplication. CDT1 showed low levels, geminin was unchanged and survivin decreased in Ax-hp16-infected cells with radiation. Those changes of factors affecting DNA licensing or chromosomal segregation might contribute to CIN. Conclusion: p16 transfer caused centrosome amplification even in G1/S phase-arrested cells. This suggests that p16 is involved in abnormal nucleation and radiosensitization in human glioma cells.
Geographic Distribution of Regional Metastatic Nodes Affects the Outcome of Trimodality-Eligible Patients with Esophageal Adenocarcinoma
Authors: Shiozaki Hironori , Slack Rebecca , Sudo Kazuki , Elimova Elena , Wadhwa Roopma , Chen Hsian-Chun , Skinner Heath D. , Komaki Ritsuko , Lee Jeffrey H. , Weston Brian , Bhutani Manoop S. , Blum Mariela A. , Rogers Jane E. , Maru Dipen M. , Hofstetter Wayne L. , Ajani Jaffer A.
Published: March 2015

Background/Aim: Malignant nodes in patients with localized esophageal adenocarcinoma (L-EAC) portend a poor prognosis. We assessed the correlation of the distribution of nodes with the outcome of patients undergoing chemoradiation/surgery (trimodality therapy). Methods: We studied 209 L-EAC patients who had confirmed or suspicious nodes at baseline staging. All patients received trimodality therapy and were grouped according to the nodal geography: above the diaphragm (AD), below the diaphragm (BD), or above and below the diaphragm (ABD). Survival estimates were calculated using the Kaplan-Meier method, and the outcomes of the groups were assessed by the log-rank test. Results: Patients were primarily Caucasian (91%) and male (93%), with a baseline stage III L-EAC (89%). The median follow-up was 2.8 years (range, 0.4-11.7). Of the 209 patients, 35% (n = 73) had AD nodes, 20% (n = 41) had BD nodes, and 45% (n = 95) had ABD nodes. ABD patients had a 5-year overall survival rate of 33%, whereas this rate was 55% in AD patients and 60% in BD patients (p = 0.02). Patients with a higher histology grade were also at a higher risk of relapse and had a poor survival (p < 0.01 for both). Conclusions: L-EAC patients in the ABD group had the worst outcome after trimodality treatment compared to those in the AD or BD group. Novel strategies are needed for ABD patients.
Chronic Spinal Cord Stimulation in the Treatment of Cerebral and Spinal Spasticity
Authors: Dekopov Andrey V. , Shabalov Vladimir A. , Tomsky Aleksey A. , Hit Mariya V. , Salova Ekaterina M.
Published: March 2015

Objectives: The aim of this investigation is to assess the effectiveness of spinal cord stimulation (SCS) in different groups of patients with spasticity of different origin. Materials and Methods: A retrospective study of the use of the method of SCS in 71 patients. The patient population was divided into two groups: 52 cerebral palsy (CP) cases and 19 patients diagnosed with spasticity caused by spinal injury. The mean age was 7.14 ± 4.06 and 35.68 ± 12.42 years, respectively. The CP group included 41 cases of paraparesis and 11 cases tetraparesis. One quadripolar electrode was implanted into the posterior epidural space at Th10-Th12 level and an implantable pulse generator (Itrel3, Medtronic) was placed in a standard fashion. We performed 3-5 stimulation sessions per day; each lasted 30 min. The stimulation parameters were as follows: rate 100-130 Hz, pulse width 120-300 ms, amplitude 1.5-4 V. The follow-up ranged from 2 to 9 years. Results: Decrease in muscle tone was observed in all cases in the group of patients with spinal spasticity: from 3.71 ± 0.61 on the Ashworth scale before the operation to 2.26 ± 0.56 after the operation (p < 0.001). In the group of cerebral spasticity a significant decrease in muscle tone was observed only in patients with spastic lower paraparesis: from 3.36 ± 0.41 before the operation to 1.97 ± 0.91 after the operation (p < 0.005). In patients with spastic tetraparesis we did not observe any significant change in muscle tone. In 8 cases we discontinued the therapy several years after the procedure due to improvement in spasticity: in the CP group in 7 cases and in 1 spinal spasticity case, where SCS systems were explanted. Conclusion: Chronic SCS may be a method of choice for patients with moderate spinal and cerebral spasticity with predominant spastic lower paraparesis. In patients with spastic tetraparesis SCS therapy did not prove to be effective. We encountered improvement of the spasticity and no need for further SCS therapy in a small group of patients (11%). This phenomenon requires further investigation.
Feasibility and Safety of MR-Guided Focused Ultrasound Lesioning in the Setting of Deep Brain Stimulation
Authors: Dallapiazza Robert , Khaled Mohamad , Eames Matthew , Snell John , Lopes M. Beatriz , Wintermark Max , Elias W. Jeffrey
Published: March 2015

Background: Patients treated with deep brain stimulation (DBS) often develop symptom progression. If safe, focused ultrasound (FUS) lesioning could be used for patients unable to undergo further DBS surgery. Objective: To test the feasibility and safety of MR-guided FUS surgery in the setting of a previously implanted DBS system. Methods: Three preclinical experiments were designed to test feasibility and safety. Hydrogels were implanted with an electrode, and FUS lesions were targeted adjacently. Cadavers were implanted with a thalamic electrode, and FUS lesions were targeted in the contralateral thalamus. Finally, DBS systems were implanted in swine, and FUS lesioning was targeted to the contralateral thalamus, MRI was used to assess the treatments, and histological analyses were performed at 2 days and at 1 month. Results: In gel experiments and cadavers, FUS resulted in target heating to 29-32°C without any heating at the electrode. In animal experiments, there were no FUS-related MRI signal changes near the electrode. Histological analysis showed typical FUS lesions with no evidence of damage surrounding the electrode tracts. Conclusions: FUS is feasible in the setting of a preimplanted DBS device. There was minimal heating of the device during the procedure and no apparent FUS-related tissue injury.
Serial Plasma Metabolites Following Hypoxic-Ischemic Encephalopathy in a Nonhuman Primate Model
Authors: Chun Pattaraporn T. , McPherson Ronald J. , Marney Luke C. , Zangeneh Sahar Z. , Parsons Brendon A. , Shojaie Ali , Synovec Robert E. , Juul Sandra E.
Published: March 2015

Biomarkers that indicate the severity of hypoxic-ischemic brain injury and response to treatment and that predict neurodevelopmental outcomes are urgently needed to improve the care of affected neonates. We hypothesize that sequentially obtained plasma metabolomes will provide indicators of brain injury and repair, allowing for the prediction of neurodevelopmental outcomes. A total of 33 Macaca nemestrina underwent 0, 15 or 18 min of in utero umbilical cord occlusion (UCO) to induce hypoxic-ischemic encephalopathy and were then delivered by hysterotomy, resuscitated and stabilized. Serial blood samples were obtained at baseline (cord blood) and at 0.1, 24, 48, and 72 h of age. Treatment groups included nonasphyxiated controls (n = 7), untreated UCO (n = 11), UCO + hypothermia (HT; n = 6), and UCO + HT + erythropoietin (n = 9). Metabolites were extracted and analyzed using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry and quantified by PARAFAC (parallel factor analysis). Using nontargeted discovery-based methods, we identified 63 metabolites as potential biomarkers. The changes in metabolite concentrations were characterized and compared between treatment groups. Further comparison determined that 8 metabolites (arachidonic acid, butanoic acid, citric acid, fumaric acid, lactate, malate, propanoic acid, and succinic acid) correlated with early and/or long-term neurodevelopmental outcomes. The combined outcomes of death or cerebral palsy correlated with citric acid, fumaric acid, lactate, and propanoic acid. This change in circulating metabolome after UCO may reflect cellular metabolism and biochemical changes in response to the severity of brain injury and have potential to predict neurodevelopmental outcomes.
Identification and Functional Studies of Regulatory Variants Responsible for the Association of NRG3 with a Delusion Phenotype in Schizophrenia
Authors: Zeledón Mariela , Eckart Nicole , Taub Margaret , Vernon Hilary , Szymanski Megan , Wang Ruihua , Chen Pei-Lung , Nestadt Gerry , McGrath John A. , Sawa Akira , Pulver Ann E. , Avramopoulos Dimitrios , Valle David
Published: March 2015

We previously reported a genetic linkage for schizophrenia (SZ; nonparametric linkage score of 4.27) at 10q22 in an Ashkenazi Jewish (AJ) population. In follow-up fine-mapping, we found strong evidence for an association between 3 intronic single nucleotide variants (SNVs) in the 5′ end of neuregulin 3 (NRG3) and the delusion factor score of our phenotypic principal component analysis. Two independent groups replicated these findings, indicating that variants in NRG3 confer a risk for a delusion-rich SZ subtype. To identify the causative variants, we sequenced the 162-kb linkage disequilibrium block covering the NRG3 5′ end in 47 AJ SZ patients at the extremes of the delusion factor quantitative trait distribution. Among the identified variants, we found 5 noncoding SNVs which were present on the high delusion factor haplotype and significantly overrepresented in high delusion factor subjects. We tested these for regulatory effects and found that risk alleles of rs10883866 and rs60827755 decreased and increased, respectively, the expression of a reporter gene as compared to the reference allele. In postmortem brain mRNA quantification experiments, we found the same variants also perturb the relative expression of alternative NRG3 isoforms. In summary, we have identified regulatory SNVs contributing to the association of NRG3 with delusion symptoms in SZ.
Development of a Hypoallergenic Recombinant Parvalbumin for First-in-Man Subcutaneous Immunotherapy of Fish Allergy
Authors: Zuidmeer-Jongejan Laurian , Huber Hans , Swoboda Ines , Rigby Neil , Versteeg Serge A. , Jensen Bettina M. , Quaak Suzanne , Akkerdaas Jaap H. , Blom Lars , Asturias Juan , Bindslev-Jensen Carsten , Bernardi Maria L. , Clausen Michael , Ferrara Rosa , Hauer Martina , Heyse Jet , Kopp Stephan , Kowalski Marek L. , Lewandowska-Polak Anna , Linhart Birgit , Maderegger Bernhard , Maillere Bernard , Mari Adriano , Martinez Alberto , Mills E.N. Clare , Neubauer Angela , Nicoletti Claudio , Papadopoulos Nikolaos G. , Portoles Antonio , Ranta-Panula Ville , Santos-Magadan Sara , Schnoor Heidi J. , Sigurdardottir Sigurveig T. , Stahl-Skov Per , Stavroulakis George , Stegfellner Georg , Vázquez-Cortés Sonia , Witten Marianne , Stolz Frank , Poulsen Lars K. , Fernandez-Rivas Montserrat , Valenta Rudolf , van Ree Ronald
Published: March 2015

Background: The FAST (food allergy-specific immunotherapy) project aims at developing safe and effective subcutaneous immunotherapy for fish allergy, using recombinant hypoallergenic carp parvalbumin, Cyp c 1. Objectives: Preclinical characterization and good manufacturing practice (GMP) production of mutant Cyp (mCyp) c 1. Methods:Escherichia coli-produced mCyp c 1 was purified using standard chromatographic techniques. Physicochemical properties were investigated by gel electrophoresis, size exclusion chromatography, circular dichroism spectroscopy, reverse-phase high-performance liquid chromatography and mass spectrometry. Allergenicity was assessed by ImmunoCAP inhibition and basophil histamine release assay, immunogenicity by immunization of laboratory animals and stimulation of patients' peripheral blood mononuclear cells (PBMCs). Reference molecules were purified wild-type Cyp c 1 (natural and/or recombinant). GMP-compliant alum-adsorbed mCyp c 1 was tested for acute toxicity in mice and rabbits and for repeated-dose toxicity in mice. Accelerated and real-time protocols were used to evaluate stability of mCyp c 1 as drug substance and drug product. Results: Purified mCyp c 1 behaves as a folded and stable molecule. Using sera of 26 double-blind placebo-controlled food-challenge-proven fish-allergic patients, reduction in allergenic activity ranged from 10- to 5,000-fold (1,000-fold on average), but with retained immunogenicity (immunization in mice/rabbits) and potency to stimulate human PBMCs. Toxicity studies revealed no toxic effects and real-time stability studies on the Al(OH)3-adsorbed drug product demonstrated at least 20 months of stability. Conclusion: The GMP drug product developed for treatment of fish allergy has the characteristics targeted for in FAST: i.e. hypoallergenicity with retained immunogenicity. These results have warranted first-in-man immunotherapy studies to evaluate the safety of this innovative vaccine.
Percentage Change in Plasma Cytokeratin 18 Is Associated with Clinical Outcomes in Patients Receiving Pemetrexed and Carboplatin for the Adenocarcinoma Subtype of NSCLC
Authors: Strimpakos Alexios S. , Banerji Udai , Thavasu Parames , Tsilimagou Alexandra , Psyrri Amanta , Syrigos Kostas N.
Published: March 2015

Background: The adenocarcinoma subtype of non-small cell lung cancer (adeno-NSCLC) is routinely treated with chemotherapy if patients do not have molecular aberrations such as epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements. There are currently no validated biomarkers that can predict if patients will gain clinical benefit from chemotherapy, leading to a majority of patients receiving many cycles of unnecessary chemotherapy. We hypothesized that the percentage rise in plasma caspase-cleaved cytokeratin 18 (cCK18) and total cytokeratin 18 (tCK18) assessed before and after chemotherapy correlates with the radiological response to chemotherapy. Methods: Plasma samples from 40 patients with stage IV adeno-NSCLC, treated with first-line chemotherapy with carboplatin (AUC5) plus pemetrexed (500 mg/m2), were collected prior to chemotherapy and 48 h after treatment. ELISA was used to quantify cCK18 and tCK18. Results: The male-to-female ratio was 3:1, and the median age of patients was 63 years. Patients who had a clinical benefit (complete response, partial response or stable disease) at the first radiological assessment following chemotherapy had a significantly higher percentage change in plasma tCK18 levels compared to those who had no clinical benefit, i.e. progressive disease (69.5 ± 75.1 vs. 25.3 ± 30.9%, respectively; p = 0.042). The receiver operating characteristic area was 0.712 (p = 0.039). There was an increase in the percentage change in cCK18 in patients with clinical benefit compared to those without clinical benefit but this was not statistically significant (57.6 ± 112.8 vs. 24.38 ± 45.1%, respectively; p = 0.85). Conclusions: The percentage change in plasma tCK18 levels before and after the first cycle of pemetrexed and carboplatin chemotherapy is associated with clinical benefit. If validated in larger cohorts, this test can be used to identify patients unlikely to respond to treatment who can thus be offered alternative treatments or entry into clinical trials.
A Case of Fibrillary Glomerulonephritis Associated with Thrombotic Microangiopathy and Anti-Glomerular Basement Membrane Antibody
Authors: Momose Akishi , Nakajima Taku , Chiba Shigetoshi , Kumakawa Kenjirou , Shiraiwa Yasuo , Sasaki Nobuhiro , Watanabe Kazuo , Kitano Etsuko , Hatanaka Mitiyo , Kitamura Hajime
Published: March 2015

We present the first report of a case of fibrillary glomerulonephritis (FGN) associated with thrombotic microangiopathy (TMA) and anti-glomerular basement membrane antibody (anti-GBM antibody). A 54-year-old man was admitted to our hospital for high fever and anuria. On the first hospital day, we initiated hemodialysis for renal dysfunction. Laboratory data revealed normocytic-normochromic anemia with schistocytes in the peripheral smear, thrombocytopenia, increased serum lactate dehydrogenase, decreased serum haptoglobin, and negative results for both direct and indirect Coombs tests. Based on these results, we diagnosed TMA. Assays conducted several days later indicated a disintegrin-like and metalloprotease with a thrombospondin motif 13 (ADAMTS13) activity of 31.6%, and ADAMTS13 inhibitors were negative. We started plasma exchange using fresh frozen plasma and steroid pulse therapy. Anti-GBM antibody was found to be positive. Renal biopsy showed FGN. Blood pressure rose on the 46th hospital day, and mild convulsions developed. Based on magnetic resonance imaging of the head, the patient was diagnosed with reversible posterior leukoencephalopathy syndrome. Hypertension persisted despite administration of multiple antihypertensive agents, and the patient experienced a sudden generalized seizure. Computed tomography of the head showed multiple cerebral hemorrhages. However, his blood pressure subsequently decreased and the platelet count increased. TMA remitted following 36 plasma exchange sessions, but renal function was not restored, and maintenance hemodialysis was continued. The patient was discharged on the 119th day of hospitalization. In conclusion, it was shown that TMA, FGN and anti-GBM antibody were closely related.
Clinical Considerations for the Association between Vascular Damage and Chronic Kidney Disease
Authors: Tomiyama Hirofumi , Yamashina Akira
Published: March 2015

Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. Recently, noninvasive and simple morphological and functional methods have been introduced to assess atherosclerotic vascular damage. This review describes the association of CKD with vascular damage as assessed by these methods. Carotid intima-media thickness (IMT) and coronary artery calcium score (CACS) are morphological parameters of vascular damage, and an ankle-brachial index (ABI) <0.90 suggests the presence of peripheral arterial disease (i.e., it represents advanced atherosclerosis). Several prospective studies have demonstrated that CKD is a risk factor for an increased IMT, an increased CACS and a decreased ABI. While it has not been clarified whether measuring the IMT or CACS might be useful to predict the progression of renal function decline, a reduced ABI has been demonstrated as a predictor of accelerated renal function decline. On the other hand, pulse wave velocity (PWV) is a marker of arterial stiffness rather than atherosclerosis, reflecting functional abnormalities caused by vascular damage, and moderate-to-severe CKD may be a risk factor for the progression of arterial stiffness. The measurement of functional markers, especially of PWV or pulse pressure, has been demonstrated to be useful to predict the rate of progression of renal function decline. Thus, renal dysfunction and atherogenic states may be components of a vicious cycle, and vascular function abnormalities associated with atherosclerosis may accelerate this cycle. As the next step, we propose to examine whether improvement of vascular function abnormalities can interrupt this vicious cycle.
Cytological Scoring and Prognosis of Poorly Differentiated Endometrioid Adenocarcinoma
Authors: Kato Rina , Hasegawa Kiyoshi , Torii Yutaka , Hirasawa Yutaka , Udagawa Yasuhiro , Fukasawa Ichio
Published: March 2015

Objective: Histopathological variation has been demonstrated in grade 3 endometrioid adenocarcinomas. We attempted to evaluate the clinicopathological features of grade 3 tumors by endometrial cytological features using a scoring system. Study Design: Twenty-one endometrial cytological samples were evaluated using 5 cytological features: rates of cluster formation in tumor cells; nuclear pleomorphism; nuclear dimension; size of nucleoli, and chromatin structure and distribution. The relationships between cytological scores and clinicopathological factors or prognosis were investigated. Results: The median cytological score was 6 (range 4-14); therefore, samples with scores of 4-5 were defined as having low scores, while those with scores of 6-14 were defined as high scores. The accuracy of the cytological diagnosis for grade 3 tumors in the high score group (8/10 patients, 80.0%) was significantly higher than that of the low score group (2/11 patients, 18.2%; p = 0.009). Significant relationships between cytological scores and lymph node metastases or positive peritoneal cytology were observed (p = 0.03 and 0.035, respectively). The overall survival rate was significantly worse in the high score group (30.0%) than the low score group (88.9%; p = 0.02). Conclusions: Grade 3 endometrioid adenocarcinomas varied in cytological features; according to the scoring system used, high scores were associated with worse clinicopathological factors and poorer prognosis than low scores.