bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of suanzaoren decoction for chronic insomnia disorder in adults: study protocol for randomised, double-blind, double-dummy, placebo-controlled trial
Authors: Zhou Qi-Hui , Wang Hui-Lin , Zhou Xiao-Li , Xu Meng-Bei , Zhang Hong-feng , Huang Li-bo , Zheng Guo-qing , Lin Yan 
Published: April 2017

BackgroundInsomnia disorder is defined as a combination of dissatisfaction with sleep quantity or quality and a significant negative impact on daytime functioning. Chronic insomnia disorder refers to clinical symptoms of persistent insomnia at least three nights a week for at least 3 months. Prevalence estimates of insomnia disorder range from 12% to 20% in the adult population, with approximately 50% having a chronic course. The potential side effects of hypnotic medications hinder their clinical application. Thus, traditional Chinese medicine is considered as an alternative option for treating insomnia.ObjectiveTo evaluate the efficacy and safety of suanzaoren decoction (SZRD), a classic Chinese herbal prescription, for adult chronic insomnia disorder.Methods/analysisThis is a randomised, double-blind, double-dummy, placebo-controlled clinical trial. A total of 150 patients with chronic insomnia disorder are randomised, allocated in a ratio of 1:1:1 to three groups: intervention group, control group and placebo group. The intervention group receives SZRD granule plus zolpidem tartrate (ZT) placebo; the control group receives ZT tablet plus SZRD granule placebo; and the placebo group receives ZT placebo and SZRD granule placebo. The patients receive medicine or placebo for 5 weeks and are followed up at 20 weeks. The primary outcome measures are polysomnography and Pittsburgh Sleep Quality Index. Secondary outcome measures are the Insomnia Severity Index, sleep diary and safety assessment. Outcomes will be assessed at baseline and after treatment.Trial registration numberChiCTR-IOR-16009198. pre-results.
Predisposing factors for recanalization of cerebral aneurysms after endovascular embolization: a multivariate study
Authors: Zhang Qianqian , Jing Linkai , Liu Jian , Wang Kun , Zhang Ying , Paliwal Nikhil , Meng Hui , Wang Yang , Wang Shengzhang , Yang Xinjian 
Published: April 2017

BackgroundThe recanalization of cerebral aneurysms after endovascular embolization (coiling or stent-assisted coiling) has been a matter of concern.ObjectiveTo systematically evaluate the predisposing factors for cerebral aneurysm recanalization using multidimensional analysis in a large patient cohort.MethodsIn 238 patients with 283 aneurysms, patient baseline characteristics, aneurysm morphological characteristics, treatment-related factors, and changes in flow hemodynamics after endovascular treatment (coiling or stent-assisted coiling) were compared between the recanalization and non-recanalization groups. Multivariate logistic regression analysis was performed to determine independent risk factors correlated with recanalization.Results16 aneurysms treated by coiling recanalized, with a recurrence rate of 18.6%, and 24 recanalized in the lesions treated by stent-assisted coiling, with a recanalization rate of 12.2%. Large aneurysms (>10 mm, p=0.002) and a follow-up interval >1 year (p=0.027) were shown to be statistically significant between the recanalization and non-recanalization groups. For flow hemodynamic changes, three parameters (velocity on the neck plane, wall shear stress on the neck wall, and wall shear stress on the whole aneurysm) showed a relatively lower amplitude of decrease after endovascular treatment in the recanalization group. Interestingly, the velocity on the neck plane and wall shear stress on the neck wall may be elevated after treatment. Specifically, the reduction ratio (RR) of velocity on the neck plane showed significant difference between the groups in the multivariate analysis (p=0.013), and was considered an independent risk factor for recanalization.ConclusionsThe aneurysm size, follow-up interval, and flow hemodynamic changes, especially the RR of velocity on the neck plane, have important roles in aneurysm recanalization.
Scaling Online Games with NetConnectors
Authors: Mildner Philip , Triebel Tonio , Kopf Stephan , Effelsberg Wolfgang 
Published: April 2017

This article presents a peer-to-peer overlay for massively multiplayer online games with a focus on fast-paced action. More than other genres, action games like first-person shooters employ fast and dynamic game mechanics. In multiplayer environments, these properties have to be reflected by the underlying network structure. At the same time, the system should be able to support a huge amount of users in order to deliver a massive experience to the participating players. The capacity of current client/server systems limits the number of players in a game, preventing the desired massive experience.
To provide both a scalable and a responsive system, we use a fully distributed peer-to-peer network with a dynamic connection scheme. By exploiting local interests in the virtual world, our system supports a huge number of users. Therefore, an area-of-interest mechanism is applied to the connection scheme. Users do not connect to all participating users, but they only establish connections to other users they are interested in. These neighbors are determined by the user's perception of the virtual world. Instead of using a purely distance-based approach, our system uses a more flexible neighbor-based approach that supports the use of multiple metrics to determine the set of interesting nodes for each user. A second kind of connection—so-called NetConnectors—utilizes the players' distribution in the virtual world to ensure overlay consistency. For the dissemination of messages, we use a publish/subscribe mechanism. This prevents inconsistencies introduced by unidirectional neighborhood relations that can occur with sender-oriented models. Further, the publish/subscribe mechanism models the users' interests more accurately. In addition to the regular sending mechanism, we implemented a Geocast algorithm that allows information distribution to arbitrary regions of the virtual world. While regular messages are always addressed to specific users, Geocasts cover certain geographical regions. Thus, Geocasts can be used to disseminate messages to all users that are located in the addressed region.
Simulations show that our design performs well in terms of scalability. By keeping the amount of connections per user nearly constant, users do not get overloaded with too many connections. This also applies for crowded regions where the user density is much higher compared to an evenly populated virtual world. Another important aspect of fast-paced multiplayer games is the users' motion behavior. Different movement strategies are evaluated for their impact on network load and connection dynamics.
Effect of silhouetting and inversion on view invariance in the monkey inferotemporal cortex
Authors: Ratan Murty N. Apurva , Arun S. P. 
Published: April 2017

We effortlessly recognize objects across changes in viewpoint, but we know relatively little about the features that underlie viewpoint invariance in the brain. Here, we set out to characterize how viewpoint invariance in monkey inferior temporal (IT) neurons is influenced by two image manipulations—silhouetting and inversion. Reducing an object into its silhouette removes internal detail, so this would reveal how much viewpoint invariance depends on the external contours. Inverting an object retains but rearranges features, so this would reveal how much viewpoint invariance depends on the arrangement and orientation of features. Our main findings are 1) view invariance is weakened by silhouetting but not by inversion; 2) view invariance was stronger in neurons that generalized across silhouetting and inversion; 3) neuronal responses to natural objects matched early with that of silhouettes and only later to that of inverted objects, indicative of coarse-to-fine processing; and 4) the impact of silhouetting and inversion depended on object structure. Taken together, our results elucidate the underlying features and dynamics of view-invariant object representations in the brain. NEW & NOTEWORTHY We easily recognize objects across changes in viewpoint, but the underlying features are unknown. Here, we show that view invariance in the monkey inferotemporal cortex is driven mainly by external object contours and is not specialized for object orientation. We also find that the responses to natural objects match with that of their silhouettes early in the response, and with inverted versions later in the response—indicative of a coarse-to-fine processing sequence in the brain.
Parallel processing of internal and external feedback in the spinocerebellar system of primates
Authors: Cohen Oren , Harel Ran , Aumann Tim D. , Israel Zvi , Prut Yifat 
Published: April 2017

Cerebellar control of voluntary movements is achieved by the integration of external and internal feedback information to adjust and correct properly ongoing actions. In the forelimb of primates, rostral-spinocerebellar tract (RSCT) neurons are thought to integrate segmental, descending, and afferent sources and relay upstream a compound signal that contains both an efference copy of the spinal-level motor command and the state of the periphery. We tested this hypothesis by implanting stimulating electrodes in the superior cerebellar peduncle and recording the activity of cervical spinal neurons in primates. To dissociate motor commands and proprioceptive signals, we used a voluntary wrist task and applied external perturbations to the movement. We identified a large group of antidromically activated RSCT neurons located in deep dorsal sites and a smaller fraction of postsynaptically activated (PSA) cells located in intermediate and ventral laminae. RSCT cells received sensory input from broad, proximally biased receptive fields (RFs) and were not affected by applied wrist perturbations. PSA cells received sensory information from distal RFs and were more strongly related to active and passive movements. The anatomical and functional properties of RSCT and PSA cells suggest that descending signals converging on PSA cells contribute to both motor preparation and motor control. In parallel, RSCT neurons relay upstream an integrated signal that encodes the state of working muscles and can contribute to distal-to-proximal coordination of action. Thus the rostral spinocerebellar system sends upstream an efference copy of the motor command but does not signal abrupt errors in the performed movement. NEW & NOTEWORTHY Cerebellar coordination of voluntary movements relies on integrating feedback information to update motor output. With the use of a novel protocol, we identified spinal neurons constituting the ascending and descending components of the forelimb spinocerebellar system in behaving primates. The data suggest that descending information contributes to both motor preparation and execution, whereas ascending information conveys the spinal level motor command, such that internal and external feedback is relayed through parallel pathways.
Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non–Small Cell Lung Cancers
Authors: Deb Dhruba , Rajaram Satwik , Larsen Jill E. , Dospoy Patrick D. , Marullo Rossella , Li Long Shan , Avila Kimberley , Xue Fengtian , Cerchietti Leandro , Minna John D. , Altschuler Steven J. , Wu Lani F. 
Published: April 2017

Abstract
Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations of TP53, KRAS, and MYC—oncogenic alterations commonly found in non–small cell lung cancer (NSCLC). We interrogated at single-cell resolution how these alterations could affect classic readouts (β-CATENIN, SMAD2/3, phospho-STAT3, P65, FOXO1, and phospho-ERK1/2) of key pathways commonly affected in NSCLC. All three oncogenic alterations were required concurrently to observe significant signaling changes, and significant heterogeneity arose in this condition. Unexpectedly, we found two mutually exclusive altered subpopulations: one with STAT3 upregulation and another with SMAD2/3 downregulation. Treatment with a STAT3 inhibitor eliminated the upregulated STAT3 subpopulation, but left a large surviving subpopulation with downregulated SMAD2/3. A bioinformatics search identified BCL6, a gene downstream of SMAD2/3, as a novel pharmacologically accessible target of our transformed HBECs. Combination treatment with STAT3 and BCL6 inhibitors across a panel of NSCLC cell lines and in xenografted tumors significantly reduced tumor cell growth. We conclude that BCL6 is a new therapeutic target in NSCLC and combination therapy that targets multiple vulnerabilities (STAT3 and BCL6) downstream of common oncogenes, and tumor suppressors may provide a potent way to defeat intratumor heterogeneity. Cancer Res; 77(11); 3070–81. ©2017 AACR.
Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry
Authors: Feng Ye , Rhie Suhn Kyong , Huo Dezheng , Ruiz-Narvaez Edward A. , Haddad Stephen A. , Ambrosone Christine B. , John Esther M. , Bernstein Leslie , Zheng Wei , Hu Jennifer J. , Ziegler Regina G. , Nyante Sarah , Bandera Elisa V. , Ingles Sue A. , Press Michael F. , Deming Sandra L. , Rodriguez-Gil Jorge L. , Zheng Yonglan , Yao Song , Han Yoo-Jeong , Ogundiran Temidayo O. , Rebbeck Timothy R. , Adebamowo Clement , Ojengbede Oladosu , Falusi Adeyinka G. , Hennis Anselm , Nemesure Barbara , Ambs Stefan , Blot William , Cai Qiuyin , Signorello Lisa , Nathanson Katherine L. , Lunetta Kathryn L. , Sucheston-Campbell Lara E. , Bensen Jeannette T. , Chanock Stephen J. , Marchand Loic Le , Olshan Andrew F. , Kolonel Laurence N. , Conti David V. , Coetzee Gerhard A. , Stram Daniel O. , Olopade Olufunmilayo I. , Palmer Julie R. , Haiman Christopher A. 
Published: April 2017

AbstractBackground: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry.Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT).Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant (P &lt; 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality.Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry.Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016–26. ©2017 AACR.
Vulvar Squamous Cell Carcinoma (VSCC) as Two Diseases: HPV Status Identifies Distinct Mutational Profiles Including Oncogenic Fibroblast Growth Factor Receptor 3
Authors: Weberpals Johanne I. , Lo Bryan , Duciaume Marc M. , Spaans Johanna N. , Clancy Aisling A. , Dimitroulakos Jim , Goss Glenwood D. , Sekhon Harman S. 
Published: April 2017

Abstract
Purpose: Patients with advanced or recurrent invasive vulvar squamous cell carcinoma (VSCC) have limited treatment options and a grave prognosis. Understanding the genomic landscape may facilitate the identification of new therapies and improve clinical outcomes.
Experimental Design: A retrospective chart review and molecular analysis of patients with VSCC from 2000 to 2016 was performed at the Ottawa Hospital Research Institute. The presence of oncogenic human papillomavirus (HPV) was determined by nested PCR and amplified DNA was sequenced using the Ion AmpliSeq Cancer Hotspot v2 Panel. The patients were divided into two groups according to HPV status (HPV-positive versus HPV-negative) and clinical outcome correlated with mutation status using descriptive statistics.
Results: In 43 VSCC patients, there was a high mutation rate in both HPV-positive (73%) and HPV-negative (90%) disease with the two subgroups expressing distinct genetic profiles. HPV-positive tumors were characterized by oncogenic mutations in PIK3CA (27%), FGFR3 (14%), and PTEN (9%), whereas HPV-negative tumors were found to have mutations in TP53 (57%), HRAS (24%), PI3KCA (19%), and CDKN2A (14%). Mutation S249C in FGFR3 occurred in 14% of HPV-positive tumors. While there were notable differences in the occurrence of TP53, HRAS, PTEN, and FGFR3 mutations according to HPV status, only the rate of TP53 mutations was statistically significant (P = 0.0004). No significant difference in prognosis was found between patients with HPV-positive and HPV-negative VSCC.
Conclusions: HPV-positive VSCC is characterized by oncogenic FGFR3 mutations that helps classify this subtype as a separate disease. Inhibitors of FGFR3 merit consideration as a therapeutic strategy in this neglected cancer in women. Clin Cancer Res; 23(15); 4501–10. ©2017 AACR.
Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma
Authors: Subbiah Vivek , Meyer Christian , Zinner Ralph , Meric-Bernstam Funda , Zahurak Marianna L. , O'Connor Ashley , Roszik Jason , Shaw Kenna , Ludwig Joseph A. , Kurzrock Razelle , Azad Nilofer A. 
Published: April 2017

Abstract
Purpose: Pazopanib, a multireceptor tyrosine kinase inhibitor targeting primarily VEGFRs1–3, is approved for advanced soft tissue sarcoma (STS) and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using trametinib would synergize with pazopanib in advanced STS.
Experimental Design: In an open-label, multicenter, investigator-initiated National Comprehensive Cancer Network (NCCN)-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate, and disease control rate.
Results: Twenty-five patients were enrolled. The median age was 49 years (range, 22–77 years) and 52% were male. Median PFS was 2.27 months [95% confidence interval (CI), 1.9–3.9], and the 4-month PFS rate was 21.1% (95% CI, 9.7–45.9), which was not an improvement over the hypothesized null 4-month PFS rate of 28.3% (P = 0.79). Median overall survival was 9.0 months (95% CI, 5.7–17.7). A partial response occurred in 2 (8%) of the evaluable patients (95% CI, 1.0–26.0), one with PIK3CA E542K-mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma. The disease control rate was 14/25 (56%; 95% CI, 34.9–75.6). The most common adverse events were diarrhea (84%), nausea (64%), and fatigue (56%).
Conclusions: The combination of pazopanib and trametinib was tolerable without indication of added activity of the combination in STS. Further study may be warranted in RAS/RAF aberrant sarcomas. Clin Cancer Res; 23(15); 4027–34. ©2017 AACR.
Preclinical Activity of the Novel Anti-Prolactin Receptor (PRLR) Antibody–Drug Conjugate REGN2878-DM1 in PRLR-Positive Breast Cancers
Authors: Kelly Marcus P. , Hickey Carlos , Makonnen Sosina , Coetzee Sandra , Jalal Sumreen , Wang Yu , Delfino Frank , Shan Jing , Potocky Terra B. , Chatterjee Ishita , Andreev Julian , Kunz Arthur , D'Souza Christopher , Giurleo Jason T. , Nittoli Thomas , Trail Pamela A. , Thurston Gavin , Kirshner Jessica R. 
Published: April 2017

Abstract
The Prolactin Receptor (PRLR) is a type 1 cytokine receptor that is expressed in a subset of breast cancers and may contribute to its pathogenesis. It is relatively overexpressed in approximately 25% of human breast tumors while expressed at low levels in some normal human tissues including the mammary gland. We developed an anti-PRLR antibody-drug conjugate (ADC), to target PRLR-positive breast cancer. REGN2878-DM1 is comprised of a fully human high-affinity function-blocking anti-PRLR IgG1 antibody (REGN2878) conjugated via a noncleavable SMCC linker to the cytotoxic maytansine derivative DM1. Both unconjugated REGN2878 and conjugated REGN2878-DM1 block PRL-mediated activation in vitro and are rapidly internalized into lysosomes. REGN2878-DM1 induces potent cell-cycle arrest and cytotoxicity in PRLR-expressing tumor cell lines. In vivo, REGN2878-DM1 demonstrated significant antigen-specific antitumor activity against breast cancer xenograft models. In addition, REGN2878-DM1 showed additive activity when combined with the antiestrogen agent fulvestrant. These results illustrate promising antitumor activity against PRLR-positive breast cancer xenografts and support the evaluation of anti-PRLR ADCs as potential therapeutic agents in breast cancer. Mol Cancer Ther; 16(7); 1299–311. ©2017 AACR.
Addition of non-invasive ventilatory support to combined aerobic and resistance training improves dyspnea and quality of life in heart failure patients: a randomized controlled trial
Authors: Bittencourt Hugo Souza , Cruz Cristiano Gonçalves , David Bruno Costa , Rodrigues-Jr Erenaldo , Abade Camille Magalhães , Junior Roque Aras , Carvalho Vitor Oliveira , dos Reis Francisco Borges Faria , Gomes Neto Mansueto 
Published: April 2017

Objective:To test the hypothesis that combined aerobic and resistance training and non-invasive ventilatory support result in additional benefits compared with combined aerobic and resistance training alone in heart failure patients.Design:A randomized, single-blind, controlled study.Setting:Cardiac rehabilitation center.Participants:A total of 46 patients with New York Heart Association class II/III heart failure were randomly assigned to a 10-week program of combined aerobic and resistance training, plus non-invasive ventilatory support ( n = 23) or combined aerobic and resistance training alone ( n = 23).Methods:Before and after intervention, results for the following were obtained: 6-minute walk test, forced vital capacity, forced expiratory volume at one second, maximal inspiratory muscle pressure, and maximal expiratory muscle pressure, with evaluation of dyspnea by the London Chest Activity of Daily Living scale, and quality of life with the Minnesota Living With Heart Failure questionnaire.Results:Of the 46 included patients, 40 completed the protocol. The combined aerobic and resistance training plus non-invasive ventilatory support, as compared with combined aerobic and resistance training alone, resulted in significantly greater benefit for dyspnea (mean change: 4.8 vs. 1.3, p = 0.004), and quality of life (mean change: 19.3 vs. 6.8, p = 0.017 ). In both groups, the 6-minute walk test improved significantly (mean change: 45.7 vs. 44.1, p = 0.924), but without a statistically significant difference.Conclusion:Non-invasive ventilatory support combined with combined aerobic and resistance training provides additional benefits for dyspnea and quality of life in moderate heart failure patients. Trial registration: ClinicalTrials.gov identifier: NCT02384798. Registered 03 April 2015.