bluuebunny/crossref_metadata_2025_split huggingface dataset:
Joint Neural Collaborative Filtering for Recommender Systems
Authors: Chen Wanyu , Cai Fei , Chen Honghui , Rijke Maarten De 
Published: August 2019

We propose a Joint Neural Collaborative Filtering (J-NCF) method for recommender systems. The J-NCF model applies a joint neural network that couples deep feature learning and deep interaction modeling with a rating matrix. Deep feature learning extracts feature representations of users and items with a deep learning architecture based on a user-item rating matrix. Deep interaction modeling captures non-linear user-item interactions with a deep neural network using the feature representations generated by the deep feature learning process as input. J-NCF enables the deep feature learning and deep interaction modeling processes to optimize each other through joint training, which leads to improved recommendation performance. In addition, we design a new loss function for optimization that takes both implicit and explicit feedback, point-wise and pair-wise loss into account.
Experiments on several real-world datasets show significant improvements of J-NCF over state-of-the-art methods, with improvements of up to 8.24% on the MovieLens 100K dataset, 10.81% on the MovieLens 1M dataset, and 10.21% on the Amazon Movies dataset in terms of HR@10. NDCG@10 improvements are 12.42%, 14.24%, and 15.06%, respectively. We also conduct experiments to evaluate the scalability and sensitivity of J-NCF. Our experiments show that the J-NCF model has a competitive recommendation performance with inactive users and different degrees of data sparsity when compared to state-of-the-art baselines.
Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation
Authors: Zhao Peng , Han Sheng-Na , Arumugam Suyavaran , Yousaf Muhammad Nadeem , Qin Yanqin , Jiang Joy X. , Torok Natalie Julia , Chen Yonglin , Mankash Mohd Salah , Liu Junbao , Li Jiansheng , Iwakiri Yasuko , Ouyang Xinshou 
Published: August 2019

The cardiac glycoside digoxin was identified as a potent suppressor of pyruvate kinase isoform 2-hypoxia-inducible factor-α (PKM2-HIF-1α) pathway activation in liver injury mouse models via intraperitoneal injection. We have assessed the therapeutic effects of digoxin to reduce nonalcoholic steatohepatitis (NASH) by the clinically relevant oral route in mice and analyzed the cellular basis for this effect with differential involvement of liver cell subsets. C57BL/6J male mice were placed on a high-fat diet (HFD) for 10 wk and started concurrently with the gavage of digoxin (2.5, 0.5, 0.125 mg/kg twice a week) for 5 wk. Digoxin significantly reduced HFD-induced hepatic damage, steatosis, and liver inflammation across a wide dosage range. The lowest dose of digoxin (0.125 mg/kg) showed significant protective effects against liver injury and sterile inflammation. Consistently, digoxin attenuated HIF-1α sustained NLRP3 inflammasome activation in macrophages. We have reported for the first time that PKM2 is upregulated in hepatocytes with hepatic steatosis, and digoxin directly improved hepatocyte mitochondrial dysfunction and steatosis. Mechanistically, digoxin directly bound to PKM2 and inhibited PKM2 targeting HIF-1α transactivation without affecting PKM2 enzyme activation. Thus, oral digoxin showed potential to therapeutically inhibit liver injury in NASH through the regulation of PKM2-HIF-1α pathway activation with involvement of multiple cell types. Because of the large clinical experience with oral digoxin, this may have significant clinical applicability in human NASH. NEW & NOTEWORTHY This study is the first to assess the therapeutic efficacy of oral digoxin on nonalcoholic steatohepatitis (NASH) in a high-fat diet (HFD) mouse model and to determine the divergent of cell type-specific effects. Oral digoxin reduced liver damage, steatosis, and inflammation in HFD mice. Digoxin attenuated hypoxia-inducible factor (HIF)-1α axis-sustained inflammasome activity in macrophages and hepatic oxidative stress response in hepatocytes via the regulation of PKM2-HIF-1α axis pathway activation. Oral digoxin may have significant clinical applicability in human NASH.
Mechanical coupling through the skin affects whisker movements and tactile information encoding
Authors: Ego-Stengel Valerie , Abbasi Aamir , Larroche Margot , Lassagne Henri , Boubenec Yves , Shulz Daniel E. 
Published: August 2019

Rats use their whiskers to extract sensory information from their environment. While exploring, they analyze peripheral stimuli distributed over several whiskers. Previous studies have reported cross-whisker integration of information at several levels of the neuronal pathways from whisker follicles to the somatosensory cortex. In the present study, we investigated the possible coupling between whiskers at a preneuronal level, transmitted by the skin and muscles between follicles. First, we quantified the movement induced on one whisker by deflecting another whisker. Our results show significant mechanical coupling, predominantly when a given whisker’s caudal neighbor in the same row is deflected. The magnitude of the effect was correlated with the diameter of the deflected whisker. In addition to changes in whisker angle, we observed curvature changes when the whisker shaft was constrained distally from the base. Second, we found that trigeminal ganglion neurons innervating a given whisker follicle fire action potentials in response to high-magnitude deflections of an adjacent whisker. This functional coupling also shows a bias toward the caudal neighbor located in the same row. Finally, we designed a two-whisker biomechanical model to investigate transmission of forces across follicles. Analysis of the whisker-follicle contact forces suggests that activation of mechanoreceptors in the ring sinus region could account for our electrophysiological results. The model can fully explain the observed caudal bias by the gradient in whisker diameter, with possible contribution of the intrinsic muscles connecting follicles. Overall, our study demonstrates the functional relevance of mechanical coupling on early information processing in the whisker system. NEW & NOTEWORTHY Rodents explore their environment actively by touching objects with their whiskers. A major challenge is to understand how sensory inputs from different whiskers are merged together to form a coherent tactile percept. We demonstrate that external sensory events on one whisker can influence the position of another whisker and, importantly, that they can trigger the activity of mechanoreceptors at its base. This cross-whisker interaction occurs pre-neuronally, through mechanical transmission of forces in the skin.
Optimization of a Hydrothermal Growth Process for Low Resistance 1D Fluorine-Doped Zinc Oxide Nanostructures
Authors: Napi Muhammad L. M. , Sultan S. M. , Ismail Razali , Ahmad Mohd K. , Chai G. M. T. 
Published: August 2019

Design of Experiment (DOE) has been used for the optimization of a hydrothermal growth process of one-dimensional fluorine-doped zinc oxide (1D-FZO). Box-Behnken design was used in the DOE which includes three design points on each of the synthesis condition parameters. The condition parameters were the gold sputtering time (10 s, 15 s, and 20 s), hydrothermal reaction time (3 hours, 6.5 hours, and 10 hours), and hydrothermal temperature (50°C, 75°C, and 100°C). This statistical method of DOE was used to study the effects of these hydrothermal conditions on the quality of 1D-FZO produced. Au nanoparticles were used as the catalyst to enable the growth of the 1D-FZO. The XRD and EDX analysis confirmed the formation of polycrystalline FZO with the presence of fluorine, zinc, and oxygen elements. SEM observations indicated that the sputtering time of the Au nanoparticles has significant effect on the morphology and growth process of 1D-FZO. The lowest resistance value of 22.57 Ω was achieved for 1D-FZO grown with the longest Au sputtering time at growth temperature below 100°C.
The Immunoscore: Colon Cancer and Beyond
Authors: Angell Helen K. , Bruni Daniela , Barrett J. Carl , Herbst Ronald , Galon Jérôme 
Published: August 2019

AbstractTumors evolve in close interaction with their microenvironment, which encompasses a continual tension between the developing tumor and the host immune system. Clinical trials have shown that appropriate enhancement of a tumor immune response can lead to long-lasting clinical responses and patient benefit. Understanding the contribution of the immune contexture, in addition to the molecular subtype across different tumor indications, is a significant knowledge gap with limited sagacity to drive rational immunotherapy combinations. To better inform clinical studies, we must first strive to understand the multifaceted elements of the tumor-immune interaction, the spatiotemporal interplay of numerous different immune cell types, in conjunction with an understanding of the oncogenic drivers and mutations that may lead to presentation of neoepitopes and could drive changes within the tumor microenvironment. In this review, we discuss the Immunoscore and its probable universal characteristic. The overlay of immune quantification with the molecular segments of disease and how this may benefit identification of patients at high risk of tumor recurrence will be discussed. The Immunoscore may translate to provide a tumor agnostic method to define immune fitness of a given tumor and predict and stratify patients who will benefit from certain therapies (in particular immune therapies) and, ultimately, help save the lives of patients with cancer.
Combination of Metformin and Gefitinib as First-Line Therapy for Nondiabetic Advanced NSCLC Patients with EGFR Mutations: A Randomized, Double-Blind Phase II Trial
Authors: Li Li , Jiang Liyan , Wang Yubo , Zhao Yizhuo , Zhang Xiao-Ju , Wu Guoming , Zhou Xiangdong , Sun Jianguo , Bai Jun , Ren Biyong , Tian Kun , Xu Zhi , Xiao Hua-liang , Zhou Qi , Han Rui , Chen Hengyi , Wang Haidong , Yang Zhenzhou , Gao Chan , Cai Shangli , He Yong 
Published: August 2019

Abstract

Purpose:
Preclinical and retrospective studies suggested a role for metformin in sensitizing patients who have diabetes with non–small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors (TKIs). We therefore examined its effects in combination with gefitinib in patients without diabetes harboring EGFR mutations (EGFRm).

Patients and Methods:
A total of 224 patients without diabetes with treatment-naïve stage IIIB–IV EGFRm NSCLC were randomly assigned in a 1:1 ratio to receive gefitinib plus either metformin or placebo. The primary endpoint was progression-free survival (PFS) rate at 1 year and secondary endpoints included overall survival (OS), PFS, objective response rate (ORR), and safety. Serum levels of IL6 were also examined in an exploratory analysis.

Results:
The median duration of follow-up was 19.15 months. The estimated 1-year PFS rates were 41.2% [95% confidence interval (CI), 30.0–52.2] with gefitinib plus metformin and 42.9% (95% CI, 32.6–52.7) with gefitinib plus placebo (P = 0.6268). Median PFS (10.3 months vs. 11.4 months) and median OS (22.0 months vs. 27.5 months) were numerically lower in the metformin group, while ORRs were similar between the two arms (66% vs. 66.7%). No significant treatment group differences were detected across all subgroups with respect to PFS, including those with elevated levels of IL6. Metformin combined with gefitinib resulted in a remarkably higher incidence of diarrhea compared with the control arm (78.38% vs. 43.24%).

Conclusions:
Our study showed that addition of metformin resulted in nonsignificantly worse outcomes and increased toxicity and hence does not support its concurrent use with first-line EGFR-TKI therapy in patients without diabetes with EGFRm NSCLC.
Antitumor Activity and Mechanistic Characterization of APE1/Ref-1 Inhibitors in Bladder Cancer
Authors: Fishel Melissa L. , Xia Hanyu , McGeown Jack , McIlwain David W. , Elbanna May , Craft Ariel A. , Kaimakliotis Hristos Z. , Sandusky George E. , Zhang Chi , Pili Roberto , Kelley Mark R. , Jerde Travis J. 
Published: August 2019

Abstract

Bladder cancer is the ninth most common cause of cancer-related deaths worldwide. Although cisplatin is used routinely in treating bladder cancer, refractory disease remains lethal for many patients. The recent addition of immunotherapy has improved patient outcomes; however, a large cohort of patients does not respond to these treatments. Therefore, identification of innovative molecular targets for bladder cancer is crucial. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein involved in both DNA repair and activation of transcription factors through reduction–oxidation (redox) regulation. High APE1/Ref-1 expression is associated with shorter patient survival time in many cancer types. In this study, we found high APE1/Ref-1 expression in human bladder cancer tissue relative to benign urothelium. Inhibition of APE1/Ref-1 redox signaling using APE1/Ref-1–specific inhibitors attenuates bladder cancer cell proliferation in monolayer, in three-dimensional cultures, and in vivo. This inhibition corresponds with an increase in apoptosis and decreased transcriptional activity of NF-κB and STAT3, transcription factors known to be regulated by APE1/Ref-1, resulting in decreased expression of downstream effectors survivin and Cyclin D1 in vitro and in vivo. We also demonstrate that in vitro treatment of bladder cancer cells with APE1/Ref-1 redox inhibitors in combination with standard-of-care chemotherapy cisplatin is more effective than cisplatin alone at inhibiting cell proliferation. Collectively, our data demonstrate that APE1/Ref-1 is a viable drug target for the treatment of bladder cancer, provide a mechanism of APE1/Ref-1 action in bladder cancer cells, and support the use of novel redox-selective APE1/Ref-1 inhibitors in clinical studies.

Significance:
This work identifies a critical mechanism for APE1/Ref-1 in bladder cancer growth and provides compelling preclinical data using selective redox activity inhibitors of APE1/Ref-1 in vitro and in vivo.
Lenalidomide Augments the Antitumor Activities of Eps8 Peptide-Specific Cytotoxic T Lymphocytes against Multiple Myeloma
Authors: Xie Xiaoling , Chen Yiran , Hu Yuxing , He Yanjie , Zhang Honghao , Li Yuhua 
Published: August 2019

Abstract
Cancer immunotherapy is a promising new approach to cancer treatment. It has been demonstrated that a high number of tumor-specific cytotoxic T cells (CTL) is associated with increased survival in patients with multiple myeloma. Here, we focused on EGFR pathway substrate 8 (Eps8) as a candidate tumor-associated antigen (TAA) in multiple myeloma. Previous work has shown that Eps8-based immunotherapy in HLA-A2+ cancer patients may result in efficient antitumor immune responses against diverse tumor types. To improve immunotherapy for patients with multiple myeloma, we constructed a cocktail vaccine by combining several HLA-A2–restricted epitopes derived from Eps8 (Eps8cocktail), including Eps8101-2L (WLQDMILQV), Eps8276-1Y9V (YLDDIEFFV), and Eps8455-1Y (YLAESVANV). The CTLs induced by Eps8cocktail (Eps8cocktail-CTLs) showed highly effective anti–multiple myeloma activity, including Th1 cytokines production, cell proliferation, and cytotoxicity against HLA-A2+ multiple myeloma cells. This study highlights the importance of using a cocktail vaccine instead of a single-peptide vaccine to induce a robust response. Importantly, we revealed that lenalidomide effectively stimulated the antitumor activity of the Eps8cocktail-CTLs, with increasing expression trends for T-cell markers (CD28, CD40L, 41BB, and OX40). Compared with unstimulated CTLs and Eps8cocktail-CTLs, lenalidomide-treated Eps8cocktail-CTLs showed superior anti–multiple myeloma activity in humanized multiple myeloma models, including delaying tumor burden increases due to enhanced immune function. These results provide the framework for an Eps8 cocktail vaccination therapy to induce effective Eps8-specific CTLs in HLA-A2+ patients with multiple myeloma. Moreover, these studies further demonstrate that lenalidomide augments the immune response, providing a possibility for its use in combination with peptide vaccines to improve patient outcomes.
Association Between Baseline, Achieved, and Reduction of CRP and Cardiovascular Outcomes After LDL Cholesterol Lowering with Statins or Ezetimibe: A Systematic Review and Meta‐Analysis
Authors: Zhang Xin‐Lin , Lan Rong‐Fang , Zhang Xiao‐Wen , Xu Wei , Wang Lian , Kang Li‐Na , Xu Biao 
Published: August 2019

Background

Several lipid‐lowering therapies reduce CRP (C‐reactive protein) independently of LDL‐C (low‐density lipoprotein cholesterol) reduction, but the association between
CRP
parameters and benefits from more‐intensive
LDL
‐C lowering is inconclusive. We aimed to determine whether the benefits of more‐ versus less‐intensive
LDL
‐C lowering on cardiovascular events related to baseline, achieved, or magnitude of reduction in
CRP
concentrations.

Methods and Results

PubMed,
EMBASE
, and Cochrane were searched through July 2, 2018. We included randomized controlled cardiovascular outcome trials of
LDL
‐C lowering with statins or ezetimibe. Two reviewers independently extracted study data and rated study quality. Data were analyzed using meta‐analysis and metaregression analysis. Rate ratios of mortality and cardiovascular outcomes associated with baseline, achieved, and magnitude reduction of
CRP
concentration were calculated. Twenty‐four trials were included, with 171 250 patients randomly assigned to more‐ or less‐intensive
LDL
‐C–lowering treatments. Median follow‐up duration was 4.2 years. More‐intensive
LDL
‐C lowering resulted in a significant reduction in incidences of all outcomes. Compared with less‐intensive
LDL
‐C lowering, more‐intensive
LDL
‐C lowering was associated with less reductions in myocardial infarction with a higher baseline
CRP
concentration (change in rate ratios per 1‐mg/L increase in log‐transformed
CRP
, 1.12 [95%
CI
, 1.04–1.22;
P
=0.007]), but not other outcomes. Similar risk reductions occurred for more‐ versus less‐intensive
LDL
‐C–lowering therapy regardless of the magnitude of
CRP
reduction or the achieved
CRP
level for all outcomes.

Conclusions

Baseline
CRP
concentrations might be associated with the benefits of
LDL
‐C lowering on myocardial infarction, but no other outcomes, whereas the achieved and magnitude of reduction in
CRP
did not seem to have an important association.
Stroke Mechanisms in Symptomatic Intracranial Atherosclerotic Disease
Authors: Feng Xueyan , Chan Ka Lung , Lan Linfang , Abrigo Jill , Liu Jia , Fang Hui , Xu Yuming , Soo Yannie , Leng Xinyi , Leung Thomas W. 
Published: August 2019

Background and Purpose—
In patients with symptomatic intracranial atherosclerotic stenosis, identifying the underlying stroke mechanisms may inform secondary prevention. We aimed to propose reproducible classification criteria for stroke mechanisms based on routine neuroimaging in symptomatic intracranial atherosclerotic stenosis and explore their clinical implications.

Methods—
We recruited patients with acute ischemic stroke attributed to 50% to 99% intracranial atherosclerotic stenosis in anterior circulation from 2 centers. Two investigators independently classified probable stroke mechanisms as parent artery atherosclerosis occluding penetrating artery, artery-to-artery embolism, hypoperfusion, and mixed mechanisms, with prespecified criteria based on infarct topography and magnetic resonance/computed tomography angiography. These stroke mechanisms were correlated with features of the patients at baseline and recurrent ischemic stroke in the same territory or relevant transient ischemic attack within 1 year.

Results—

Among 153 patients recruited, the most common stroke mechanisms were isolated hypoperfusion (35.3%) and mixed mechanism of artery-to-artery embolism and hypoperfusion (37.3%) that was associated with higher incidence of dyslipidemia (
P
=0.045) and hypertension (
P
=0.033) than patients with other stroke mechanisms. The proposed criteria showed substantial to excellent intrarater and interrater reproducibilities (κ, 0.791–0.908). Overall, 31 patients received interventional treatment of the diseased intracranial artery; 122 received medical treatment, among whom a mixed mechanism of artery-to-artery embolism and hypoperfusion at baseline was associated with higher risk of ischemic stroke in the same territory within 1 year (24.4% versus 7.8%; hazard ratio, 3.40; 95% CI, 1.25–9.20; log-rank
P
=0.010) than other mechanisms combined.

Conclusions—
Artery-to-artery embolism and hypoperfusion commonly coexist in ischemic stroke attributed to intracranial atherosclerotic stenosis, which may be associated with higher risk of stroke relapse.
Assessing the Impact of the South China Sea Arbitration on Small Island States: A Case Study of Kiribati
Authors: Kaye Stuart 
Published: August 2019

Abstract
The Annex VII Tribunal in the South China Sea Arbitration placed a high threshold on States seeking to claim an exclusive economic zone (EEZ) around small features. The implications of such an interpretation are potentially significant for the maritime jurisdiction of a number of States, particularly in the Pacific. This article considers the implications of the decision of the Tribunal, and applies it to Kiribati as a case study. It also considers possible ways States may minimize the risk associated with the Tribunal’s interpretation.
Stratiform and Convective Radar Reflectivity–Rain Rate Relationships and Their Potential to Improve Radar Rainfall Estimates
Authors: Kirsch Bastian , Clemens Marco , Ament Felix 
Published: August 2019

AbstractThe variability of the raindrop size distribution (DSD) contributes to large parts of the uncertainty in radar-based quantitative rainfall estimates. The variety of microphysical processes acting on the formation of rainfall generally leads to significantly different relationships between radar reflectivity Z and rain rate R for stratiform and convective rainfall. High-resolution observation data from three Micro Rain Radars in northern Germany are analyzed to quantify the potential of dual Z–R relationships to improve radar rainfall estimates under idealized rainfall type identification and separation. Stratiform and convective rainfall are separated with two methods, establishing thresholds for the rain rate-dependent mean drop size and the α coefficient of the power-law Z–R relationship. The two types of dual Z–R relationships are tested against a standard Marshall–Palmer relationship and a globally adjusted single relationship. The comparison of DSD-based and reflectivity-derived rain rates shows that the use of stratiform and convective Z–R relationships reduces the estimation error of the 6-month accumulated rainfall between 30% and 50% relative to a single Z–R relationship. Consistent results for neighboring locations are obtained at different rainfall intensity classes. The range of estimation errors narrows by between 20% and 40% for 10-s-integrated rain rates, dependent on rainfall intensity and separation method. The presented technique also considerably reduces the occurrence of extreme underestimations of the true rain rate for heavy rainfall, which is particularly relevant for operational applications and flooding predictions.