bluuebunny/crossref_metadata_2025 huggingface dataset:
Labeling Stem Cells with a New Hybrid Bismuth/Carbon Nanotube Contrast Agent for X-Ray Imaging
Authors: Hernández-Rivera Mayra , Cho Stephen Y. , Moghaddam Sakineh E. , Cheong Benjamin Y. , Cabreira-Hansen Maria da Graça , Willerson James T. , Perin Emerson C. , Wilson Lon J.
Published: June 2019

The poor retention and survival of cells after transplantation to solid tissue represent a major obstacle for the effectiveness of stem cell-based therapies. The ability to track stem cells in vivo can lead to a better understanding of the biodistribution of transplanted cells, in addition to improving the analysis of stem cell therapies’ outcomes. Here, we described the use of a carbon nanotube-based contrast agent (CA) for X-ray computed tomography (CT) imaging as an intracellular CA to label bone marrow-derived mesenchymal stem cells (MSCs). Porcine MSCs were labeled without observed cytotoxicity. The CA consists of a hybrid material containing ultra-short single-walled carbon nanotubes (20–80 nm in length, US-tubes) and Bi(III) oxo-salicylate clusters which contain four Bi3+ ions per cluster (Bi4C). The CA is thus abbreviated as Bi4C@US-tubes.
The Three P’s: Parotid, PD-L1, and Pembrolizumab
Authors: Wiggins Amanda , Arter Zhaohui , Kerns Tamie
Published: June 2019

We present a case of recurrent, platinum-refractory undifferentiated carcinoma of the parotid which was treated with checkpoint inhibitor, Pembrolizumab, and achieved a complete response to therapy. We review the literature of checkpoint inhibitor use in undifferentiated carcinoma of the parotid.
Pathogenic Effects and Potential Regulatory Mechanisms of Tea Polyphenols on Obesity
Authors: Li Zhandong , Liu Yue , Zhao Weihao , Wu Xiuhua , Jiang Xiujuan , Yang Lili , Xing Chaoqun , You Lixin , Song Jiwei , Li Hao
Published: June 2019

Overweight and obesity are major threats to human health. Tea polyphenols exert multiple beneficial effects on human health and may play a positive regulatory role in fat assumption. However, how tea polyphenols contribute to the regulation of fat metabolism remains unclear to date. Small RNA expression profile can be regulated by tea polyphenols in adipocytes. Therefore, tea polyphenols may regulate fat metabolism by controlling small RNA-associated biological processes. In this study, we developed a systematic research platform based on mouse models and performed small RNA sequencing to identify the specific role of small RNAs in the regulatory effect of tea polyphenols on fat metabolism. We compared the expression levels of different small RNA subtypes, including piRNAs and miRNAs, and identified a group of differentially expressed small RNAs in the experimental and control groups. Most of these small RNAs participate in lipid metabolism, suggesting that small RNAs play a significant role in tea polyphenol-associated obesity and related pathogenesis. Furthermore, gene ontology and KEGG pathway enrichment indicated that small RNAs influence the regulatory effects of tea polyphenols on obesity, revealing the potential pathogenic mechanisms for such nutritional disease.
Repairing and Strengthening of Damaged RC Columns Using Thin Concrete Jacketing
Authors: Tayeh Bassam A. , Naja Mohammed Abu , Shihada Samir , Arafa Mohammed
Published: June 2019

This research aims to investigate the efficiency of repairing damaged concrete columns using thin concrete jacketing. The experimental program included casting of nine reference 300 mm long reinforced concrete column specimens: three specimens had a cross‐sectional dimension of 100 mm × 100 mm, three specimens had a cross‐sectional dimension of 150 mm × 150 mm, and three specimens had a cross‐sectional dimension of 170 mm × 170 mm. A total of 36 identical column cores were cast with similar cross sections of 100 mm × 100 mm and a height of 300 mm. These cores were damaged by loading them with approximately 90% of their actual ultimate axial load capacities. Then, the columns were repaired and strengthened by applying two jacketing materials, which were 25 and 35 mm thick, on all four sides. Group 1 consisted of 18 column cores jacketed by normal strength concrete with a maximum aggregate size of 4.75 mm and steel reinforcement, whereas Group 2 consisted of 18 column cores jacketed using ultrahigh‐performance fibre‐reinforced self‐compacting concrete with steel reinforcement. The experimental program showed that the Group 1 specimens had ultimate load capacities more than twice those of the unjacketed reference columns and the same axial capacity as the monolithically cast reference columns. The Group 2 specimens showed a significant increase in ultimate load capacity, which was approximately 3 times that of the unjacketed reference column and 1.86 times that of the monolithically cast reference columns. Moreover, using the shear studs was found to be the most effective among the three surface preparation techniques.
Quick Leukocyte Nucleus Segmentation in Leukocyte Counting
Authors: Wang Yapin , Cao Yiping
Published: June 2019

The leukocyte nucleus quick segmentation is one of the key techniques in leukocyte real-time online scanning of human blood smear. We propose a quick leukocyte nucleus segmentation method based on the component difference in RGB color space. By analyzing the captured microscopic images of the peripheral blood smears from the autoscanning microscope, it is found that the difference values between B component and G component (B−G values) in the regions of the leukocyte nuclei and the platelets are much bigger than those in the other regions, even in the regions including the stains. So, the B−G values can segment the leukocyte nuclei and the platelets with an appropriate empirical threshold because the platelets are much smaller than the leukocyte nuclei, so the leukocyte nuclei can be segmented by size filtering. Also, only an 8 bit subtraction operation is performed for the B−G values, and it can improve the leukocyte nucleus segmentation speed significantly. Experimental results show that the proposed method performs well for the five types of leukocyte segmentation with a quick speed. It is very suitable for the real-time peripheral blood smear autoscanning test application. In addition, the five types of leukocytes can be counted accurately.
Mathematical Global Dynamics and Control Strategies on Echinococcus multilocularis Infection
Authors: Hassan A. S. , Munganga J. M. W.
Published: June 2019

Echinococcus multilocularis, a major cause of echinococcosis in human, is a parasitic sylvatic disease between two major hosts in a predator-prey relation. A new model for the transmission dynamics of Echinococcus multilocularis in the population of red foxes and voles with environment as a source of infection is formulated and rigorously analyzed. The model is used to access the impact of treatment on red foxes and environmental disinfection as control strategies on the disease dynamics. The control reproduction number is computed and is used to rigorously prove the local and global dynamics of models’ equilibria. Using available data on Echinococcus, elasticity indices and partial rank correlation coefficients of control reproduction number and cumulative new cases in red foxes and voles are computed. Parameters that have high influence locally and globally are identified. Numerical experiments indicate that administering disinfection of environment only induces more positive impact than applying treatment only on red foxes in controlling the infection. Generally, interventions towards treating red foxes and environmental disinfection could be sufficient in tackling transmission of disease in the populations.
An Approach of Beans Plant Development Classification Using Fuzzy Logic
Authors: Correa Pedro , Bautista Pedro , Lopez Marlene , Villaseñor Marcos , García Carlos , Rostro-González Horacio , Perez-Pinal Francisco J.
Published: June 2019

In this paper, a method to monitor the growth of bean plants from images taken in their vegetative stage is presented. Through a fuzzy system and the RGB image components, the growth stages of the plant are classified to achieve a powerful tool in the precision agricultural field, which can reduce cost and increase system portability. This also serves as a reference for the growth of the plant according to its age, vigor, and healthy that could help to create the necessary environmental conditions. To carry out this research, the development of twenty bean plants was periodically monitored from their germinal to the first trifoliate leaf stage. Images were obtained with controlled background and lighting; later they were segmented by color to count the pixel’s average for each case. These data were used to propose six different fuzzy systems to choose the best one within them. Finally, it was found that the artificial vision system can identify the vegetative stages of germination, emergence, primary leaves, and first trifoliate leaf.
Long Noncoding RNA Expression Profile in BV2 Microglial Cells Exposed to Lipopolysaccharide
Authors: Li Yajuan , Li Qingmin , Wang Cunjuan , Li Shengde , Yu Lingzhi
Published: June 2019

Neuropathic pain, which is one of the most common forms of chronic pain, seriously increases healthcare costs and impairs patients’ quality of life with an incidence of 7–10% worldwide. Microglia cell activation plays a key role in the progression of neuropathic pain. Better understanding of novel molecules modulating microglia cell activation and these underlying functions will extremely benefit the exploration of new treatment. Recent studies suggested long noncoding RNAs may be involved in neuropathic pain. However, its underlying functions and mechanisms in microglia cell activation remain unclear. To identify the differentially expressed lncRNAs and predict their functions in the progression of microglia cell activation, GSE103156 was analyzed using integrated bioinformatics methods. The expression levels of selected lncRNAs and mRNAs were determined by real-time PCR. In the present study, a total of 56 lncRNAs and 298 mRNAs were significantly differentially expressed. The differentially expressed mRNAs were mainly enriched in NF-kappa B signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, and NOD-like receptor signaling pathway. The top 10 hub genes were Tnf, Il6, Stat1, Cxcl10, Il1b, Tlr2, Irf1, Ccl2, Irf7, and Ccl5 in the PPI network. Our results showed that Gm8989, Gm8979, and AV051173 may be involved in the progression of microglia cell activation. Taken together, our findings suggest that lots of lncRNAs may be involved in BV2 microglia cell activation in vitro. The findings may provide relevant information for the development of promising targets for the microglial cells activation of neuropathic pain in vivo in the future.
Automatic Classification of Microseismic Signals Based on MFCC and GMM‐HMM in Underground Mines
Authors: Peng Pingan , He Zhengxiang , Wang Liguan
Published: June 2019

In order to mitigate economic and safety risks during mine life, a microseismic monitoring system is installed in a number of underground mines. The basic step for successfully analyzing those microseismic data is the correct detection of various event types, especially the rock mass rupture events. The visual scanning process is a time‐consuming task and requires experience. Therefore, here we present a new method for automatic classification of microseismic signals based on the Gaussian Mixture Model‐Hidden Markov Model (GMM‐HMM) by using only Mel‐frequency cepstral coefficient (MFCC) features extracted from the waveform. The detailed implementation of our proposed method is described. The performance of this method is tested by its application to microseismic events selected from the Dongguashan Copper Mine (China). A dataset that contains a representative set of different microseismic events including rock mass rupture, blasting vibration, mechanical drilling, and electromagnetic noise is collected for training and testing. The results show that our proposed method obtains an accuracy of 92.46%, which demonstrates the effectiveness of the method for automatic classification of microseismic data in underground mines.
Effects of Low-Frequency Pulsed Electromagnetic Fields on High-Altitude Stress Ulcer Healing in Rats
Authors: Jiao Mingke , Yin Hong , Hu Jie , Xu Wenjuan , Zhang Xiao , Zhang Peng
Published: June 2019

High-altitude stress ulcer (HSU) has constantly been a formidable clinical challenge for high-altitude and severe hypoxia. Pulsed electromagnetic fields (PEMFs) have been verified to have the ability to penetrate tissues, and the biological effects have been confirmed effective on various tissue restorations. However, the therapeutic effect of PEMFs on HSU has been rarely reported. This study aimed to evaluate the effects of PEMFs on HSU healing systematically. Sprague–Dawley rats were assigned to control, HSU, and HSU+PEMF groups. The HSU models were induced by restraint stress under low-pressure hypoxia. The HSU+PEMF group was subjected to PEMF exposure. During the HSU healing, gastric juice pH values, ulcer index (UI), and histopathologic changes were investigated. Furthermore, tumor necrosis factor-α (TNF-α) was determined to analyze the severity of gastric membrane inflammations. Norepinephrine (NE), which influences gastric acid secretion, was measured. Results indicated the UI of the HSU+PEMF decreased faster than that of the HSU group. Histopathologic observation suggested that the ulcer tissue healing is faster in the HSU+PEMF group than in the HSU group. The TNF-α/total protein results revealed that the inflammation of the HSU+PEMF group is suppressed effectively. The pH values are higher in the HSU+PEMF group than in the HSU, as confirmed by NE examination. The results indicated that low-frequency PEMFs can penetrate stomach tissues to relieve the symptoms of HSU and promote the regeneration of disturbed tissues, thus implying the clinical potential of PEMF therapy for HSU treatment.
Intra-Arrest Administration of Cyclosporine and Methylprednisolone Does Not Reduce Postarrest Myocardial Dysfunction
Authors: Chonde Meshe , Flickinger Katharyn L. , Sundermann Matthew L. , Koller Allison C. , Salcido David D. , Dezfulian Cameron , Menegazzi James J. , Elmer Jonathan
Published: June 2019

Objective. To determine whether the administration of intra-arrest cyclosporine (CCY) and methylprednisolone (MP) preserves left ventricular ejection fraction (LVEF) and cardiac output (CO) after return of spontaneous circulation (ROSC). Methods. Eleven, 25-30kg female swine were randomized to receive 10mg/kg CCY + 40mg MP or placebo, anesthetized and given a transthoracic shock to induce ventricular fibrillation. After 8 minutes, standard CPR was started. After two additional minutes, the experimental agent was administered. Animals with ROSC were supported for up to 12h with norepinephrine as needed. Echocardiography was performed at baseline, and 1, 2, 6 and 12h post-ROSC. Analysis was performed using generalized estimating equations (GEE) after downsampling continuously sampled data to 5 minute epochs. Results. Eight animals (64%) achieved ROSC after a median of 7 [IQR 5-13] min of CPR, 2 [ IQR 1-3] doses of epinephrine and 2 [IQR 1-5] defibrillation shocks. Animals receiving CCY+MP had higher post ROSC MAP (GEE coefficient -10.2, P = <0.01), but reduced cardiac output (GEE coefficient 0.8, P = <0.01) compared to placebo. There was no difference in LVEF or vasopressor use between arms. Conclusions. Intra-arrest cyclosporine and methylprednisolone decreased post-arrest cardiac output and increased mean arterial pressure without affecting left ventricular ejection fraction.
Pose Determination for Malfunctioned Satellites Based on Depth Information
Authors: Yu Feng , Zhao Yi , Zhang Yanhua
Published: June 2019

Autonomous on-orbit servicing is the future space activity which can be utilized to extend the satellite life. Relative pose estimation for a malfunctioned satellite is one of the key technologies to achieve robotic on-orbit servicing. In this paper, a relative pose determination method by using point cloud is presented for the final phase of the rendezvous and docking of malfunctioned satellites. The method consists of three parts: (1) planes are extracted from point cloud by utilizing the random sample consensus algorithm. (2) The eigenvector matrix and the diagonal eigenvalue matrix are calculated by decomposing the point cloud distribution matrix of the extracted plane. The eigenvalues are utilized to recognize rectangular planes, and the eigenvector matrix is the attitude rotation matrix from the sensor to the plane. The solution of multisolution problem is also presented. (3) An extended Kalman filter is designed to estimate the translational states, the rotational states, the location of mass center, and the moment-of-inertia ratios. Because the method only utilizes the local features without observing the whole satellite, it is suitable for the final phase of rendezvous and docking. The algorithm is validated by a series of mathematical simulations.
A Framework to Assess the Seismic Resilience of Urban Hospitals
Authors: Yu Peng , Wen Weiping , Ji Duofa , Zhai Changhai , Xie Lili
Published: June 2019

The phenomenon of hospital functional interruption has been widely observed in the historical moderate‐strong earthquakes, indicating that hospital functionality cannot be well considered in the current seismic design methods. The concept of seismic resilience pays enough attention to postearthquake functionality of buildings, and it is particularly significant for the urban hospitals which play critical role in the urban postearthquake rescue and recovery. This study proposes a framework to assess the seismic resilience of urban hospitals, by incorporating the fault tree analysis (FTA) to consider the interdependency between the damage of nonstructural components and the functionality of medical equipment, as well as the effect of external supplies on the functionality of hospital. The proposed framework is then applied to a case‐study hospital, and the results indicate that this hospital needs 1.1 days to resume emergency functionality under REDi repair strategy after design basis earthquake (DBE), while it needs 28.8 days to resume emergency functionality under REDi repair strategy after maximum considered earthquake (MCE). It is found that the seismic resilience of this hospital after MCE cannot meet the community requirements on the recovery time, and necessary measures are needed to improve the seismic resilience. The proposed framework provides the quantitative results of seismic resilience assessment in the preearthquake environment and can further support emergency response planning and seismic retrofits strategies.
Molecular and Clinical Profiles of Human Pegivirus Type 1 Infection in Individuals Living with HIV-1 in the Extreme South of Brazil
Authors: Mota Luísa D. Da , Finger-Jardim Fabiana , Silva Cláudio M. , Germano Fabiana N. , Nader Maiba M. , Gonçalves Carla V. , Luquez Karen Y. Sánchez , Chies José A. B. , Groll Andrea V. , Hora Vanusa P. Da , Silveira Jussara , Basso Rossana P. , Soares Marcelo A. , Martínez Ana M. B.
Published: June 2019

Human pegivirus type 1 (HPgV-1) infection has been associated with a beneficial effect on the prognosis of human immunodeficiency virus type 1 (HIV-1)-coinfected individuals. However, the mechanisms involved in this protection are not yet fully elucidated. To date, circulating HPgV-1 genotypes in HIV-1-infected individuals have not yet been identified in the extreme south of Brazil. The present study aimed to determine the genotypic circulation of HPgV-1 and the influence of HPgV-1 status and persistence time on the evolution of HIV-1 infection. A retrospective cohort of 110 coinfected individuals was analyzed. Samples were subjected to viral RNA extraction, cDNA synthesis, nested PCR, and genotyping. Genotypes 1 (2.8%), 2 (47.9% of subtype 2a and 42.3% of subtype 2b), and 3 (7%) were identified. In antiretroviral treatment-naïve subjects HPgV-1 subtype 2b was associated with lower HIV-1 viral load (VL) rates (p= 0.04) and higher CD4+ T-cell counts (p= 0.03) than was subtype 2a, and the positivity for HPgV-1 was associated with higher CD4+ T-cell counts (p= 0.02). However, there was no significant difference in HIV-1 VL between HPgV-1-positive and HPgV-1-negative subjects ​​(p= 0.08). There was no significant association between the different groups in HPgV-1 persistence and median HIV-1 VL (p= 0.66) or CD4+ T-cell counts (p= 0.15). HPgV-1 subtype 2b is associated with better prognosis of HIV-1 infection. Although HPgV-1 infection is persistent, our data suggest that the time of infection does not influence HIV-1 VL or CD4+ T-cell counts in coinfected subjects.
RMMDI: A Novel Framework for Role Mining Based on the Multi-Domain Information
Authors: Bai Wei , Pan Zhisong , Guo Shize , Chen Zhe
Published: June 2019

Role-based access control (RBAC) is widely adopted in network security management, and role mining technology has been extensively used to automatically generate user roles from datasets in a bottom-up way. However, almost all role mining methods discover the user roles from existing user-permission assignments, which neglect the dependency relationships between user permissions. To extend the ability of role mining technology, this paper proposes a novel role mining framework based on multi-domain information. The framework estimates the similarity between different permissions based on the fundamental information in the physical, network, and digital domains and attaches interdependent permissions to the same role. Three simulated network scenarios with different multi-domain configurations are used to validate the effectiveness of our method. The experimental results show that the method can not only capture the interdependent relationships between permissions, but also detect user roles and permissions more reasonably.
ABO-Incompatible Adult Living Donor Liver Transplantation in the Era of Rituximab: A Systematic Review and Meta-Analysis
Authors: Yadav Dipesh Kumar , Hua Yong Fei , Bai Xueli , Lou Jianying , Que Risheng , Gao Shunling , Zhang Yun , Wang Ji , Xie Qinfen , Edoo Muhammad Ibrahim Alhadi , Chutturghoon Vikram Kumar , Liang Tingbo
Published: June 2019

Aim. The primary aim of this study is to compare the short- and long-term outcomes between ABO-incompatible (ABOi) adult living donor liver transplantation (ALDLT) with rituximab prophylaxis and ABO-compatible (ABOc) ALDLT. Background. The strategy of ABOi liver transplantation (LT) was originated initially to increase the donor pool and to enable liver transplantation in emergency conditions. However, ABOi ALDLT remains a controversial approach in comparison to ABOc ALDLT. Methods. PubMed, Embase, and the Cochrane Library study search were accomplished to recognize studies comparing ABOi and ABOc ALDLT. Meta-analyses were conducted based on the evaluation of heterogeneity using a fixed-effect model and a random-effect model to assess the short- and long-term outcomes following ABOi ALDLT with rituximab prophylaxis. Results. Nine studies comprising a total of 3,922 patients (ABOi=671 and ABOc=3,251) were identified. There was no significant difference between ABOi and ABOc groups for 1-year, 3-year, and 5-year OS and graft survival, respectively. Moreover, 1-year and 3-year OS and DFS were similar between both groups for HCC patients. However, ABOi ALDLT had higher incidences of CMV infection, AMR, overall biliary complications, and biliary stricture than ABOc ALDLT and had other comparable postoperative complications. Conclusion. Our meta-analysis included studies comparing ABOi and ABOc ALDLT after the introduction of rituximab in a desensitization protocol for ABOi ALDLT. The results of ABOi ALDLT were comparable with those of ABOc ALDLT. However, biliary complications, CMV infection, and AMR remain a concern in the era of rituximab.
The Possible Pathogenesis of Idiopathic Pulmonary Fibrosis consideringMUC5B
Authors: Zhang Qinghua , Wang Yan , Qu Danhua , Yu Jinyan , Yang Junling
Published: June 2019

Background.Overexpression of the MUC5B protein is associated with idiopathic pulmonary fibrosis (IPF), but little information is available regarding the pathogenic effects and regulatory mechanisms of overexpressed MUC5B in IPF.Main Body.The overexpression of MUC5B in terminal bronchi and honeycomb cysts produces mucosal host defensive dysfunction in the distal airway which may play an important role in the development of IPF. This review addresses the possible association of overexpression ofMUC5B, withMUC5Bpromoter polymorphism,MUC5Bgene epigenetic changes, effects of some transcriptional factors, and inflammatory mediators in IPF. In addition, the associated signaling pathways which may influence the expression ofMUC5Bare also discussed.Conclusion.This work has important implications for further exploration of the mechanisms of overexpression of MUC5B in IPF, and future personalized treatment.
Design and Outcomes of a Community Trial to Increase Pap Testing in Pacific Islander Women
Authors: Tanjasiri Sora Park , Mouttapa Michele , Sablan-Santos Lola , Weiss Jie W. , Chavarria Alisa , Lacsamana Jasmine DeGuzman , May Vanessa Tuiòne , Quitugua Lourdes , Tupua Marina , Schmidt-Vaivao Dorothy
Published: June 2019

Background:

Pap tests remain an essential cervical cancer detection method in the United States, yet they are underutilized among Pacific Islanders (PI) who experience elevated cervical cancer incidence and mortality. This study describes the design, methods, participants, and outcomes of a multiyear (2010–2016), community-based randomized intervention trial in southern California. Based upon strong collectivistic norms, the trial tested the efficacy of a unique social support intervention targeting Chamorro, Samoan, and Tongan women and their male husbands/partners.

Methods:

A single-session educational intervention was designed and tailored for ethnic- and gender-specific groups to increase men's social support for their female wives/partners to receive a Pap test, and for women to receive a Pap test. The comparison group received preexisting brochures on Pap testing (for women) or general men's health (for men). Pretest and 6-month follow-up data were analyzed.

Results:

Intervention and comparison groups were mostly equivalent on pretest demographics and outcome variables. Intervention women who were not compliant with Pap screening recommendations at pretest were significantly more likely to have scheduled and received a Pap test at 6-month follow-up. However, 6-month follow-up results indicated no intervention effect on changes in women's Pap testing knowledge, fatalistic attitudes, or perceived social support from their male partner.

Conclusions:

Ethnic- and gender-tailored community interventions can successfully increase Pap test behaviors for PI women, although more research is needed on the specific pathways leading to behavior change.

Impact:

Collaborative community-based interventions lead to increases in women's cancer prevention and early detection for Pacific Islander and other collectivistic communities.
A Phase I Trial of the VEGF Receptor Tyrosine Kinase Inhibitor Pazopanib in Combination with the MEK Inhibitor Trametinib in Advanced Solid Tumors and Differentiated Thyroid Cancers
Authors: Kurzrock Razelle , Ball Douglas W. , Zahurak Marianna L. , Nelkin Barry D. , Subbiah Vivek , Ahmed Shabina , O'Connor Ashley , Karunsena Enusha , Parkinson Rose M. , Bishop Justin A. , Ha Yoonji , Sharma Rajni , Gocke Christopher D. , Zinner Ralph , Rudek Michelle A. , Sherman Steven I. , Azad Nilofer S.
Published: June 2019

Purpose:

Differentiated thyroid cancer (DTC) responds to VEGF receptor inhibitors. VEGF signals through RAS/RAF/MEK signaling. We evaluated the safety and efficacy of the VEGF receptor inhibitor pazopanib and MEK inhibitor trametinib in advanced solid tumors and DTC.

Patients and Methods:

Patients with advanced solid tumors were enrolled in a phase I, multicenter trial with a DTC expansion cohort. Patients received pazopanib 400–800 mg and trametinib 1–2 mg daily. Efficacy in the expansion cohort was assessed with objective response (OR) at 6 months of treatment.

Results:

Twenty-six patients were enrolled in five dose levels. MTD was not reached; the recommended phase II dose was pazopanib 800 mg orally and trametinib 2 mg orally every day. There was one dose-limiting toxicity on dose level 1 with grade 3 fatigue and muscle weakness. Common grade 3 adverse events were elevated transaminases (19%), diarrhea (15%), hypertension (12%), and fatigue (8%). Thirteen patients were enrolled in the DTC cohort; OR was 33% (95% confidence interval, 9.9, 65.1%) and median progression-free survival was 10.7 months. The cohort was terminated after planned interim analysis suggested insufficiently increased activity against the historical control of pazopanib alone. Reduction in tumor diameter negatively correlated with p-ERK change in tumor (Spearman ρ = −0.71; P = 0.05). NRAS mutation was associated with response (Fisher exact P = 0.008).

Conclusions:

Pazopanib + trametinib was tolerable at full single-agent doses with clinical activity in DTC but did not achieve the prespecified response rate target.
Dissecting the Stromal Signaling and Regulation of Myeloid Cells and Memory Effector T Cells in Pancreatic Cancer
Authors: Blair Alex B. , Kim Victoria M. , Muth Stephen T. , Saung May Tun , Lokker Nathalie , Blouw Barbara , Armstrong Todd D. , Jaffee Elizabeth M. , Tsujikawa Takahiro , Coussens Lisa M. , He Jin , Burkhart Richard A. , Wolfgang Christopher L. , Zheng Lei
Published: June 2019

Purpose:

Myeloid cells are a prominent immunosuppressive component within the stroma of pancreatic ductal adenocarcinoma (PDAC). Previously, targeting myeloid cells has had limited success. Here, we sought to target the myeloid cells through modifying a specific stromal component.

Experimental Design:

A murine model of metastatic PDAC treated with an irradiated whole-cell PDAC vaccine and PDAC specimens from patients treated with the same type of vaccine were used to assess the immune-modulating effect of stromal hyaluronan (HA) degradation by PEGPH20.

Results:

Targeting stroma by degrading HA with PEGPH20 in combination with vaccine decreases CXCL12/CXCR4/CCR7 immunosuppressive signaling axis expression in cancer-associated fibroblasts, myeloid, and CD8+ T cells, respectively. This corresponds with increased CCR7− effector memory T-cell infiltration, an increase in tumor-specific IFNγ, and improved survival. In the stroma of human PDACs treated with the same vaccine, decreased stromal CXCR4 expression significantly correlated with decreased HA and increased cytotoxic activities, suggesting CXCR4 is an important therapeutic target.

Conclusions:

This study represents the first to dissect signaling cascades following PDAC stroma remodeling via HA depletion, suggesting this not only overcomes a physical barrier for immune cell trafficking, but alters myeloid function leading to downstream selective increases in effector memory T-cell infiltration and antitumor activity.
Identification of Targetable Recurrent MAP3K8 Rearrangements in Melanomas Lacking Known Driver Mutations
Authors: Lehmann Brian D. , Shaver Timothy M. , Johnson Douglas B. , Li Zhu , Gonzalez-Ericsson Paula I. , Sánchez Violeta , Shyr Yu , Sanders Melinda E. , Pietenpol Jennifer A.
Published: June 2019

Melanomas are characterized by driver and loss-of-function mutations that promote mitogen-activated protein kinase (MAPK) signaling. MEK inhibitors are approved for use in BRAF-mutated melanoma; however, early-phase clinical trials show occasional responses in driver-negative melanoma, suggesting other alterations conferring MAPK/ERK dependency. To identify additional structural alterations in melanoma, we evaluated RNA-Seq from a set of known MAPK/ERK regulators using a novel population-based algorithm in The Cancer Genome Atlas (TCGA). We identified recurrent MAP3K8 rearrangements in 1.7% of melanomas in TCGA, occurring in more than 15% of tumors without known driver mutations (BRAF, NRAS, KIT, GNAQ, GNA11, and NF1). Using an independent tumor set, we validated a similar rearrangement frequency by FISH. MAP3K8-rearranged melanomas exhibit a low mutational burden and absence of typical UV-mutational patterns. We identified two melanoma cell lines that harbor endogenous truncating MAP3K8 rearrangements that demonstrate exquisite dependency. Rearrangement and amplification of the MAP3K8 locus in melanoma cells result in increased levels of a truncated, active MAP3K8 protein; oncogenic dependency on the aberrant MAP3K8; and a concomitant resistance to BRAF inhibition and sensitivity to MEK or ERK1/2 inhibition. Our findings reveal and biochemically characterize targetable oncogenic MAP3K8 truncating rearrangements in driver mutation–negative melanoma, and provide insight to therapeutic approaches for patients with these tumors. These data provide rationale for using MEK or ERK inhibitors in a subset of driver-negative, MAPK/ERK–dependent melanomas harboring truncating MAP3K8 rearrangements.

Implications:

This is the first mechanistic study and therapeutic implications of truncating MAP3K8 rearrangements in driver-negative melanoma.
β-Catenin Activation Promotes Immune Escape and Resistance to Anti–PD-1 Therapy in Hepatocellular Carcinoma
Authors: Ruiz de Galarreta Marina , Bresnahan Erin , Molina-Sánchez Pedro , Lindblad Katherine E. , Maier Barbara , Sia Daniela , Puigvehi Marc , Miguela Verónica , Casanova-Acebes María , Dhainaut Maxime , Villacorta-Martin Carlos , Singhi Aatur D. , Moghe Akshata , von Felden Johann , Tal Grinspan Lauren , Wang Shuang , Kamphorst Alice O. , Monga Satdarshan P. , Brown Brian D. , Villanueva Augusto , Llovet Josep M. , Merad Miriam , Lujambio Amaia
Published: June 2019

PD-1 immune checkpoint inhibitors have produced encouraging results in patients with hepatocellular carcinoma (HCC). However, what determines resistance to anti–PD-1 therapies is unclear. We created a novel genetically engineered mouse model of HCC that enables interrogation of how different genetic alterations affect immune surveillance and response to immunotherapies. Expression of exogenous antigens in MYC;Trp53−/− HCCs led to T cell–mediated immune surveillance, which was accompanied by decreased tumor formation and increased survival. Some antigen-expressing MYC;Trp53−/− HCCs escaped the immune system by upregulating the β-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in MYC;CTNNB1 HCCs had no effect, demonstrating that β-catenin promoted immune escape, which involved defective recruitment of dendritic cells and consequently impaired T-cell activity. Expression of chemokine CCL5 in antigen-expressing MYC;CTNNB1 HCCs restored immune surveillance. Finally, β-catenin–driven tumors were resistant to anti–PD-1. In summary, β-catenin activation promotes immune escape and resistance to anti–PD-1 and could represent a novel biomarker for HCC patient exclusion.

Significance:

Determinants of response to anti–PD-1 immunotherapies in HCC are poorly understood. Using a novel mouse model of HCC, we show that β-catenin activation promotes immune evasion and resistance to anti–PD-1 therapy and could potentially represent a novel biomarker for HCC patient exclusion.

See related commentary by Berraondo et al., p. 1003.

This article is highlighted in the In This Issue feature, p. 983
Normative Features of Phoneme Acquisition in Brazilian Portuguese
Authors: Ilha Ceron Marizete , Barichello Gubiani Marileda , Rosa de Oliveira Camila , Keske-Soares Márcia
Published: June 2019

Purpose: To analyze the influence of gender, age, and types of school (public or private) on phoneme production, and provide normative data on phonological acquisition in Brazilian Portuguese (BP). Patients and Methods: The sample consisted of 733 children (ages 3 years to 8 years and 11 months), all monolingual speakers of BP with typical phonological development. Participants were evaluated using the spontaneous naming task from the Phonological Assessment Tool (Instrumento de Avaliação Fonológica – INFONO). The children’s speech production was audio-recorded, transcribed, and submitted to phonological analysis. Results: The effect of age was significant for all phonemes and syllable structures, especially when analyzed in combination with types of school and gender. Overall, phoneme production accuracy increased with age and varied depending on the types of school attended by the children, but did not differ between genders. Conclusion: Age had a greater impact on phoneme production. The normative data on phonological acquisition highlighted the differences between the ages of mastery for different phonemes, with elements such as the /r/ sound and complex onsets being acquired much later in development than some of the other phonemes analyzed.
Height Gain and Safety Outcomes in Growth Hormone-Treated Children with Idiopathic Short Stature: Experience from a Prospective Observational Study
Authors: Child Christopher J. , Quigley Charmian A. , Cutler, Jr Gordon B. , Moore Wayne V. , Wintergerst Kupper A. , Ross Judith L. , Rosenfeld Ron G. , Blum Werner F.
Published: June 2019

Background/Objectives: Growth hormone (GH) treatment of idiopathic short stature (ISS) received US Food and Drug Administration approval in 2003. We assessed height gain and safety in 2,450 children with ISS treated with GH in US clinical practice. Methods: Short-term height gain, near-adult height (NAH), and safety outcomes were investigated using Genetics and Neuroendocrinology of Short Stature International Study data. Results: Compared to children with isolated idiopathic GH deficiency (IGHD), those with ISS were shorter at baseline but had similar age and GH dose. Mean ± SD height SD score (SDS) increase was similar for ISS and IGHD, with 0.6 ± 0.3 (first), 0.4 ± 0.3 (second), 0.3 ± 0.3 (third), and 0.1 ± 0.3 (fourth year) for ISS. Girls with ISS (27% of subjects) were younger and shorter than boys but had similar height gain over time. At NAH in the ISS group (n = 467), mean ± SD age, GH duration, and height SDS were 17.3 ± 2.3 years, 4.6 ± 2.7 years, and –1.2 ± 0.9, respectively. Height gain from baseline was 1.1 ± 1.0 SDS and was greater for boys than girls (1.2 ± 1.0 vs. 0.9 ± 0.9), but boys were treated longer (5.1 ± 2.8 vs. 3.6 ± 2.5 years). Adverse events were reported for 24% with ISS versus 20% with IGHD – most were common childhood conditions or previously reported in GH-treated patients. Conclusions: GH-treated children with ISS achieved substantial height gain, similar to patients with IGHD. Fewer GH-treated girls were enrolled than boys, but with similar height SDS gain over time. No ISS-specific safety issues were identified. Thus, GH treatment of ISS appears to have a safety/effectiveness profile similar to that of IGHD.
Multimorbidity and Disease Severity by Age Groups, in Inpatients: Cross-Sectional Study
Authors: Broeiro-Gonçalves Paula , Nogueira Paulo , Aguiar Pedro
Published: June 2019

Introduction: Multimorbidity (MM) by age groups curves behaviour and its relationship with disease severity are not well established. Considering the Charlson Index as a prognosis instrument to measure disease severity, the objectives were to characterise the MM and its severity through the Charlson index in Portuguese inpatients. Methods: A cross-sectional, descriptive study with an analytical component was drawn through data exported from the hospitalisations Homogeneous Diagnostic Groups database of the Portuguese-NHS during the year 2015. The study included 22 chronic health conditions: the 15 predicted in the Charlson index and 7 more (hypertension, obesity, dyslipidaemia, osteoarthritis, osteoporosis, anxiety and depression). The bi and multivariable analyses were performed through the generalised linear model considering binary logistic regression. In the analysis, the IBM SPSS version 24.0 tool was used. Results: A total of 800,376 hospitalisations were analysed, from which 42% (336,398) corresponds to males and 58% (463,978) to females. The average age of the sample was 59.8 years, being higher in men (62.34 years) than in women (57.95 years). The mean number of diagnostics per person was 1.6, being greater in men (1.8). Disease severity was also higher in males. The greatest disease severity (Charlson >5) occurred at middle-aged (between 55 and 74 years). Throughout life behaviour of the average number of conditions and the average Charlson index without adjustment for age is similar. By the weight attributed to age, the Charlson index age-adjusted shows a sharper tendency of elevation after the forty years. The distribution by age groups of the age-adjusted Charlson index, categorised according to the cut-offs defined in the methodology (cut-off 0 to <5; cut-off 5 to <9; cut-off ≥9), showed an abrupt growth for the cut-off ≥9 at 55/59 years, peaking at 75/79 years, while for cut-off 5 at <9 the most marked growth occurs at 65/69 and the peak about 5 years later than for the cut-off ≥9. After the 90 years old all measures averages (MM and severity disease) suffer a decline. Discussion: The results suggest that the greatest disease severity are male associated and occurred at middle ages. There was an association between any MM measure and the Charlson index. The MM curves behaviour showed a decline in nonagenary age, suggesting healthy people live longer. Questioned if the MM and its severity is not a middle age health issue. As limitations, we identified its cross-sectional design and the omission of socioeconomic information and the use of the same medical conditions to measure MM and disease severity. Other studies and analysis models should explore the complexity of the MM phenomenon and its impact on long life.
A Global Evolutionary Trend of the Frequency of Primary Glomerulonephritis over the Past Four Decades
Authors: Woo Keng Thye , Chan Choong Meng , Lim Cynthia , Choo Jason , Chin Yok Mooi , Teng Esther Wei Ling , Mok Irene , Kwek Jia Liang , Loh Alwin H.L. , Choong Hui Lin , Tan Han Kim , Lee Grace S.L. , Lee Evan , Wong Kok Seng , Tan Puay Hoon , Foo Marjorie
Published: June 2019

Objective: The pattern of glomerulonephritis (GN) in Singapore is compared with that of 19 other countries to review changing trends in the evolution of GN in Asian, Eastern, and Western countries. Method: Three thousand two hundred and eighty-nine renal biopsies in Singapore were reviewed and compared with that of 19 other countries. Results: IgA nephritis is on the decline in many countries, including Singapore, though it still remains the commonest GN in Singapore. Membranous GN that if used to be more frequently present in Western countries has also declined though it continues a rising trend in countries such as Singapore and China. Worldwide, the frequency of focal sclerosing glomerulosclerosis (FSGS) continues to increase in many countries, but in some countries, the frequency is still low with mesangiocapillary GN remaining indigenous. Conclusion: Urbanization and socioeconomic changes and less exposure to parasitic and other infestations have transformed Singapore’s pattern, which is tending toward that of more developed countries. Antigenic exposure due to lifestyle changes, environmental, and industrial pollution are significant contributory factors that affect the evolutionary trend of GN in many countries. The rising trend in the frequency of FSGS may reflect aging and obesity.
Lack of an Association between a Polymorphism in the KRAS 3′ Untranslated Region (rs61764370) and Endometriosis in a Large European Case-Control Study
Authors: D’Hooghe Thomas M. , Grechukhina Olga , Cho SiHyun , Fassbender Amelie , O Dorien , Peterse Daniëlle , Weidhaas Joanne , Taylor Hugh S.
Published: June 2019

Background: Endometriosis is a common disorder that affects 6–10% of reproductive age women. In a previous study, we demonstrated that a polymorphism in let-7 microRNA-binding site in the 3' untranslated region of the KRAS gene was found in 31% of subjects with endometriosis resistant to medical therapy. This polymorphism was now tested in a large, case-control study. Methods: Peripheral blood or peritoneal biopsies from 2,077 European subjects with or without endometriosis and known infertility were tested for the presence of the variant allele using polymerase chain reaction. Results: Histologically proven endometriosis was found in 1,140 subjects, while 937 subjects were disease free. Variant allele carrier rates in subjects with and without endometriosis were 15.7 and 15.1%, respectively. No association between the variant KRAS allele and stage of the disease, age at surgery, body mass index, or type of infertility was identified. Conclusion: A germ-line single-nucleotide polymorphism in the let-7 microRNA-binding site of the KRAS gene was not associated with sporadic endometriosis in an infertile Caucasian population in this large case-control study. However, it remains possible that this gene variant may be a marker of treatment resistance. Further studies on the role of this polymorphism in endometriosis are needed.
Insulin Suppresses Type 1 Diabetes Mellitus-Induced Ventricular Cardiomyocyte Damage Associated with the Inhibition of Biomarkers of Inflammation and Oxidative Stress in Rats
Authors: Dallak Mohammad , Al-Ani Bahjat , Abdel Kader Dina H. , Eid Refaat A. , Haidara Mohamed A.
Published: June 2019

Aims: We sought to determine whether insulin can protect against type 1 diabetes mellitus (T1DM)-induced cardiac ultrastructural alterations in an animal model of the disease. This has not been investigated before. Methods: Rats were either injected once with 65 mg/kg streptozotocin (STZ) before being sacrificed after 8 weeks or were treated with a daily injection of insulin 2 days by STZ and continued until being sacrificed. Results: Harvested tissues obtained from left ventricles in the untreated T1DM rats showed substantial damage to the cardiomyocyte ultrastructure as demonstrated by disintegrated myofibrils and their sarcomeres, damaged mitochondria and lipid droplets, which was substantially protected by insulin. Insulin also significantly inhibited T1DM-induced hyperglycemia (p < 0.001), dyslipidemia (p < 0.0001), malondialdehyde (MDA; p < 0.0001), tumor necrosis factor-alpha (TNF-α; p < 0.001) and interleukin-6 (p < 0.001). We further demonstrated a significant (p ≤ 0.001) correlation between either sarcomere or mitochondrial injury scoring and the serum levels of glucose, dyslipidemia, and biomarkers of oxidative stress (OxS) and inflammation. Conclusions: These results indicate that insulin effectively suppresses left ventricular cardiomyocyte ultrastructural damage, which substantially slows down the progression of diabetic cardiomyopathy for 8 weeks in a rat model of T1DM, possibly due to the glycemic control and inhibition of dyslipidemia, OxS and inflammation.