bluuebunny/crossref_metadata_2025 huggingface dataset:
The Synthesis and Application of Nitrogen-Doped Graphene Quantum Dots on Brilliant Blue Detection
Authors: Jin Li , Wang Ying , Yan Fengkai , Zhang Jianpo , Zhong Fangli
Published: May 2019

Nitrogen-doped graphene quantum dots had been successfully synthesized and characterized by using transmission electron microscope, X-ray photoelectron spectroscopy, absorbance spectrum, fluorescence emission spectrum, and fluorescence decay curve. TEM results indicated that the diameters of the as-prepared nitrogen-doped graphene quantum dots were in the range of 2 - 5 nm and the lattice space is about 0.276 nm; Raman spectrum result indicated that there were two characteristic peaks, generally named D (~1408 cm−1) and G (~1640 cm−1) bands; both TEM and Raman spectrum results indicated that the as-synthesized product was graphene quantum dots. Deconvoluted high resolution XPS spectra for C1s, O1s, and N1s results indicated that there are -NH-, -COOH, and -OH groups on the surface of nitrogen-doped graphene quantum dot. Fluorescence emission spectrum indicated that the maximum fluorescence emission spectrum of nitrogen-doped graphene quantum dots was blue shift about 30.1 nm and the average fluorescence decay time of nitrogen-doped graphene quantum dots increased about 2 ns, compared with graphene quantum dots without doping of nitrogen. Then, the as-prepared nitrogen-doped graphene quantum dots were used to quantitatively analyze brilliant blue based on the fluorescent quenching of graphene quantum dots, and the effect of pH and reaction time on this fluorescent quenching system was also obtained. Under selected condition, the linear regression equations were F0/F=0.0087 (brilliant blue) + 0.9553 and F0/F=0.01205 (brilliant blue) + 0.6695, and low detection limit was 3.776 μmol/L (3.776 nmol/mL). Once more diluted N-GQDs (0.05 mg/mL) were used, the low detection limit could reach 94.87 nmol/L. Then, temperature-dependent experiment, absorbance spectra, and dynamic fluorescence quenching rate constant were used to study the quenching mechanism; all results indicated that this quenching process was a static quenching process based on the formation of complex between nitrogen-doped graphene quantum dots and brilliant blue through hydrogen bond. Particularly, this method was used to quantitatively analyze the wine sample, of which results have a high consistence with the results of the spectrophotometric method; demonstrating this fluorescence quenching method could be used in practical sample application.
Does Adjuvant Treatment with Chinese Herbal Medicine to Antidiabetic Agents Have Additional Benefits in Patients with Type 2 Diabetes? A System Review and Meta-Analysis of Randomized Controlled Trials
Authors: Jin De , Tian Jiaxing , Bao Qi , Zhang Haiyu , Ding Qiyou , Lian Fengmei , Xiao-lin Tong
Published: May 2019

Introduction. In the present meta-analysis, we aimed to determine the effects of adjuvant treatment with Chinese herbal medicine (CHM) on antidiabetic agents having additional benefits in patients with type 2 diabetes. Methods. Randomized controlled trials were identified by searching the Cochrane Library, PUBMED, EMBASE, MEDLINE, the China National Knowledge Internet, Web of Science, Global Health, International Pharmaceutical Abstracts and the China biology medicine, Wanfang, and VIP databases. The intervention group received CHM as add-on treatment to antidiabetic agents therapy, and the control group received placebos in addition to antidiabetic agents or antidiabetic agents alone. We assessed pooled data, including weighted mean differences and 95% confidence intervals (CIs) using a random-effects model. Results. A total of 125 randomized controlled trials were included. 10 articles were included based on literature screening. All trials contrasted Chinese herbal medicines or Chinese herbal medicines + antidiabetic agents with placebo or antidiabetic agents + placebo and included a total of 2004 individuals with T2DM. All selected trials displayed evidence of high methodological quality and possessed a low risk of bias. Meta-analysis of the trials demonstrated that Chinese herbal medicines resulted in a more favorable blood glucose profile in contrast to placebo (P<0.05). The total efficacy rate differed significantly between the two groups (P<0.001). All ten included studies reported the occurrence of tolerable adverse effects. Conclusions. The results showed that in the intervention group, greater reductions were achieved for glucose control and body weight. The combined use of drugs improves the curative effect and has fewer adverse events and has additional benefits in patients with type 2 diabetes. This trial is registered with PROSPERO (CRD42018093867).
Threshold Values of Myopic Anisometropia Causing Loss of Stereopsis
Authors: Gawęcki Maciej
Published: May 2019

Purpose. The aim of the study was to determine the threshold values of myopic anisometropia that lead to the loss of stereoacuity in most of patients.Materials and Methods. Forty healthy subjects were included in the study. The inclusion criteria were as follows: lack of any functional or morphological ophthalmological disorders, or detectable damage to the visual system, anisometropia equal or less than 0.25 D in a spherical equivalent, and full stereoscopic vision for near and for distance. Myopic anisometropia was evoked by placing different focusing lenses in front of the right eye of the subject in the trial frame. Stereoscopic vision was assessed with the use of the Titmus test (dots) (Stereo Fly Test Stereo Optical Co. Inc.) for near and the Randot test for distance (Distance Randot Stereotest Stereo Optical Co. Inc.).Results. The threshold values for different types of myopic anisometropia for the loss of stereopsis in more than 50% of patients were determined. For near, this value was 3 D for sphere and “against the rule astigmatism” and 4 D for “with the rule astigmatism”. For distance, the values were 2 D for sphere and “against the rule astigmatism” and 3 D for “with the rule astigmatism.”Conclusions. Myopic anisometropia of more than 2 D can cause a significant impairment of binocular vision. Stereoacuity at distance is more sensitive to myopic anisometropia than stereoacuity at near. Myopic anisometropia involving “against the rule” astigmatism potentially affects binocularity more than anisometropia with regular astigmatism. A prompt correction of anisometropia of more than 2 D is needed in children to prevent the development of amblyopia.
Retinal and Corneal Toxicity and Pharmacokinetic Analysis of Intraocular Injection of Ganciclovir in Rabbit Eyes
Authors: Sun Bin-jia , Peng Rong-mei , Lu Qing , Hong Jing
Published: May 2019

Purpose. To evaluate the safety and pharmacokinetic changes of ganciclovir (GCV) intraocular injection. Methods. GCV (2 mg/0.1 mL) was injected into rabbit eyes. Aqueous GCV concentration was detected by high-performance liquid chromatography. Potential toxicity was assessed by slit-lamp examination, optical coherence tomography, fundus examination, confocal microscopy, and histology. Results. Aqueous GCV concentrations were 24.83 ± 6.41 μg/mL, 0.65 ± 0.52 μg/mL, and undetected on the 1st, 3rd, and 7th day after intravitreal injection. GCV could not be detected on the first day after intracameral injection. No corneal abnormality was found after intravitreal injection, but retinal edema was observed on the first day which receded later. Corneal edema was obvious with endothelial cytoarchitecture damaged after intracameral injection; fluid retention also existed in retina. Conclusions. GCV intravitreal injection offers effective, sustained drug concentration in the anterior chamber, and its damage to retina receded over time. Intracameral injection results in rapid drug elimination and severe damage to endothelium and thus is not recommended.
Protective Function of Novel Fungal Immunomodulatory Proteins Fip-lti1 and Fip-lti2 from Lentinus tigrinus in Concanavalin A-Induced Liver Oxidative Injury
Authors: Gao Yingnyu , Wáng Ying , Wāng Ying , Wu Yingying , Chen Hongyu , Yang Ruiheng , Bao Dapeng
Published: May 2019

Fungal immunomodulatory proteins (FIPs) are a class of small proteins that have been extensively studied for their immunomodulatory activities. In this study, two novel FIPs from Lentinus tigrinus were identified and named Fip-lti1 and Fip-lti2. The bioactive characteristics of Fip-lti1 and Fip-lti2 were compared to a well-known FIP (LZ-8 from Ganoderma lucidum) to investigate the effect of Fip-lti1 and Fip-lti2 expression on concanavalin A- (Con A-) induced liver oxidative injury. Both Fip-lti1 and Fip-lti2 protected the livers from Con A-induced necrosis, as evidenced by decreased serum aminotransferase levels (AST, ALT) and relieved liver histology. Levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and oxidative stress (SOD, MDA) were shown to be reduced by expressing Fip-lti1 and Fip-lti2. In addition, the hepatoprotective effect of Fip-lti1, Fip-lti2, and LZ-8 correlated with ameliorating the imbalance of Th1/Th2 (IFN-γ/IL-4). The observed liver protection of Fip-lti1 and Fip-lti2 was mechanistically explored. Treatments with Fip-lti1 and Fip-lti2 regulated GATA3/T-bet expression, activated the decreased Nrf-2/HO-1 pathway, and countered the upregulated NLRP3/ASC/NF-κBp65 signaling in Con A-stimulated liver injury. Nrf2 activation was shown to be involved in the mechanisms underlying the protection of Fip-lti by RNA interference. In conclusion, we identified two new fungal proteins (Fip-lti1 and Fip-lti2) that can protect the liver from Con A-induced liver oxidative injury through the Nrf2/NF-κB/NLRP3/IL-1β pathway.
Fluid Inclusions and H-O-C-S Isotopes of the Wushan Copper Polymetallic Deposit in the Suizao Area, Hubei Province: Implications for Ore Genesis
Authors: Niu Pan-Pan , Jiang Shao-Yong , Xiong Suo-Fei , Hu Qi-Sheng , Xu Tian-liang
Published: May 2019

The Wushan copper polymetallic deposit is located in the Tongbai-Dabie orogenic belt in central China. Two small granitoid stocks (Donggushan and Xigushan) occur in the deposit, which is next to the largest Qijianfeng Granite Complex in the Suizao area. The mineralization of Wushan copper polymetallic deposit is mainly composed of ore-bearing quartz veins and quartz stockworks. Two hydrothermal stages are identified as the quartz-sulfide stage (early stage) and the barren quartz stage (late stage). A detailed petrographic study shows four types of fluid inclusions in quartz, including the aqueous fluid inclusions (L+V/V+L), the aqueous-carbonic fluid inclusions (L+V+CO2), the pure carbon dioxide fluid inclusions (pure CO2), and the daughter mineral-bearing multiphase fluid inclusions (S). The daughter mineral-bearing multiphase fluid inclusions (S) are further divided into three subclasses according to their different solid mineral assemblages, including (1) S1: L+V+Hal, (2) S2: L+V+CO2+S (chalcopyrite), and (3) S3: L+V+S (calcite, chalcopyrite, and hematite)±Hal. A laser Raman spectroscopic analysis shows that the main components of fluid inclusions are water and carbon dioxide. The solid minerals of the S-type fluid inclusions include halite, calcite, chalcopyrite, and hematite. The homogenization temperatures of fluid inclusions are 377 to 468°C for the early stage, with a salinity of 11.1 to 34.1 wt.% NaCl equivalent (11.1 to 17.4 wt.% NaCl equivalent and 28.4 to 34.1 wt.% NaCl equivalent, respectively) and an estimated pressure of 89 to 137 MPa. The homogenization temperatures of fluid inclusions in the late stage are 267 to 380°C with salinity of 7.0 to 12.1 wt.% NaCl equivalent and an estimated pressure of 46 to 115 MPa. Therefore, the temperature, salinity, and pressure of the fluid show a decreasing trend from the early to the late stage. In the early stage, the fluid is immiscible, which leads to the precipitation of sulfides. Pyrite shows a δ34S of approximately 0 (-1.8 to +3.4‰), and chalcopyrite also shows a similar δ34S of approximately 0 (+1.5 to +2.4‰), which indicates that the sulfur in the ore-forming fluid is mainly derived from deep-seated magma. Combined with C-H-O isotopic compositions, the initial ore-forming fluid is likely magmatic water, but with the addition of meteoric water in the late stage. By comparing with the typical characteristics of magmatic hydrothermal vein deposit and orogenic deposit related to shear zones, we suggest that the Wushan copper polymetallic deposit is most likely a magmatic hydrothermal vein deposit, which is of great significance for the further exploration work in the Wushan and surrounding areas. This new finding also fills the gap that no magmatic hydrothermal vein type Cu deposits have been found in the Suizao area or even in the Qinling-Dabie orogenic belt in central China.
New Link Functions for Distribution–Specific Quantile Regression Based on Vector Generalized Linear and Additive Models
Authors: Miranda-Soberanis V. F. , Yee T. W.
Published: May 2019

In the usual quantile regression setting, the distribution of the response given the explanatory variables is unspecified. In this work, the distribution is specified and we introduce new link functions to directly model specified quantiles of seven 1–parameter continuous distributions. Using the vector generalized linear and additive model (VGLM/VGAM) framework, we transform certain prespecified quantiles to become linear or additive predictors. Our parametric quantile regression approach adopts VGLMs/VGAMs because they can handle multiple linear predictors and encompass many distributions beyond the exponential family. Coupled with the ability to fit smoothers, the underlying strong assumption of the distribution can be relaxed so as to offer a semiparametric–type analysis. By allowing multiple linear and additive predictors simultaneously, the quantile crossing problem can be avoided by enforcing parallelism constraint matrices. This article gives details of a software implementation called the VGAMextra package for R. Both the data and recently developed software used in this paper are freely downloadable from the internet.
A New Scheduling Quantitative Feedback Theory‐Based Controller Integrated with Fault Detection for Effective Vibration Control
Authors: Jeyasenthil R. , Lee Yang-Sup , Choi Seung-Bok
Published: May 2019

In this work, a new integrated fault detection and control (IFDC) method is presented for single‐input/single‐output systems (SISOs). The idea is centered on comparing the closed‐loop output between the faulty system and fault‐free one to schedule/switch the feedback control once the fault occurs. The problem addressed in this work is the output disturbance rejection. The set of feedback controllers are designed using quantitative feedback theory (QFT) for fault‐free and faulty systems. In the context of QFT‐based IFDC, the proposed active approach is novel, simple, and easy to implement from an engineering point of view. The efficiency of the proposed method is assessed on a flexible smart structure system featuring a piezoelectric actuator. The actuator and sensor faults considered are the multiplicative type with both fixed and time‐varying magnitudes. In the fixed magnitude fault case, the actuator/sensor output delivering capability is reduced by 50% (multiplying a factor of 0.5 to its actual output), while in the time‐varying magnitude case, it becomes 60% to 50% for a particular time interval. In both cases, the proposed control method identifies the fault and activates the required controller to satisfy the specification with less control effort as opposed to the passive QFT design featured by faulty system design alone.
A Theoretical Study on the Inclusion of Fe, Cu, and Zn in Illite Clays
Authors: Sánchez-Coronilla Antonio , Martín Elisa I. , Fernández-de-Cordova Francisco José , Santos Francisco Javier , Toledo José Hidalgo
Published: May 2019

The inclusion of Fe, Cu, and Zn in (1, 0, 0), (0, 0.5, 0), and (0.5, 0.5, 0.5) sites of an illite with the KAl2Si4O12H2 structure has been studied. For the inclusion of the metals, their common oxidation states were chosen, that is, 0, +2, +3 and 0, +1, +2, for Fe and Cu, respectively, while 0 and +2 for Zn. Periodic DFT calculations were performed to know the most favourable site of incorporation of the ions. Energetically the most favourable site for the inclusion corresponds to the (1, 0, 0) coordinate for all the ions independently of their oxidation state. However, the highest oxidation state of the metals (Fe3+, Cu2+, and Zn2+) was the most favoured for being incorporated into the illite structure and was the selected ion for the discussion. In those structures, metal oxygen interaction plays an important role in stabilizing the systems. Structural and energetic results indicate that illite presents good adsorption characteristic of those Fe3+, Cu2+, and Zn2+ in the (1, 0, 0) site. Thus, those ions may be available for plants for its extraction by phytoextraction techniques and the consequent soil regeneration. The inclusion of a second metallic ion revealed the most favourable inclusion corresponding to the inclusion of Fe3+ ion. The inclusion of this ion modifies the coordination sphere around the first metal being available for subsequent extraction by phytoremediation or other techniques for clean-up of the soil and its regeneration.
Design and Optimization of a Coherent Beamforming Network for an Aperiodic Concentric Ring Array
Authors: Arce Armando , Stevens-Navarro Enrique , Cardenas-Juarez Marco , Pineda-Rico Ulises , Simon Jorge , Panduro Marco A.
Published: May 2019

In this work, a flexible and reconfigurable feeding network design for a nonuniform aperture on circular concentric ring arrays is proposed and analyzed. The network subsystem delivers coherent in-phase outputs with a Gaussian-like amplitude distribution, in a modular and basic topology based on sets of alternated power combiners and dividers. A complete antenna system in a monobeam configuration with a coherent network based on grouped inputs (blocks) per ring for an aperiodic concentric ring array with beam scanning and beam shaping properties is synthesized and analyzed. Additionally, a comparative analysis based on nonuniform and uniform concentric ring arrays fed by the proposed coherent network configuration is conducted and assessed. The optimization of the aperiodic layout on the antenna aperture (radii and interelement antenna spacings) is done by the differential evolution algorithm. Numeric experimentation demonstrates the performance advantages and capabilities of the proposed coherent network configuration with a nonuniform aperture over its uniform counterpart, with an improvement in average equal to −8.7 dB of side lobe level and 3.9 dB of directivity. Furthermore, the numeric examples show a complexity reduction on the coherent feeding network configuration based on the number of control signal inputs compared with a conventional phased antenna array; in the proposed configuration, the main beam is steered and shaped with N-1 control feeding ports per ring in this antenna system.
Determination of In Vitro Antimicrobial Activity of Five Sri Lankan Medicinal Plants against Selected Human Pathogenic Bacteria
Authors: De Zoysa Manikkuwadura Hasara Nethmini , Rathnayake Hasanga , Hewawasam Ruwani Punyakanthi , Gaya Bandara Wijayaratne Weerasinghe Mudiyanselage Dilip
Published: May 2019

Introduction. Antibiotic resistance is one of the greatest threats of the 21st century. Scientists search for potential antimicrobial sources that can cope with antibiotic resistance. Plants used in traditional medicine can be identified as potential candidates for the synthesis of novel drug compounds to act against antibiotic-resistant bacteria. Objective. To determine the potential antimicrobial effects of ethanol, aqueous, and hexane extracts of five Sri Lankan medicinal plants against four human pathogens. Methods. Asparagus falcatus (tubers), Asteracantha longifolia (whole plant), Vetiveria zizanioides (roots), Epaltes divaricata (whole plant), and Coriandrum sativum (seeds) were used in the study. Plant extracts were screened against four clinically important Gram-positive and Gram-negative bacterial strains, Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), and Klebsiella pneumoniae (ATCC 700603). Antibacterial activity of plant extracts were monitored using the agar disc diffusion method. Eight concentrations of each positive plant extract were used to determine the minimum inhibitory concentration (MIC) by 5-fold dilution of plant extracts yielding a serial dilution of the original extract. Results. Ethanol, aqueous, and hexane extracts of E. divaricata gave the maximum zones of inhibition of 16.3 mm, 7.4 mm, and 13.7 mm and MIC values of 0.48 mg/ml, 1.2 mg/ml, and 1.6 mg/ml, respectively, against S. aureus. Ethanol and hexane extracts of V. zizanioides gave the maximum zones of inhibition of 12.1 mm and 11.4 mm and MIC values 2.4 mg/ml and 0.003 mg/ml, respectively, against S. aureus. None of the other plants were effective against any microorganism used for the study. Conclusions. It can be concluded that E. divaricata and V. zizanioides crude ethanol, aqueous, and hexane extracts exhibited significant in vitro antibacterial activity against S. aureus, and the active compounds isolated from them can be potential sources for the synthesis of antibacterial drugs.
Antiepileptic Effects of Protein-Rich Extract from Bombyx batryticatus on Mice and Its Protective Effects against H2O2-Induced Oxidative Damage in PC12 Cells via Regulating PI3K/Akt Signaling Pathways
Authors: Hu Meibian , Liu Yujie , He Liying , Yuan Xing , Peng Wei , Wu Chunjie
Published: May 2019

Bombyx batryticatus is a known traditional Chinese medicine (TCM) utilized to treat convulsions, epilepsy, cough, asthma, headaches, and purpura in China for thousands of years. This study is aimed at investigating the antiepileptic effects of protein-rich extracts from Bombyx batryticatus (BBPs) on seizure in mice and exploring the protective effects of BBPs against H2O2-induced oxidative stress in PC12 cells and their underlying mechanisms. Maximal electroshock-induced seizure (MES) and pentylenetetrazole- (PTZ-) induced seizure in mice and the histological analysis were carried out to evaluate the antiepileptic effects of BBPs. The cell viability of PC12 cells stimulated by H2O2 was determined by MTT assay. The apoptosis and ROS levels of H2O2-stimulated PC12 cells were determined by flow cytometry analysis. Furthermore, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), lactate dehydrogenase (LDH), and glutathione (GSH) in PC12 cells were assayed by ELISA and expressions of caspase-3, caspase-9, Bax, Bcl-2, PI3K, Akt, and p-Akt were evaluated by Western blotting and quantitative real-time polymerase chain reaction (RT-qPCR) assays. The results revealed that BBPs exerted significant antiepileptic effects on mice. In addition, BBPs increased the cell viability of H2O2-stimulated PC12 cells and reduced apoptotic cells and ROS levels in H2O2-stimulated PC12 cells. By BBPs treatments, the levels of MDA and LDH were reduced and the levels of SOD and GSH-Px were increased in H2O2-stimulated PC12 cells. Moreover, BBPs upregulated the expressions of PI3K, Akt, p-Akt, and Bcl-2, whereas they downregulated the expressions of caspase-9, caspase-3, and Bax in H2O2-stimulated PC12 cells. These findings suggested that BBPs possessed potential antiepileptic effects on MES and PTZ-induced seizure in mice and protective effects on H2O2-induced oxidative stress in PC12 cells by exerting antioxidative and antiapoptotic effects via PI3K/Akt signaling pathways.
Efficacy of the LED Red Light Therapy in the Treatment of Temporomandibular Disorders: Double Blind Randomized Controlled Trial
Authors: Al-Quisi Ahmed Fadhel , Al-Anee Auday M. , AL-jumaily Hassanien A. , Bahr Eman F. , Finjan Dina A.
Published: May 2019

Background. Temporomandibular dysfunction syndrome (TMD) is a common disease among dental patients. It occurs as a consequence of malfunction of the tempromandibular and/or surrounding facial muscles. LED red light therapy is not been well established, and it is important to find out the role of this technique in the treatment of temporomandibular disorders. Aim of the Study. To evaluate the efficacy of the LED red light in the treatment of the tempromandibular dysfunction syndrome. Material and Methods. Fifty students of the College of Dentistry/University of Baghdad with myofacial pain associated with Tempromandibular Disorder volunteered to participate in this study and be evaluated during both treatment and follow-up periods. They were 40 (80%) females and 10 (20%) males. Patients were divided into 2 groups: Group A treated by TenDlite® Medical Device model 204 with a LED’s of wavelength 660 nm (red light) and Group B given placebo (no treatment at all) by just putting the TenDlite device near the tender points without battery and turning ON the device. Results. The changes in the pain value and number of the tender muscles in both groups were highly significant, only placebo group less but with no significant differences. Conclusions. This study showed that red LED therapy could be useful in improving patient’s symptoms regarding pain, clicking, and number of tender muscles. In addition, this study showed the importance of the psychological part of treatment of those patients. This trial is registered with TCTR20190406002.
Vagus Nerve Stimulation Attenuates Hepatic Ischemia/Reperfusion Injury via the Nrf2/HO-1 Pathway
Authors: Zhang Qianqian , Lai Yanqiu , Deng Jielin , Wang Menglong , Wang Zhenya , Wang Meng , Zhang Yifeng , Yang Xiaomeng , Zhou Xiaoya , Jiang Hong
Published: May 2019

It has been demonstrated that vagus nerve stimulation (VNS) plays a protective role in ischemia/reperfusion (I/R) injury of various organs. The present study investigates the protective effect of VNS on hepatic I/R injury and the potential mechanisms. Male Sprague-Dawley rats were randomly allocated into three groups: the sham operation group (Sham; n=6, sham surgery with sham VNS); the I/R group (n=6, hepatic I/R surgery with sham VNS); and the VNS group (n=6, hepatic I/R surgery plus VNS). The I/R model was established by 1 hour of 70% hepatic ischemia. Tissue samples and blood samples were collected after 6 hours of reperfusion. The left cervical vagus nerve was separated and stimulated throughout the whole I/R process. The stimulus intensity was standardized to the voltage level that slowed the sinus rate by 10%. VNS significantly reduced the necrotic area and cell death in I/R tissues. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were also decreased by VNS. In addition, VNS suppressed inflammation, oxidative stress, and apoptosis in I/R tissues. VNS significantly increased the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) in the liver. These data indicated that VNS may attenuate hepatic I/R injury by inhibiting inflammation, oxidative stress, and apoptosis possibly via the Nrf2/HO-1 pathway.
Preexisting Commensal Dysbiosis Is a Host-Intrinsic Regulator of Tissue Inflammation and Tumor Cell Dissemination in Hormone Receptor–Positive Breast Cancer
Authors: Buchta Rosean Claire , Bostic Raegan R. , Ferey Joshua C.M. , Feng Tzu-Yu , Azar Francesca N. , Tung Kenneth S. , Dozmorov Mikhail G. , Smirnova Ekaterina , Bos Paula D. , Rutkowski Melanie R.
Published: May 2019

It is unknown why some patients with hormone receptor–positive (HR+) breast cancer present with more aggressive and invasive disease. Metastatic dissemination occurs early in disease and is facilitated by cross-talk between the tumor and tissue environment, suggesting that undefined host-intrinsic factors enhance early dissemination and the probability of developing metastatic disease. Here, we have identified commensal dysbiosis as a host-intrinsic factor associated with metastatic dissemination. Using a mouse model of HR+ mammary cancer, we demonstrate that a preestablished disruption of commensal homeostasis results in enhanced circulating tumor cells and subsequent dissemination to the tumor-draining lymph nodes and lungs. Commensal dysbiosis promoted early inflammation within the mammary gland that was sustained during HR+ mammary tumor progression. Furthermore, dysbiosis enhanced fibrosis and collagen deposition both systemically and locally within the tumor microenvironment and induced significant myeloid infiltration into the mammary gland and breast tumor. These effects were recapitulated both by directly targeting gut microbes using nonabsorbable antibiotics and by fecal microbiota transplantation of dysbiotic cecal contents, demonstrating the direct impact of gut dysbiosis on mammary tumor dissemination. This study identifies dysbiosis as a preexisting, host-intrinsic regulator of tissue inflammation, myeloid recruitment, fibrosis, and dissemination of tumor cells in HR+ breast cancer.

Significance:

Identification of commensal dysbiosis as a host-intrinsic factor mediating evolution of metastatic breast cancer allows for development of interventions or diagnostic tools for patients at highest risk for developing metastatic disease.

See related commentary by Ingman, p. 3539
Discovery and Characterization of SY-1365, a Selective, Covalent Inhibitor of CDK7
Authors: Hu Shanhu , Marineau Jason J. , Rajagopal Nisha , Hamman Kristin B. , Choi Yoon Jong , Schmidt Darby R. , Ke Nan , Johannessen Liv , Bradley Michael J. , Orlando David A. , Alnemy Sydney R. , Ren Yixuan , Ciblat Stephane , Winter Dana K. , Kabro Anzhelika , Sprott Kevin T. , Hodgson J. Graeme , Fritz Christian C. , Carulli John P. , di Tomaso Emmanuelle , Olson Eric R.
Published: May 2019

Recent studies suggest that targeting transcriptional machinery can lead to potent and selective anticancer effects in cancers dependent on high and constant expression of certain transcription factors for growth and survival. Cyclin-dependent kinase 7 (CDK7) is the catalytic subunit of the CDK-activating kinase complex. Its function is required for both cell-cycle regulation and transcriptional control of gene expression. CDK7 has recently emerged as an attractive cancer target because its inhibition leads to decreased transcript levels of oncogenic transcription factors, especially those associated with super-enhancers. Here, we describe a selective CDK7 inhibitor SY-1365, which is currently in clinical trials in populations of patients with ovarian and breast cancer (NCT03134638). In vitro, SY-1365 inhibited cell growth of many different cancer types at nanomolar concentrations. SY-1365 treatment decreased MCL1 protein levels, and cancer cells with low BCL2L1 (BCL-XL) expression were found to be more sensitive to SY-1365. Transcriptional changes in acute myeloid leukemia (AML) cell lines were distinct from those following treatment with other transcriptional inhibitors. SY-1365 demonstrated substantial antitumor effects in multiple AML xenograft models as a single agent; SY-1365–induced growth inhibition was enhanced in combination with the BCL2 inhibitor venetoclax. Antitumor activity was also observed in xenograft models of ovarian cancer, suggesting the potential for exploring SY-1365 in the clinic in both hematologic and solid tumors. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers.

Significance:

These findings demonstrate the molecular mechanism of action and potent antitumor activity of SY-1365, the first selective CDK7 inhibitor to enter clinical investigation.
Imaging of Activated T Cells as an Early Predictor of Immune Response to Anti-PD-1 Therapy
Authors: Levi Jelena , Lam Tina , Goth Samuel R. , Yaghoubi Shahriar , Bates Jennifer , Ren Gang , Jivan Salma , Huynh Tony L. , Blecha Joseph E. , Khattri Roli , Schmidt Karl F. , Jennings Dominique , VanBrocklin Henry
Published: May 2019

Compelling evidence points to immune cell infiltration as a critical component of successful immunotherapy. However, there are currently no clinically available, noninvasive methods capable of evaluating immune contexture prior to or during immunotherapy. In this study, we evaluate a T-cell–specific PET agent, [18F]F-AraG, as an imaging biomarker predictive of response to checkpoint inhibitor therapy. We determined the specificity of the tracer for activated T cells in vitro and in a virally induced model of rhabdomyosarcoma. Of all immune cells tested, activated human CD8+ effector cells showed the highest accumulation of [18F]F-AraG. Isolation of lymphocytes from the rhabdomyosarcoma tumors showed that more than 80% of the intratumoral signal came from accumulation of [18F]F-AraG in immune cells, primarily CD8+ and CD4+. Longitudinal monitoring of MC38 tumor-bearing mice undergoing anti-PD-1 treatment revealed differences in signal between PD-1 and isotype antibody–treated mice early into treatment. The differences in [18F]F-AraG signal were also apparent between responders and nonresponders to anti-PD-1 therapy. Importantly, we found that the signal in the tumor-draining lymph nodes provides key information about response to anti-PD-1 therapy. Overall, [18F]F-AraG has potential to serve as a much needed immunomonitoring clinical tool for timely evaluation of immunotherapy.

Significance:

These findings reveal differences in T-cell activation between responders and nonresponders early into anti-PD-1 treatment, which may impact many facets of immuno-oncology, including patient selection, management, and development of novel combinatorial approaches.
Targeting the High-Mobility Group Box 3 Protein Sensitizes Chemoresistant Ovarian Cancer Cells to Cisplatin
Authors: Mukherjee Anirban , Huynh Van , Gaines Kailee , Reh Wade Alan , Vasquez Karen M.
Published: May 2019

Chemotherapeutic regimens for ovarian cancer often include the use of DNA interstrand crosslink–inducing agents (e.g., platinum drugs) or DNA double-strand break–inducing agents. Unfortunately, the majority of patients fail to maintain a durable response to treatment, in part, due to drug resistance, contributing to a poor survival rate. In this study, we report that cisplatin sensitivity can be restored in cisplatin-resistant ovarian cancer cells by targeting the chromatin-associated high-mobility group box 3 (HMGB3) protein. HMGB proteins have been implicated in the pathogenesis and prognosis of ovarian cancer, and HMGB3 is often upregulated in cancer cells, making it a potential selective target for therapeutic intervention. Depletion of HMGB3 in cisplatin-sensitive and cisplatin-resistant cells resulted in transcriptional downregulation of the kinases ATR and CHK1, which attenuated the ATR/CHK1/p-CHK1 DNA damage signaling pathway. HMGB3 was associated with the promoter regions of ATR and CHK1, suggesting a new role for HMGB3 in transcriptional regulation. Furthermore, HMGB3 depletion significantly increased apoptosis in cisplatin-resistant A2780/CP70 cells after cisplatin treatment. Taken together, our results indicate that targeted depletion of HMGB3 attenuates cisplatin resistance in human ovarian cancer cells, increasing tumor cell sensitivity to platinum drugs.

Significance:

This study shows that targeting HMGB3 is a potential therapeutic strategy to overcome chemoresistance in ovarian cancer.
Intratumoral Adaptive Immunosuppression and Type 17 Immunity in Mismatch Repair Proficient Colorectal Tumors
Authors: Llosa Nicolas J. , Luber Brandon , Tam Ada J. , Smith Kellie N. , Siegel Nicholas , Awan Anas H. , Fan Hongni , Oke Teniola , Zhang JiaJia , Domingue Jada , Engle Elizabeth L. , Roberts Charles A. , Bartlett Bjarne R. , Aulakh Laveet K. , Thompson Elizabeth D. , Taube Janis M. , Durham Jennifer N. , Sears Cynthia L. , Le Dung T. , Diaz Luis A. , Pardoll Drew M. , Wang Hao , Anders Robert A. , Housseau Franck
Published: May 2019

Purpose:

Approximately 10% of patients with mismatch repair–proficient (MMRp) colorectal cancer showed clinical benefit to anti-PD-1 monotherapy (NCT01876511). We sought to identify biomarkers that delineate patients with immunoreactive colorectal cancer and to explore new combinatorial immunotherapy strategies that can impact MMRp colorectal cancer.

Experimental Design:

We compared the expression of 44 selected immune-related genes in the primary colon tumor of 19 patients with metastatic colorectal cancer (mCRC) who responded (n = 13) versus those who did not (n = 6) to anti-PD-1 therapy (NCT01876511). We define a 10 gene–based immune signature that could distinguish responder from nonresponder. Resected colon specimens (n = 14) were used to validate the association of the predicted status (responder and nonresponder) with the immune-related gene expression, the phenotype, and the function of tumor-infiltrating lymphocytes freshly isolated from the same tumors.

Results:

Although both IL17Low and IL17High immunoreactive MMRp colorectal cancers are associated with intratumor correlates of adaptive immunosuppression (CD8/IFNγ and PD-L1/IDO1 colocalization), only IL17Low MMRp tumors (3/14) have a tumor immune microenvironment (TiME) that resembles the TiME in primary colon tumors of patients with mCRC responsive to anti-PD-1 treatment.

Conclusions:

The detection of a preexisting antitumor immune response in MMRp colorectal cancer (immunoreactive MMRp colorectal cancer) is not sufficient to predict a clinical benefit to T-cell checkpoint inhibitors. Intratumoral IL17-mediated signaling may preclude responses to immunotherapy. Drugs targeting the IL17 signaling pathway are available in clinic, and their combination with T-cell checkpoint inhibitors could improve colorectal cancer immunotherapy.

See related commentary by Willis et al., p. 5185
FDA Approval Summary: Glasdegib for Newly Diagnosed Acute Myeloid Leukemia
Authors: Norsworthy Kelly J. , By Kunthel , Subramaniam Sriram , Zhuang Luning , Del Valle Pedro L. , Przepiorka Donna , Shen Yuan-Li , Sheth Christopher M. , Liu Chao , Leong Ruby , Goldberg Kirsten B. , Farrell Ann T. , Pazdur Richard
Published: May 2019

On November 21, 2018, the FDA approved glasdegib (Daurismo; Pfizer), a small-molecule Hedgehog inhibitor, in combination with low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in adults ≥ 75 years or with comorbidities that preclude use of intensive induction chemotherapy. Evidence of clinical benefit came from Study BRIGHT AML 1003, a randomized trial comparing glasdegib+LDAC with LDAC alone for treatment of newly diagnosed AML in 115 patients either ≥ 75 years old or ≥ 55 years old with preexisting comorbidities. Efficacy was established by improved overall survival (OS) with the combination compared with LDAC alone (HR, 0.46; 95% confidence interval, 0.30–0.71; one-sided stratified log-rank P = 0.0002). Median OS was 8.3 months with the combination and 4.3 months with LDAC alone. Common adverse reactions included cytopenias, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. The label includes a boxed warning for embryo-fetal toxicity and a warning for QT interval prolongation. There is a limitation of use for patients with moderate-to-severe hepatic and severe renal impairment; trials studying glasdegib in these patient populations are required as a condition of this approval.

See related commentary by Fathi, p. 6015
Spontaneous Regression of Cervical Intraepithelial Neoplasia 2: A Meta-analysis
Authors: Zhang Jin , Lu Chun-xue
Published: May 2019

Background: Cervical intraepithelial neoplasia (CIN) is a precancerous condition that, if progresses, can cause cervical cancer. Less severe forms such as CIN1 regress spontaneously for most of the cases, but for high-grade CIN (CIN2 or CIN3), have higher potentials for progression. Objective: Aim of the present study was to obtain reliable estimates of spontaneous regression and progression rates of CIN2. Methods: Data were extracted from eligible studies identified after literature search in electronic databases, and meta-analyses were performed by pooling the regression and progression rates reported by these studies. Meta-regression analyses were performed for the identification of factors affecting regression rate. Results: Sixteen studies (1,481 patients; 14.86 months [95% CI 9.25–20.48] follow-up; 28.23 years [95% CI 25.07–31.39] age) were included in the meta-analysis. Overall regression rate in these conservatively observed patients was 42.66% (95% CI 35.41–49.91), but regression rate was higher in studies that recruited patients with CIN2 (50.85% [95% CI 36.11–65.60]) in comparison with those that recruited patients without discrimination of CIN2 with CIN3 (36.31% [95% CI 27.67–44.95]. Progression rate in CIN2 patients was 10.28% [95% CI 3.72–16.84]). Age was significantly negatively associated with regression rate (coefficient –1.72 [–3.53 to 0.10]; p = 0.061). Conclusion: Spontaneous regression rate of CIN2 is considerably high, especially in younger years.
Successful Treatment of Severe Hyperammonaemia with Ultra-High Dose Continuous Veno-Venous Haemodiafiltration
Authors: Boer Dirk P. , Mourik Sarah L. , van den Hoogen Martijn W.F. , Langendonk Janneke G. , de Geus Hilde R.H.
Published: May 2019

Hyperammonaemia is a severe condition and often requires a multimodal treatment regimen. Dialysis has been described as a potential treatment option, but currently it is not the standard of care. In this report, we describe a case of a 40-year-old postpartum woman who developed severe hyperammonaemia due to liver failure and acute kidney injury (AKI) combined with a large intra-abdominal haematoma producing nitrogen waste products. She was treated successfully with continuous veno-venous haemodiafiltration using an ultra-high effluent rate (100 mL/kg/h) and was discharged alive 32 days after the initial admission. Our report indicates that successful ammonia clearance in the setting of AKI can be obtained only by using this high effluent rate. This treatment modality should be considered in all patients with AKI and severe hyperammonaemia when other treatment modalities fail to lower ammonia levels within hours to prevent irreversible but preventable neurological damage.
Intragenic Deletion in MACROD2: A Family with Complex Phenotypes Including Microcephaly, Intellectual Disability, Polydactyly, Renal and Pancreatic Malformations
Authors: Lombardo Barbara , Esposito Daniela , Iossa Sandra , Vitale Andrea , Verdesca Francesco , Perrotta Carla , Di Leo Luca , Costa Valerio , Pastore Lucio , Franzé Annamaria
Published: May 2019

Diagnosing a complex genetic syndrome and correctly assigning the concomitant phenotypic traits to a well-defined clinical form is often a medical challenge. In this work, we report the analysis of a family with complex phenotypes, including microcephaly, intellectual disability, dysmorphic features, and polydactyly in the proband, with the aim of adding new aspects for obtaining a clear diagnosis. We performed array-comparative genomic hybridization and quantitative reverse transcriptase PCR (qRT-PCR) analyses. We identified a deletion of chromosome 20p12.1 involving the macrodomain containing 2/mono-ADP ribosylhydrolase 2 gene (MACROD2) in several members of the family. This gene is actually not associated with a specific syndrome but with congenital anomalies of multiple organs. qRT-PCR showed higher levels of a MACROD2 mRNA isoform in the individuals carrying the deletion. Our results, together with other data reported in the literature, support the hypothesis that the deletion in MACROD2 can affect correct embryonic development and that the presence of another associated event, such as epigenetic modifications at the MACROD2 locus, can influence the level of severity of the pathology.
Assessment of Time-Dependent Platelet Activation Using Extracellular Vesicles, CD62P Exposure, and Soluble Glycoprotein V Content of Platelet Concentrates with Two Different Platelet Additive Solutions
Authors: Valkonen Sami , Mallas Birte , Impola Ulla , Valkeajärvi Anne , Eronen Juha , Javela Kaija , Siljander Pia R.-M. , Laitinen Saara
Published: May 2019

Novel analytical measures are needed to accurately monitor the properties of platelet concentrates (PCs). Since activated platelets produce platelet-derived extracellular vesicles (EVs), analyzing EVs of PCs may provide additional information about the condition of platelets. The prospect of using EVs as an auxiliary measure of platelet activation state was investigated by examining the effect of platelet additive solutions (PASs) on EV formation and platelet activation during PC storage. The time-dependent activation of platelets in PCs with PAS-B or with the further developed PAS-E was compared by measuring the exposure of CD62P by flow cytometry and the content of soluble glycoprotein V (sGPV) of PCs by an immunoassay. Changes in the concentration and size distribution of EVs were determined using nanoparticle tracking analysis. A time-dependent increase in platelet activation in PCs was demonstrated by increased CD62P ex­posure, sGPV content, and EV concentration. Using these strongly correlating parameters, PAS-B platelets were shown to be more activated compared to PAS-E platelets. Since the EV concentration correlated well with the established platelet activation markers CD62P and sGPV, it could potentially be used as a complementary parameter for platelet activation for PCs. More detailed characterization of the resulting EVs could help to understand how the PC components contribute the functional effects of transfused PCs.
Timing and Predictors of Recurrence of Dyspepsia Symptoms after Cessation of Acotiamide Therapy for Functional Dyspepsia: A Long-Term Observational Study
Authors: Shinozaki Satoshi , Osawa Hiroyuki , Sakamoto Hirotsugu , Hayashi Yoshikazu , Kobayashi Yasutoshi , Miura Yoshimasa , Lefor Alan Kawarai , Yamamoto Hironori
Published: May 2019

Background/Aims: The long-term outcomes of patients after cessation of acotiamide therapy in patients with functional dyspepsia remains unclear. The aim of this study is to investigate the timing and predictors of recurrence of dyspepsia symptoms after cessation of acotiamide therapy for functional dyspepsia. Methods: Seventy patients treated with acotiamide for functional dyspepsia who then ceased treatment were enrolled. Changes in dyspepsia symptoms were evaluated using the Izumo scale, a self-reporting questionnaire of abdominal symptom-related quality of life. Patients were subclassified into epigastric pain, postprandial distress, and overlapped types. Results: The mean follow-up after cessation of acotiamide was 1.9 years. After cessation of acotiamide, 39 patients (56%) had recurrence. Kaplan-Meier analysis revealed a recurrence-free rate of 51% at 1 year. Predictors of recurrence evaluated with a Cox proportional hazards model showed that overlapped-type dyspepsia and consultation with the treating physician before cessation were identified as significant positive and negative predictors, respectively (p < 0.05). The resumption of acotiamide significantly decreased the score for dyspepsia symptoms at 1 month. Conclusions: Dyspepsia symptoms recur about one year after cessation of acotiamide therapy. Patients with overlapped-type dyspepsia should be carefully followed after cessation. Patients should consult their treating physician before stopping acotiamide.