bluuebunny/crossref_metadata_2025 huggingface dataset:
Polydatin Protects Diabetic Heart against Ischemia‐Reperfusion Injury via Notch1/Hes1‐Mediated Activation of Pten/Akt Signaling
Authors: Yu Liming , Li Zhi , Dong Xue , Xue Xiaodong , Liu Yu , Xu Shu , Zhang Jian , Han Jinsong , Yang Yang , Wang Huishan
Published: February 2018

Diabetes exacerbates oxidative/nitrative stress during myocardial ischemia‐reperfusion (MI/R) injury. Recent studies highlighted the cardioprotective actions of polydatin. However, its effect on diabetic MI/R injury and the underlying mechanisms remain unknown. This work was undertaken to evaluate the effect of polydatin on diabetic MI/R injury with a focus on Notch1/Hes1 signaling and myocardial oxidative/nitrative stress. Streptozotocin‐ (STZ‐) induced diabetic rats were administered with polydatin (20 mg/kg/d) in the absence or presence of DAPT (a γ‐secretase inhibitor) or LY294002 (a PI3K/Akt inhibitor) and then subjected to MI/R injury. Polydatin administration preserved cardiac function and reduced myocardial infarct size. Moreover, polydatin ameliorated myocardial oxidative/nitrative stress damage as evidenced by decreased myocardial superoxide generation, malondialdehyde, gp91phox expression, iNOS expression, NO metabolite level, and nitrotyrosine content and increased eNOS phosphorylation. However, these effects were blocked by DAPT administration. DAPT also inhibited the stimulatory effect of polydatin on the Notch1/Hes1‐Pten/Akt signaling pathway in a diabetic myocardium. Additionally, LY294002 not only abolished polydatin’s antiapoptotic effect but also reversed its inhibitory effect on myocardial oxidative/nitrative stress. Polydatin effectively reduced MI/R injury and improved left ventricular functional recovery under diabetic condition by ameliorating oxidative/nitrative stress damage. Importantly, Notch1/Hes1‐mediated activation of Pten/Akt signaling played a crucial role in this process.
A Novel Mechanism of Mesenchymal Stromal Cell‐Mediated Protection against Sepsis: Restricting Inflammasome Activation in Macrophages by Increasing Mitophagy and Decreasing Mitochondrial ROS
Authors: Li Shuang , Wu Hao , Han Dong , Ma Sai , Fan Wensi , Wang Yabin , Zhang Ran , Fan Miaomiao , Huang Yuesheng , Fu Xiaobing , Cao Feng
Published: February 2018

Sepsis, a systemic inflammatory response to infection, is the leading cause of death in the intensive care unit (ICU). Previous studies indicated that mesenchymal stromal cells (MSCs) might have therapeutic potential against sepsis. The current study was designed to investigate the effects of MSCs on sepsis and the underlying mechanisms focusing on inflammasome activation in macrophages. The results demonstrated that the bone marrow‐derived mesenchymal stem cells (BMSCs) significantly increased the survival rate and organ function in cecal ligation and puncture (CLP) mice compared with the control‐grouped mice. BMSCs significantly restricted NLRP3 inflammasome activation, suppressed the generation of mitochondrial ROS, and decreased caspase‐1 and IL‐1β activation when cocultured with bone marrow‐derived macrophages (BMDMs), the effects of which could be abolished by Mito‐TEMPO. Furthermore, the expression levels of caspase‐1, IL‐1β, and IL‐18 in BMDMs were elevated after treatment with mitophagy inhibitor 3‐MA. Thus, BMSCs exert beneficial effects on inhibiting NLRP3 inflammasome activation in macrophages primarily via both enhancing mitophagy and decreasing mitochondrial ROS. These findings suggest that restricting inflammasome activation in macrophages by increasing mitophagy and decreasing mitochondrial ROS might be a crucial mechanism for MSCs to combat sepsis.
Strengthening of RCC Beams in Shear by Using SBR Polymer‐Modified Ferrocement Jacketing Technique
Authors: Ghai Rajinder , Bansal Prem Pal , Kumar Maneek
Published: February 2018

There is a common phenomenon of shear failure in RCC beams, especially in old buildings and bridges. Any possible strengthening of such beams is needed to be explored that could strengthen and make them fit for serviceable conditions. The present research has been made to determine the performance of predamaged beams strengthened with three‐layered wire mesh polymer‐modified ferrocement (PMF) with 15% styrene‐butadiene‐rubber latex (SBR) polymer. Forty‐eight shear‐designed and shear‐deficient real‐size beams were used in this experimental work. Ultimate shear load‐carrying capacity of control beams was found at two different shear‐span (a/d) ratios 1 and 3. The sets of remaining beams were loaded with different predetermined damage levels of 45%, 75%, and 95% of the ultimate load values and then strengthened with 20 mm thick PMF. The strengthened beams were then again tested for ultimate load‐carrying capacity by conducting the shear load test at a/d = 1 and 3. As a result, the PMF‐strengthened beams showed restoration and enhancement of ultimate shear load‐carrying capacity by 5.90% to 12.03%. The ductility of strengthened beams was improved, and hence, the corresponding deflections were prolonged. On the other hand, the cracking pattern of PMF‐strengthened beams was also improved remarkably.
Ratio of Injured Lung Volume Fraction in Prognosis Evaluation of Acute PQ Poisoning
Authors: Liu JinJin , Xiong Ye , Jiang Mengmeng
Published: February 2018

Although paraquat (PQ) concentrations are the most reliable prognosis predictors of PQ poisoning, these laboratory tests are not readily available in all hospitals. In this study, we proposed an imaging related parameter, that is, the ratio of injured lung volume fraction, for the prognosis evaluation of acute PQ poisoning based on the correlation between disease progress and lung imaging features. An artificial neural network was trained and then used to classify the injured and normal lung regions. The ratio of injured lung volume fraction was calculated from the injured lung volume fractions in the first and second CT scans after three-dimensional reconstruction. Parameters of blood tests were collected. A significant difference was observed with respect to the ratio of injured lung volume fraction between survivors and nonsurvivors (0.73 ± 0.17 versus 0.40 ± 0.14, P < 0.001). No patients survived when the ratio of injured lung volume fraction was less than 0.3, while all patients survived as the ratio of injured lung volume fraction was greater than 0.8. Thus, the ratio of injured lung volume fraction may provide an alternative and informative measure for the prognosis of acute PQ poisoning.
Improved Left Ventricular Aneurysm Repair with Cell- and Cytokine-Seeded Collagen Patches
Authors: Qu Hui , Xie Bao-dong , Wu Jian , Lv Bo , Chuai Jun-bo , Li Jian-zhong , Cai Jun , Wu Hua , Jiang Shu-lin , Leng Xiao-ping , Kang Kai
Published: February 2018

Background. Engineered heart tissues (EHTs) present a promising alternative to current materials for surgical ventricular restoration (SVR); however, the clinical application remains limited by inadequate vascularization postimplantation. Moreover, a suitable and economic animal model for primary screening is another important issue.Methods. Recently, we used 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride chemistry (EDC) to initiate a strengthened, cytokine-conjugated collagenous platform with a controlled degradation speed. In vitro, the biomaterial exhibited an enhanced mechanical strength maintaining a porous ultrastructure, and the constant release of cytokines promoted the proliferation of seeded human mesenchymal stem cells (hMSCs). In vivo, with the hMSC-seeded, cytokine-immobilized patch (MSCs + GF patch), we performed modified SVR for rats with left ventricular aneurysm postmyocardial infarction (MI). Overall, the rats that underwent modified SVR lost less blood and had lower mortality. After 4 weeks, the rats repaired with this cell-seeded, cytokine-immobilized patch presented preserved cardiac function, beneficial morphology, enhanced cell infiltration, and functional vessel formation compared with the cytokine-free (MSC patch), cell-free (GF patch), or blank controls (EDC patch). Furthermore, the degradable period of the collagen patch in vivo extended up to 3 months after EDC treatment.Conclusions. EDC may substantially modify collagen scaffold and provide a promising and practical biomaterial for SVR.
Role of miR‐200c in Myogenic Differentiation Impairment via p66Shc: Implication in Skeletal Muscle Regeneration of Dystrophic mdx Mice
Authors: D’Agostino Marco , Torcinaro Alessio , Madaro Luca , Marchetti Lorenza , Sileno Sara , Beji Sara , Salis Chiara , Proietti Daisy , Imeneo Giulia , C. Capogrossi Maurizio , De Santa Francesca , Magenta Alessandra
Published: February 2018

Duchenne muscular dystrophy (DMD) is a genetic disease associated with mutations of Dystrophin gene that regulate myofiber integrity and muscle degeneration, characterized by oxidative stress increase. We previously published that reactive oxygen species (ROS) induce miR‐200c that is responsible for apoptosis and senescence. Moreover, we demonstrated that miR‐200c increases ROS production and phosphorylates p66Shc in Ser‐36. p66Shc plays an important role in muscle differentiation; we previously showed that p66Shc−/− muscle satellite cells display lower oxidative stress levels and higher proliferation rate and differentiated faster than wild‐type (wt) cells. Moreover, myogenic conversion, induced by MyoD overexpression, is more efficient in p66Shc−/− fibroblasts compared to wt cells. Herein, we report that miR‐200c overexpression in cultured myoblasts impairs skeletal muscle differentiation. Further, its overexpression in differentiated myotubes decreases differentiation indexes. Moreover, anti‐miR‐200c treatment ameliorates myogenic differentiation. In keeping, we found that miR‐200c and p66Shc Ser‐36 phosphorylation increase in mdx muscles. In conclusion, miR‐200c inhibits muscle differentiation, whereas its inhibition ameliorates differentiation and its expression levels are increased in mdx mice and in differentiated human myoblasts of DMD. Therefore, miR‐200c might be responsible for muscle wasting and myotube loss, most probably via a p66Shc‐dependent mechanism in a pathological disease such as DMD.
Do TSH, FT3, and FT4 Impact BAT Visualization of Clinical FDG-PET/CT Images?
Authors: Nishii Ryuichi , Nagamachi Shigeki , Mizutani Youichi , Terada Tamasa , Kiyohara Syogo , Wakamatsu Hideyuki , Fujita Seigo , Higashi Tatsuya , Yoshinaga Keiichiro , Saga Tsuneo , Hirai Toshinori
Published: February 2018

Objective. We retrospectively analyzed activated BAT visualization on FDG-PET/CT in patients with various conditions and TH levels to clarify the relationships between visualization of BAT on FDG-PET/CT and the effect of TH. Methods. Patients who underwent clinical FDG-PET/CT were reviewed and we categorized patients into 5 groups: (i) thyroid hormone withdrawal (THW) group; (ii) recombinant human thyrotropin (rhTSH) group; (iii) hypothyroidism group; (iv) hyperthyroidism group; and (v) BAT group. A total of sixty-two FDG-PET/CT imaging studies in fifty-nine patients were performed. To compare each group, gender; age; body weight; serum TSH, FT3, and FT4 levels; and outside temperature were evaluated. Results. No significant visualization of BAT was noted in any of the images in the THW, rhTSH, hypothyroidism, and hyperthyroidism groups. All patients in the BAT group were in a euthyroid state. When the BAT-negative and BAT-positive patient groups were compared, it was noted that the minimum and maximum temperature on the day of the PET study and maximum temperature of the one day before the PET study were significantly lower in BAT-positive group than in all those of other groups. Conclusions. Elevated TSH condition before RIT, hyperthyroidism, or hypothyroidism did not significantly impact BAT visualization of clinical FDG-PET/CT images.
Rutin Isolated from Chrozophora tinctoria Enhances Bone Cell Proliferation and Ossification Markers
Authors: Abdel-Naim Ashraf B. , Alghamdi Abdullah A. , Algandaby Mardi M. , Al-Abbasi Fahad A. , Al-Abd Ahmed M. , Eid Basma G. , Abdallah Hossam M. , El-Halawany Ali M.
Published: February 2018

Osteoporosis is a chronic disease in which the skeleton loses a weighty proportion of its mineralized mass and mechanical pliability. Currently available antiosteoporotic agents suffer adverse effects that include elevated risk of thrombosis and cancer. Phytochemicals may constitute a safer and effective option. In the current work, six flavonoids were obtained from Chrozophora tinctoria and identified as amentoflavone (1), apigenin‐7‐O‐β‐d‐glucopyranoside (2), apigenin‐7‐O‐6 ′′‐E‐p‐coumaroyl‐β‐d‐glucopyranoside (3), acacetin‐7‐O‐β‐d‐[α‐l‐rhamnosyl(1→6)]3 ′′‐E‐p‐coumaroyl glucopyranoside (4), apigenin‐7‐O‐(6 ′′‐Z‐p‐coumaroyl)‐β‐d‐glucopyranoside (5), and rutin (6). An extensive review of the literature as well as NMR and mass spectral techniques was employed in order to elucidate the compound structures. Proliferation was enhanced in MCF7, MG‐63, and SAOS‐2 cells after exposure to subcytotoxic levels of the tested flavonoids. Rutin was chosen for subsequent studies in SAOS‐2 cells. Rutin was not found to cause any alteration in the index of proliferation of these cells, when examining the cell cycle distribution by DNA flowcytometric analysis. Rutin was, however, found to increase osteocyte and osteoblast‐related gene expression and lower the expression of RUNX suppressor and osteoclast genes. When examining the influence of rutin on vitamin D levels and the activity of alkaline phosphatase enzyme, it was found to enhance both, while decreasing acid phosphatase which is a marker of osteoporosis. Thus, rutin enhances proliferation and ossification markers in bone cells.
Traditional Herbal Formula NPC01 Exerts Antiangiogenic Effects through Inhibiting the PI3K/Akt/mTOR Signaling Pathway in Nasopharyngeal Carcinoma Cells
Authors: Yanwei Li , Yinli Yang , Pan Zhanyu
Published: February 2018

Antiangiogenic therapy is vital in nasopharyngeal carcinoma (NPC) treatment. NPC01 has already been successfully used in treating patients with NPC in clinical practice and exerted an excellent antiangiogenetic effect. However, the potential molecular mechanism underlying the antitumor effect of NPC01 has not been well explored. The present study demonstrated that NPC01 could significantly inhibit cell proliferation and induce cell apoptosis in a dose‐dependent manner in human NPC cell lines. Furthermore, NPC01 exerted antiproliferative and antiangiogenic effects in NPC xenograft mice. Moreover, the study showed that NPC01 could significantly decrease the expression of angiogenesis‐associated factors including hypoxia‐inducible factor‐1α and vascular endothelial growth factor. Additionally, the decreased expression of these angiogenesis‐associated factors could be due to the inhibition of the phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway (PI3K/Akt/mTOR). In conclusion, the results proposed that NPC01 could exert its antitumor effect by suppressing the PI3K/Akt/mTOR signaling pathway. Further studies are warranted to elucidate the molecular mechanism.
A Novel AMR-WB Speech Steganography Based on Diameter-Neighbor Codebook Partition
Authors: He Junhui , Chen Junxi , Xiao Shichang , Huang Xiaoyu , Tang Shaohua
Published: February 2018

Steganography is a means of covert communication without revealing the occurrence and the real purpose of communication. The adaptive multirate wideband (AMR-WB) is a widely adapted format in mobile handsets and is also the recommended speech codec for VoLTE. In this paper, a novel AMR-WB speech steganography is proposed based on diameter-neighbor codebook partition algorithm. Different embedding capacity may be achieved by adjusting the iterative parameters during codebook division. The experimental results prove that the presented AMR-WB steganography may provide higher and flexible embedding capacity without inducing perceptible distortion compared with the state-of-the-art methods. With 48 iterations of cluster merging, twice the embedding capacity of complementary-neighbor-vertices-based embedding method may be obtained with a decrease of only around 2% in speech quality and much the same undetectability. Moreover, both the quality of stego speech and the security regarding statistical steganalysis are better than the recent speech steganography based on neighbor-index-division codebook partition.
Early Experience with Reduction of Unstable Pelvic Fracture Using a Computer-Aided Reduction Frame
Authors: Zhao Jing-Xin , Zhang Li-Cheng , Su Xiu-Yun , Zhao Zhe , Zhao Yan-Peng , Sun Guo-Fei , Zhang Li-Hai , Tang Pei-Fu
Published: February 2018

Purpose. The optimal closed reduction technique for unstable pelvic fractures remains controversial. The purpose of this study is to verify the effectiveness and report early experiences with the reduction of unstable pelvic fractures using a computer-aided pelvic reduction frame. Methods. From January 2015 to August 2016, a total of 10 patients with unilateral unstable pelvic fractures were included in this study. The surgical reduction procedure was based on the protocol of the computer-aided pelvic reduction frame that we proposed in a previous work. The quality of the reductions achieved using this system was evaluated with residual translational and rotational differences between the actual and virtual reduction positions of pelvis. The duration of the operation was recorded for quality control. Results. The mean times required to set up the frame, to complete the virtual surgery simulation, and to reduce the unstable pelvic fractures were 10.3, 20.9, and 7.5 min, respectively. The maximum residual translational and rotational displacements were less than 6.5 mm and 3.71 degrees, respectively. Conclusions. This computer-aided reduction frame can be a useful tool for the speedy and accurate reduction of unstable pelvic fractures. Further clinical studies should be conducted with larger patient samples to verify its safety and efficacy.
Mechanical Properties and Service Life Prediction of Modified Concrete Attacked by Sulfate Corrosion
Authors: Zhang Min , Yang Li-min , Guo Jin-Jun , Liu Wen-li , Chen Hong-li
Published: February 2018

Under the condition of drying and wetting circulation, ordinary concrete, modified concrete containing fly ash, and double‐admixture concrete containing fly ash and polypropylene fiber were corroded in the solution of Na2SO4 and (NH4)2SO4. The sulfate concentration of the solution was designed to be 1000 g/L. The compressive strength and splitting tensile strength of the concrete were tested after different number of drying and wetting cycles (0, 2, 4, 6, 8, and 10). The results indicate that the strength of concrete increases in the early stages of corrosion and decreases gradually later. The admixture significantly improves the resistance to sulfate erosion of the modified concrete, while polypropylene fiber plays a less important role on anticorrosion properties. When suffered 10 times of drying and wetting cycle, the compressive strength and splitting tensile strength of modified concrete increase by 28% and 19%, respectively. Based on the test results, the service life of the modified concrete corroded by sulfate was predicted.
A Multiagent Architecture for Mobile Robot Navigation Using Hierarchical Fuzzy and Sliding Mode Controllers
Authors: Ayedi Dorra , Boujelben Maïssa , Rekik Chokri
Published: February 2018

The challenge of this work is to implement an algorithm which enables the robot to achieve independent activities in the purpose of achieving a common goal, which consists in autonomous navigation in a partially unknown environment. The use of multiagent system is convenient for such a problem. Hence, we have designed a structure composed of four agents dedicated to perception, navigation, static, and dynamic obstacle avoidance. Those agents interact through a coordination system.
Three-Dimensional Storm Structure and Low-Level Boundaries at Different Stages of Cyclic Mesocyclone Evolution in a High-Precipitation Tornadic Supercell
Authors: Betten Daniel P. , Biggerstaff Michael I. , Ziegler Conrad L.
Published: February 2018

Nearly continuous wind retrievals every three minutes for an unprecedented 90-minute period were constructed during multiple mesocyclone cycles in a tornadic high-precipitation supercell. Asymptotic contraction rate analysis revealed the relationship between the primary and secondary rear-flank gust fronts (RFGF and SRFGFs) and the rear-flank downdraft (RFD) and occlusion downdrafts. This is thought to be the first radar-based analysis where the relationship between the near-surface gust fronts and their parent downdrafts has been explored for sequential mesocyclones. Changes in the SRFGFs were associated with surges in the RFD. During part of the mesocyclone lifecycle, the SRFGF produced a band of low-level convergence and associated deep updraft along the southwestern side of the hook echo region that ingested the RFD outflow and limited both entrainment into the RFD and reinforcement of low-level convergence along the leading edge of the primary RFGF. The second mesocyclone intensified from stretching in an occlusion updraft rather than in the primary updraft. This low-level mesocyclone remained well separated from the updraft shear region vorticity that was associated with a more traditional midlevel mesocyclone. However, the third mesocyclone initiated in the vorticity-rich region of the primary updraft zone and was amplified by stretching in the primary updraft.
FOXO Transcription Factors Both Suppress and Support Breast Cancer Progression
Authors: Hornsveld Marten , Smits Lydia M.M. , Meerlo Maaike , van Amersfoort Miranda , Groot Koerkamp Marian J.A. , van Leenen Dik , Kloet David E.A. , Holstege Frank C.P. , Derksen Patrick W.B. , Burgering Boudewijn M.T. , Dansen Tobias B.
Published: February 2018

FOXO transcription factors are regulators of cellular homeostasis and putative tumor suppressors, yet the role of FOXO in cancer progression remains to be determined. The data on FOXO function, particularly for epithelial cancers, are fragmentary and come from studies that focused on isolated aspects of cancer. To clarify the role of FOXO in epithelial cancer progression, we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular carcinoma. Strikingly, either activation or loss of FOXO function suppressed tumor growth and metastasis. We show that the multitude of cellular processes critically affected by FOXO function include proliferation, survival, redox homeostasis, and PI3K signaling, all of which must be carefully balanced for tumor cells to thrive.

Significance: FOXO proteins are not solely tumor suppressors, but also support tumor growth and metastasis by regulating a multitude of cellular processes essential for tumorigenesis. Cancer Res; 78(9); 2356–69. ©2018 AACR.
A DDX31/Mutant–p53/EGFR Axis Promotes Multistep Progression of Muscle-Invasive Bladder Cancer
Authors: Daizumoto Kei , Yoshimaru Tetsuro , Matsushita Yosuke , Fukawa Tomoya , Uehara Hisanori , Ono Masaya , Komatsu Masato , Kanayama Hiro-omi , Katagiri Toyomasa
Published: February 2018

The p53 and EGFR pathways are frequently altered in bladder cancer, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle-invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31-bound mutp53/SP1 enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Cytoplasmic DDX31 also bound EGFR and phospho-nucleolin in advanced MIBC, leading to EGFR–Akt signaling activation. High expression of both cytoplasmic DDX31 and p53 proteins correlated with poor prognosis in patients with MIBC, and blocking the DDX31/NCL interaction resulted in downregulation of EGFR/Akt signaling, eliciting an in vivo antitumor effect against bladder cancer. These findings reveal that DDX31 cooperates with mutp53 and EGFR to promote progression of MIBC, and inhibition of DDX31/NCL formation may lead to potential treatment strategies for advanced MIBC.

Significance: DDX31 cooperates with mutp53 and EGFR to promote progression of muscle invasive bladder cancer. Cancer Res; 78(9); 2233–47. ©2018 AACR.
Targeted BiTE Expression by an Oncolytic Vector Augments Therapeutic Efficacy Against Solid Tumors
Authors: Speck Tobias , Heidbuechel Johannes P.W. , Veinalde Rūta , Jaeger Dirk , von Kalle Christof , Ball Claudia R. , Ungerechts Guy , Engeland Christine E.
Published: February 2018

Purpose: Immunotherapy with bispecific T-cell engagers has achieved striking success against hematologic malignancies, but efficacy against solid tumors has been limited. We hypothesized that oncolytic measles viruses encoding bispecific T-cell engagers (MV-BiTEs) represent a safe and effective treatment against solid tumors through local BiTE expression, direct tumor cell lysis and in situ tumor vaccination.

Experimental Design: To test this hypothesis, we generated MV-BiTEs from the Edmonston B vaccine strain to target two model antigens. Replicative and oncolytic potential were assessed by infection and cell viability assays, respectively. Functionality of virus-derived BiTEs was tested in vitro by complementary binding and cytotoxicity assays. In vivo efficacy of MV-BiTE was investigated using both syngeneic and xenograft mouse models of solid cancers.

Results: We verified secretion of functional BiTE antibodies by MV-BiTE-infected cells. Further, we demonstrated therapeutic efficacy of MV-BiTE against established tumors in fully immunocompetent mice. MV-BiTE efficacy was associated with increased intratumoral T-cell infiltration and induction of protective antitumor immunity. In addition, we showed therapeutic efficacy of MV-BiTE in xenograft models of patient-derived primary colorectal carcinoma spheroids with transfer of peripheral blood mononuclear cells.

Conclusions: MV-BiTE treatment was effective in two distinct models of solid tumors without signs of toxicity. This provides strong evidence for therapeutic benefits of tumor-targeted BiTE expression by oncolytic MV. Thus, this study represents proof of concept for an effective strategy to treat solid tumors with BiTEs. Clin Cancer Res; 24(9); 2128–37. ©2018 AACR.
A First-in-Human Study of the New Oral Selective Estrogen Receptor Degrader AZD9496 for ER+/HER2− Advanced Breast Cancer
Authors: Hamilton Erika P. , Patel Manish R. , Armstrong Anne C. , Baird Richard D. , Jhaveri Komal , Hoch Matthias , Klinowska Teresa , Lindemann Justin P.O. , Morgan Shethah R. , Schiavon Gaia , Weir Hazel M. , Im Seock-Ah
Published: February 2018

Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent and selective antagonist and degrader of ERα. This first-in-human phase I study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER)+/HER2− advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity.

Patients and Methods: Forty-five patients received AZD9496 [20 mg once daily (QD) to 600 mg twice daily (BID)] in a dose-escalation, dose-expansion “rolling 6” design. Safety, tolerability, and PK activity in each cohort were reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Results: Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade ≥3 AEs. Three patients experienced a dose-limiting toxicity: one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests), and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow-up.

Conclusions: AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pretreated patients with ER+/HER2− advanced breast cancer. Clin Cancer Res; 24(15); 3510–8. ©2018 AACR.

See related commentary by Jordan, p. 3480
Shedding Light on IDH1 Mutation in Gliomas
Authors: Hollon Todd C. , Orringer Daniel A.
Published: February 2018

IDH mutation is of central importance in the diagnosis and treatment of gliomas. Fourier-transform infrared spectroscopy, in combination with a supervised machine-learning approach, can be used to detect metabolic alterations induced by IDH1 mutations in a fraction of the time of conventional techniques. Clin Cancer Res; 24(11); 2467–9. ©2018 AACR.

See related article by Uckermann et al., p. 2530
Effects of Diet on Telomere Length: Systematic Review and Meta-Analysis
Authors: Pérez Lisiane Marçal , Amaral Marina Azambuja , Mundstock Eduardo , Barbé-Tuana Florencia M. , Guma Fátima Teresinha Costa Rodrigues , Jones Marcus H. , Machado Denise Cantarelli , Sarria Edgar E. , Marques e Marques Maximiniano , Preto Luiza Tweedie , Epifanio Matias , Meinem Garbin João Guilherme , Mattiello Rita
Published: February 2018

Background: The goal of this systematic review and meta-analysis is to determine the effect of diet on telomere length. Methods: We searched the following databases: MEDLINE, Embase, LILACS, CINAHL, ISI Web of Science, and Scopus, as well as the Cochrane Central Register of Controlled Trials and the National Institutes of Health, from inception to December 2016. Articles that assessed effects of diet on telomere length were included. Results: A total of 2,128 studies were identified, 30 were read in full, and 7 were systematically reviewed. Five RCTs were included in the meta-analysis, covering 9 diets; a total of 533 participants were included. Study heterogeneity (I2) was 89%, and differences were not identified regarding average telomere lengths (mean difference 1.06; 95% CI –1.53 to 3.65). Conclusion: The available evidence suggests that there is no effect of diet on telomere length, but the strong heterogeneity in the type and duration of dietary interventions does not allow any final statement on the absence of an effect of diet on telomere length.
Bone Marrow Cell Therapy on 1,2-Dimethylhydrazine (DMH)-Induced Colon Cancer in Rats
Authors: El-Khadragy Manal F. , Nabil Heba M. , Hassan Basmaa N. , Tohamy Amany A. , Waaer Hanaa F. , Yehia Hany M. , Alharbi Afra M. , Moneim Ahmed Esmat Abdel 
Published: February 2018

Background/Aims: Stem cell based therapies are being under focus due to their possible role in treatment of various tumors. Bone marrow stem cells believed to have anticancer potential and are preferred for their activities by stimulating the immune system, migration to the site of tumor and ability for inducting apoptosis in cancer cells. The current study was aimed to investigate the tumor suppressive effects of bone marrow cells (BMCs) in 1,2-dimethylhydrazine (DMH)-induced colon cancer in rats. Methods: The rats were randomly allocated into four groups: control, BMCs alone, DMH alone and BMCs with DMH. BMCs were injected intrarectally while DMH was injected subcutaneously at 20 mg/kg body weight once a week for 15 weeks. Histopathological examination and gene expression of survivin, β-catenin and multidrug resistance-1 (MDR-1) by real-time reverse transcription-polymerase chain reaction (RT-PCR) in rat colon tissues. This is in addition to oxidative stress markers in colon were performed across all groups. Results: The presence of aberrant crypt foci was reordered once histopathological examination of colon tissue from rats which received DMH alone. Administration of BMCs into rats starting from zero-day of DMH injection improved the histopathological picture which showed a clear improvement in mucosal layer, few inflammatory cells infiltration periglandular and in the lamina propria. Gene expression in rat colon tissue demonstrated that BMCs down-regulated survivin, β-catenin, MDR-1 and cytokeratin 20 genes expression in colon tissues after colon cancer induction. Amelioration of the colon status after administration of MSCs has been evidenced by a major reduction of lipid peroxidation, nitric oxide, and increasing of glutathione content and superoxide dismutase along with catalase activities. Conclusion: Our findings demonstrated that BMCs have tumor suppressive effects in DMH-induced colon cancer as evidenced by down-regulation of survivin, β-catenin, and MDR-1 genes and enhancing the antioxidant activity.
Deficiency of Complement C3a and C5a Receptors Prevents Angiotensin II–Induced Hypertension via Regulatory T Cells
Authors: Chen Xiao-Hui , Ruan Cheng-Chao , Ge Qian , Ma Yu , Xu Jian-Zhong , Zhang Ze-Bei , Lin Jing-Rong , Chen Dong-Rui , Zhu Ding-Liang , Gao Ping-Jin
Published: February 2018

Rationale:

Inflammation and immunity play crucial roles in the development of hypertension. Complement activation-mediated innate immune response is involved in the regulation of hypertension and target-organ damage. However, whether complement-mediated T-cell functions could regulate blood pressure elevation in hypertension is still unclear.

Objective:

We aim to determine whether C3aR (complement component 3a receptor) and C5aR (complement component 5a receptor) could regulate blood pressure via modulating regulatory T cells (Tregs).

Methods and Results:

We showed that angiotensin II (Ang II)-induced hypertension resulted in an elevated expression of C3aR and C5aR in Foxp3 (forkhead box P3)+ Tregs. By using C3aR and C5aR DKO (double knockout) mice, we showed that C3aR and C5aR deficiency together strikingly decreased both systolic and diastolic blood pressure in response to Ang II compared with WT (wild type), single C3aR-deficient (C3aR−/−), or C5aR-deficient (C5aR−/−) mice. Flow cytometric analysis showed that Ang II-induced Treg reduction in the kidney and blood was also blocked in DKO mice. Histological analysis indicated that renal and vascular structure remodeling and damage after Ang II treatment were attenuated in DKO mice compared with WT mice. In vitro, Ang II was able to stimulate C3aR and C5aR expression in cultured CD4+CD25+ natural Tregs. CD3 and CD28 antibody stimuli downregulated Foxp3 expression in WT but not DKO Tregs. More important, depletion of Tregs with CD25 antibody abolished the protective effects against Ang II-induced hypertension and target-organ damage in DKO mice. Adoptive transfer of DKO Tregs showed much more profound protective effects against Ang II-induced hypertension than WT Treg transfer. Furthermore, we demonstrated that C5aR expression in Foxp3+ Tregs was higher in hypertensive patients compared with normotensive individuals.

Conclusions:

C3aR and C5aR DKO-mediated Treg function prevents Ang II-induced hypertension and target-organ damage. Targeting C3aR and C5aR in Tregs specifically may be an alternative novel approach for hypertension treatment.
Impaired Production and Diurnal Regulation of Vascular RvD
n-3 DPA
Increase Systemic Inflammation and Cardiovascular Disease
Authors: Colas Romain A. , Souza Patricia R. , Walker Mary E. , Burton Maudrian , Zasłona Zbigniew , Curtis Annie M. , Marques Raquel M. , Dalli Jesmond
Published: February 2018

Rationale:

Diurnal mechanisms are central to regulating host responses. Recent studies uncovered a novel family of mediators termed as specialized proresolving mediators that terminate inflammation without interfering with the immune response.

Objective:

Herein, we investigated the diurnal regulation of specialized proresolving mediators in humans and their role in controlling peripheral blood leukocyte and platelet activation.

Methods and Results:

Using lipid mediator profiling and healthy volunteers, we found that plasma concentrations of n-3 docosapentaenoic acid-derived D-series resolvins (RvD
n-3 DPA
) were regulated in a diurnal manner. The production and regulation of these mediators was markedly altered in patients at risk of myocardial infarct. These changes were associated with decreased 5-lipoxygenase expression and activity, as well as increased systemic adenosine concentrations. We also found a significant negative correlation between plasma RvD
n-3 DPA
and markers of platelet, monocyte, and neutrophil activation, including CD63 and CD11b. Incubation of RvD
n-3 DPA
with peripheral blood from healthy volunteers and patients with cardiovascular disease significantly and dose-dependently decreased platelet and leukocyte activation. Furthermore, administration of RvD5
n-3 DPA
to ApoE
−/−
(apolipoprotein E deficient) mice significantly reduced platelet–leukocyte aggregates, vascular thromboxane B
2
concentrations, and aortic lesions.

Conclusions:

These results demonstrate that peripheral blood RvD
n-3 DPA
are diurnally regulated in humans, and dysregulation in the production of these mediators may lead to cardiovascular disease.
Network Analysis to Risk Stratify Patients With Exercise Intolerance
Authors: Oldham William M. , Oliveira Rudolf K.F. , Wang Rui-Sheng , Opotowsky Alexander R. , Rubins David M. , Hainer Jon , Wertheim Bradley M. , Alba George A. , Choudhary Gaurav , Tornyos Adrienn , MacRae Calum A. , Loscalzo Joseph , Leopold Jane A. , Waxman Aaron B. , Olschewski Horst , Kovacs Gabor , Systrom David M. , Maron Bradley A.
Published: February 2018

Rationale:

Current methods assessing clinical risk because of exercise intolerance in patients with cardiopulmonary disease rely on a small subset of traditional variables. Alternative strategies incorporating the spectrum of factors underlying prognosis in at-risk patients may be useful clinically, but are lacking.

Objective:

Use unbiased analyses to identify variables that correspond to clinical risk in patients with exercise intolerance.

Methods and Results:

Data from 738 consecutive patients referred for invasive cardiopulmonary exercise testing at a single center (2011–2015) were analyzed retrospectively (derivation cohort). A correlation network of invasive cardiopulmonary exercise testing parameters was assembled using |r|>0.5. From an exercise network of 39 variables (ie, nodes) and 98 correlations (ie, edges) corresponding to
P
<9.5e
−46
for each correlation, we focused on a subnetwork containing peak volume of oxygen consumption (pV
o
2
) and 9 linked nodes. K-mean clustering based on these 10 variables identified 4 novel patient clusters characterized by significant differences in 44 of 45 exercise measurements (
P
<0.01). Compared with a probabilistic model, including 23 independent predictors of pV
o
2
and pV
o
2
itself, the network model was less redundant and identified clusters that were more distinct. Cluster assignment from the network model was predictive of subsequent clinical events. For example, a 4.3-fold (
P
<0.0001; 95% CI, 2.2–8.1) and 2.8-fold (
P
=0.0018; 95% CI, 1.5–5.2) increase in hazard for age- and pV
o
2
-adjusted all-cause 3-year hospitalization, respectively, were observed between the highest versus lowest risk clusters. Using these data, we developed the first risk-stratification calculator for patients with exercise intolerance. When applying the risk calculator to patients in 2 independent invasive cardiopulmonary exercise testing cohorts (Boston and Graz, Austria), we observed a clinical risk profile that paralleled the derivation cohort.

Conclusions:

Network analyses were used to identify novel exercise groups and develop a point-of-care risk calculator. These data expand the range of useful clinical variables beyond pV
o
2
that predict hospitalization in patients with exercise intolerance.
TLR9 (Toll-Like Receptor 9) Agonist Suppresses Angiogenesis by Differentially Regulating VEGFA (Vascular Endothelial Growth Factor A) and sFLT1 (Soluble Vascular Endothelial Growth Factor Receptor 1) in Preeclampsia
Authors: He Biwei , Yang Xingyu , Li Yamei , Huang Ding , Xu Xin , Yang Wenjun , Dai Yan , Zhang Huijuan , Chen Zhengjun , Cheng Weiwei
Published: February 2018

Preeclampsia is a common pregnancy-specific disorder characterized by elevated blood pressure and proteinuria. Activation of the maternal immune system and impaired placental angiogenesis are thought to contribute to the pathogenesis of preeclampsia. TLR9 (Toll-like receptor 9) plays a role in innate immunity, defending the organism against infection. The purpose of this study was to determine whether TLR9 inhibits angiogenesis at the fetomaternal interface under conditions of preeclampsia. We confirmed the downregulation of VEGFA (vascular endothelial growth factor A) and upregulation of TLR9 and sFLT1 (soluble vascular endothelial growth factor receptor 1) in placentas from preeclamptic women. Then, we established a mouse model with preeclampsia-like symptoms using the synthetic TLR9 agonist CpG (cytidine–phosphate–guanosine)-ODN (oligodeoxynucleotide; ODN1826). We observed the downregulation of VEGFA and the upregulation of sFLT1 in placentas from the preeclampsia-like animal model and in trophoblasts treated with CpG-ODN (ODN2006). In addition, silencing TLR9 promoted the migration and invasion of HTR8/SVneo cells. In conclusion, TLR9 is capable of robustly suppressing angiogenesis by differentially regulating the expression of VEGFA and sFLT1 at the fetomaternal interface, potentially contributing to the development of preeclampsia.
Dyslipidemia and Risk of Cardiovascular Events in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Therapy: Insights From the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) Trial
Authors: Pol Tymon , Held Claes , Westerbergh Johan , Lindbäck Johan , Alexander John H. , Alings Marco , Erol Cetin , Goto Shinya , Halvorsen Sigrun , Huber Kurt , Hanna Michael , Lopes Renato D. , Ruzyllo Witold , Granger Christopher B. , Hijazi Ziad
Published: February 2018

Background

Dyslipidemia is a major risk factor for cardiovascular events. The prognostic importance of lipoproteins in patients with atrial fibrillation is not well understood. We aimed to explore the association between apolipoprotein A1 (ApoA1) and B (ApoB) and cardiovascular events in patients with atrial fibrillation receiving oral anticoagulation.

Methods and Results

Using data from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, ApoA1 and ApoB plasma levels were measured at baseline in 14 884 atrial fibrillation patients. Median length of follow‐up was 1.9 years. Relationships between continuous levels of ApoA1 and ApoB and clinical outcomes were evaluated using Cox models adjusted for cardiovascular risk factors, medication including statins, and cardiovascular biomarkers. A composite ischemic outcome (ischemic stroke, systemic embolism, myocardial infarction, and cardiovascular death) was used as the primary end point. Median (25th, 75th) ApoA1 and ApoB levels were 1.10 (0.93, 1.30) and 0.70 g/L (0.55, 0.85), respectively. In adjusted analyses, higher levels of ApoA1 were independently associated with a lower risk of the composite ischemic outcome (hazard ratio, 0.81;
P
<0.0001). Similar results were observed for the individual components of the composite outcome. ApoB was not significantly associated with the composite ischemic outcome (
P
=0.8240). Neither apolipoprotein was significantly associated with major bleeding. There was no interaction between lipoproteins and randomized treatment for the primary outcome (both
P
values ≥0.2448).

Conclusions

In patients with atrial fibrillation on oral anticoagulation, higher levels of ApoA1 were independently associated with lower risk of ischemic cardiovascular outcomes. Investigating therapies targeting dyslipidemia may thus be useful to improve cardiovascular outcomes in patients with atrial fibrillation.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00412984.
On the Need of Conviviality: Experiences of Religious Diversity of Nordic Youth
Authors: Vähäkangas Auli , Leis-Peters Annette
Published: February 2018

This article studies young people’s experiences of religious diversity in two Nordic localities in Finland and in Norway. In the Nordic discourse, the concept of conviviality gained importance through the lwf’s policy document Seeking Conviviality in 2013. Haugen’s three “Rs”, respect, relationality and reciprocity will be used as a starting point for the analysis of the experiences of young people. The aim of the study is to understand how young people experience religious diversity and what these experiences can contribute to Haugen’s reformulation of conviviality. The results show that conviviality tends to be more easily discussed than practised. They indicate that living in the same neighbourhood with youth from other religious traditions helps to face religious diversity but that this coexistence does not in itself generate reciprocity. Rather, in order to really live together there is a need to get to know each other’s practices and values more deeply.
Revision of Banded Knifefishes of the Gymnotus carapo and G. tigre clades (Gymnotidae Gymnotiformes) from the Southern Neotropics
Authors: CRAIG JACK M. , MALABARBA LUIZ R. , CRAMPTON WILLIAM G. R. , ALBERT JAMES S.
Published: February 2018

Banded Knifefishes (Gymnotus, Gymnotidae) comprise the most species-rich, ecologically tolerant (eurytopic), and geographically widespread genus of Neotropical electric fishes (Gymnotiformes), with 40 valid species occupying most habitats and regions throughout the humid Neotropics. Despite substantial alpha-taxonomic work in recent years, parts of the genus remain characterized by taxonomic confusion. Here we describe and delimit species of the G. carapo and G. tigre clades from the southern Neotropics, using body proportions (caliper-based morphometrics), fin-ray, scale and laterosensory-pore counts (meristics), quantitative shape differences (geometric morphometrics), osteology, color patterns and electric organ discharges. We report these data from 174 Gymnotus specimens collected from 100 localities throughout the southern Neotropics, and delimit species boundaries in a multivariate statistical framework. We find six species of the G. carapo clade (G. carapo australis, G. cuia n. sp., G. chimarrao, G. omarorum, G. pantanal, and G. sylvius), and two species of the G. tigre clade (G. inaequilabiatus and G. paraguensis) in the southern Neotropics. The new species G. cuia is readily distinguished from the morphologically similar and broadly sympatric G. c. australis by a shorter head and deeper head and body, and from the morphologically similar and sympatric G. omarorum by fewer lateral-line ventral rami and fewer pored lateral-line scales anterior to the first ventral ramus. We also review the geographic distributions of all eight species of the G. carapo and G. tigre clades in the southern Neotropics, showing that G. cuia is the most widespread species in the region. These results affirm the importance of understanding the structure of variation within and between species, both geographic and ontogenetic, in delimiting species boundaries.
Meeting Report on the Fifth AMS Symposium on Education
Authors: Smith David R. , Bastiaans Lisa M. , Zeitler Jon W. , McPherson Renee A. , Rydell Nezette N. , Rao G.V. , Warthan H. Patricia , KIoeseI Kevin A. , Heckman Brian E. , Ramamurthy Mohan K.
Published: February 2018

The American Meteorological Society (AMS) held its Fifth Symposium on Education in conjunction with the 76th Annual Meeting in Atlanta, Georgia. The theme of this year's symposium was “Atmospheric and Oceanic Sciences: Building the Future on a Solid Foundation.” Thirty-four oral presentations and 41 poster presentations summarized a variety of educational programs or examined issues of importance for both the precollege and university levels. There was also a joint session with the 12th International Conference on Interactive Information and Processing Systems for Meteorology, Oceanography, and Hydrography on new technologies for the classroom. Over 200 people representing a wide spectrum of the Society attended one or more of the sessions in this two-day conference, where they increased their awareness of educational initiatives of members and institutions associated with AMS.