bluuebunny/crossref_metadata_2025 huggingface dataset:
LWeb: information flow security for multi-tier web applications
Authors: Parker James , Vazou Niki , Hicks Michael
Published: January 2019

This paper presents LWeb, a framework for enforcing label-based, information flow policies in database-using web applications. In a nutshell, LWeb marries the LIO Haskell IFC enforcement library with the Yesod web programming framework. The implementation has two parts. First, we extract the core of LIO into a monad transformer (LMonad) and then apply it to Yesod’s core monad. Second, we extend Yesod’s table definition DSL and query functionality to permit defining and enforcing label-based policies on tables and enforcing them during query processing. LWeb’s policy language is expressive, permitting dynamic per-table and per-row policies. We formalize the essence of LWeb in the λ

LWeb

calculus and mechanize the proof of noninterference in Liquid Haskell. This mechanization constitutes the first metatheoretic proof carried out in Liquid Haskell. We also used LWeb to build a substantial web site hosting the Build it, Break it, Fix it security-oriented programming contest. The site involves 40 data tables and sophisticated policies. Compared to manually checking security policies, LWeb imposes a modest runtime overhead of between 2% to 21%. It reduces the trusted code base from the whole application to just 1% of the application code, and 21% of the code overall (when counting LWeb too).
Estimation of the baroreflex total loop gain by the power spectral analysis of continuous arterial pressure recordings
Authors: Mannoji Hiroshi , Saku Keita , Nishikawa Takuya , Tohyama Takeshi , Kamada Kazuhiro , Abe Kiyokazu , Sunagawa Genya , Kishi Takuya , Sunagawa Kenji , Tsutsui Hiroyuki
Published: January 2019

Baroreflex dysfunction contributes to the pathogenesis of cardiovascular diseases. The baroreflex comprises a negative feedback loop to stabilize arterial pressure (AP); its pressure-stabilizing capacity is defined as the gain ( G) of the transfer function ( H) of the baroreflex total loop. However, no method exists to evaluate G in a clinical setting. A feedback system with H attenuates pressure disturbance (PD) to PD/(1 + H). We hypothesized that the baroreflex attenuates the power spectrum density (PSD) of AP in the baroreflex functioning frequency range. We created graded baroreflex dysfunction in rats using a modified sinoaortic denervation (SAD) method [SAD; control (no SAD): n = 9; partial SAD (SAD in the right carotid sinus): n = 6, and total SAD (SAD in the bilateral carotid sinuses): n = 6] and evaluated the PSD of 12-h telemetric AP recordings in the light phase. Using the ratio of PSD at 0.01–0.1 Hz (PSD slope), we normalized them with the PSD in rats with complete baroreflex failure and derived the baroreflex index (BRI), which directly reflects G. We compared BRI and G obtained from a baroreflex open-loop experiment (reference G). The PSD slope became steeper with progression of baroreflex dysfunction. BRI (control: 2.00 ± 0.31, partial SAD: 1.28 ± 0.30, and total SAD: 0.06 ± 0.10, P < 0.05) was linearly correlated with reference G ( R2 = 0.91, P < 0.01). BRI accurately estimated G of the baroreflex and may serve as a novel tool for estimating the pressure-stabilizing capacity of the baroreflex in clinical settings.

NEW & NOTEWORTHY This study proposed a novel method to estimate the gain of the baroreflex total loop, the so-called “baroreflex index” (BRI). BRI focuses on action potential variability in the frequency domain, considering baroreflex low-pass filter characteristics within 0.01–0.1 Hz. We demonstrated that BRI was linearly correlated with the reference gain of baroreflex in rats. Thus, BRI may contribute greatly to the development of a clinical tool for estimating baroreflex pressure-stabilizing capacity.
Brown and Red Seaweeds Serve as Potential Efflux Pump Inhibitors for Drug-Resistant Escherichia coli
Authors: Lu Wen-Jung , Lin Hsuan-Ju , Hsu Pang-Hung , Lai Margaret , Chiu Jen-Yu , Lin Hong-Ting Victor
Published: January 2019

Multidrug-resistant pathogens are a significant clinical problem. Efflux pump inhibitors (EPIs) can restore the activities of existing antibiotics by interfering with drug efflux pumps located in bacterial cell membranes. Seaweeds are important sources of biologically active metabolites of natural origin; however, their potential as EPIs remains uninvestigated. Here, functional extracts from the brown seaweeds Laminaria japonica and Sargassum horneri and the red seaweeds Gracilaria sp. and Porphyra dentata were evaluated as potential EPIs against drug-resistant Escherichia coli. All these extracts were found to potentiate the activities of drugs in modulation tests, although not to the same extent. Synergistic effects of the extracts and the drug clarithromycin were observed from the onset of Time-kill assays, with no evidence of bacterial regrowth. Ethidium bromide accumulation studies revealed that the efflux decreased in the presence of each extract, as indicated by the presence of EPIs. Most identified EPIs that have been discovered to date have aromatic structures, and the seaweed extracts were found to contain various terpenes, terpenoids, phenolic compounds, indoles, pyrrole derivatives, alkaloids, and halogenated aromatic compounds. Our study highlights the potential of these compounds of the seaweeds as drug EPIs.
Yangyin Qingre Huoxue Method in Traditional Chinese Medicine Ameliorates Atherosclerosis in ApoE−/− Mice Suffering from High-Fat Diet and HSP65 Aggression
Authors: Qiu Runze , Long Jun , Zhou Liyu , Ma Yuanjing , Zhao Lingang , Liu Fumin , Yuan Dongping
Published: January 2019

Atherosclerosis (AS) is a complicated arterial disease resulting from abnormal lipid deposition and inflammatory injury, which is attributed to Yin deficiency, accumulation of heat materials, and stasis of blood flow in Traditional Chinese Medicine (TCM) theory. Thus, according to TCM theory, the method of nourishing Yin (Yangyin), clearing away heat (Qingre), and promoting blood circulation (Huoxue) is a reasonable strategy, which has achieved remarkable clinical efficacy in the treatment of AS, but the mechanisms remain to be known. In this study, we evaluated the effects of Yangyin Qingre Huoxue Prescription (YQHP) on AS in ApoE-/- mice suffering from a high-fat diet and heat shock protein (HSP65) attack. YQHP regulated levels of blood lipids and inflammation-linked cytokines as well as Th17/Treg ratio in peripheral blood. Suppressed IL-6-p-STAT3 signaling and restored IL-2-p-STAT5 signaling in the presence of YQHP may partake in the regulation of Th17 and Treg differentiation. Moreover, YQHP modulated transcriptional levels of costimulator CD80 in aortas as well corresponding to the downregulation of GM-CSF in serum and CD3 expression in CD4+ T cells, which might indicate the potential of YQHP to regulate antigen presenting cells. All these effects eventually promoted the improvement of atherosclerotic lesions. In addition, YQHP promoted less monocyte infiltration in the liver and lower levels of AST, ALT, and AKP production than simvastatin. Conclusively, lipid-regulating and anti-inflammatory functions mediated by YQHP with lower hepatotoxicity than simvastatin hindered the progression of HSP65 aggravated AS in ApoE-/- mice, indicating the effectiveness of Yangyin Qingre Huoxue Method in the treatment of AS.
Effects of Limited Computational Precision on the Discrete Chaotic Sequences and the Design of Related Solutions
Authors: Fan Chunlei , Ding Qun
Published: January 2019

In this paper, we analyzed the periodicity of discrete Logistic and Tent sequences with different computational precision in detail. Further, we found that the process of iterations of the Logistic and Tent mapping is composed of transient and periodic stages. Surprisingly, for the different initial iterative values, we first discovered that all periodic stages have the same periodic limit cycles. This phenomenon has seriously affected the security of chaotic cipher. To solve this problem, we designed a novel discrete chaotic sequence generator based on m‐sequence and discrete chaotic mapping. The experimental results indicated that the chaotic sequence generator can generate pseudorandom chaotic sequences with large periodicity and good performance under the condition of limited computational precision.
Ginsenoside Re Improves Isoproterenol-Induced Myocardial Fibrosis and Heart Failure in Rats
Authors: Wang Quan-wei , Yu Xiao-feng , Xu Hua-li , Zhao Xue-zhong , Sui Da-yuan
Published: January 2019

Objective. Panax ginseng is used widely for treatment of cardiovascular disorders in China. Ginsenoside Re is the main chemical component of P. ginseng. We aimed to investigate the protective effect of ginsenoside Re on isoproterenol-induced myocardial fibrosis and heart failure in rats. Methods. A model of myocardial fibrosis and heart failure was established by once-daily subcutaneous injection of isoproterenol (5 mg/kg/day) to rats for 7 days. Simultaneously, rats were orally administrated ginsenoside Re (5 or 20 mg/kg) or vehicle daily for 4 weeks. Results. Isoproterenol enhanced the heart weight, myocardial fibrosis, and hydroxyproline content in rat hearts. Ginsenoside Re inhibited (at least in part) the isoproterenol-induced increase in heart weight, myocardial fibrosis, and hydroxyproline content. Compared with the isoproterenol group, treatment with ginsenoside Re ameliorated changes in left ventricular systolic pressure, left ventricular end diastolic pressure, and the positive and negative maximal values of the first derivative of left ventricular pressure. Ginsenoside Re administration also resulted in decreased expression of transforming growth factor (TGF)-β1 in serum and decreased expression of Smad3 and collagen I in heart tissue. Conclusion. Ginsenoside Re can improve isoproterenol-induced myocardial fibrosis and heart failure by regulation of the TGF-β1/Smad3 pathway.
Reproducibility of BiliCare™ Transcutaneus Bilirrubin Meter in Mexican Newborns
Authors: Oldak David , García Gabriela , Gonzalez Estela E. , Aillon Enver , Falcon Juan C. , Ayala Ernesto , Oldak Bernardo
Published: January 2019

Background. Newborn hyperbilirubinemia is considered a worldwide health problem that demands medical evaluation. Noninvasive transcutaneous bilirubin (TcB) has been used as a screening method with different devices but there has not been any evaluation of reproducibility of the same brand devices. The BiliCare™ system is evaluated to demonstrate consistency between measurements with four different devices.Methods. 336 TcB measurements were obtained with four BiliCare™ devices in 21 Mexican icteric newborns with a mean postnatal age of 44.1 hours of life and 38 weeks of gestation (33–41). Two measurements were taken in the same ear alternatively at the scaphoid fossa with each device. TcB values were compared between devices. Validity was compared with total serum bilirubin (TB).Results. intraclass correlation coefficient demonstrates a minimum limit in the study of 0.945 and maximum of 0.988 with the same device. Correlations with serum and between devices gave results above 0.932.Conclusions. BiliCare™ transcutaneous bilirubin measurement instrument has very good intra- and interdevice reproducibility; also correlation of TcS with serum bilirubin gave statistically the same results.
Floods of 18 and 19 November 2016 in Batouri (East Cameroon): Interpretation of the Hydro-Meteorological Parameters and Historical Context of the Post-Event Survey Episode
Authors: Kalédjé Paulin Sainclair Kouassy , Ngoupayou Jules-Rémy Ndam , Takounjou Alain Fouépé , Zebsa Mireille , Rakotondrabe Felaniaina , Ondoa Joseph Mvondo
Published: January 2019

During the night of November 18 to 19, 2016, many stormy cells are not very mobile organized on the east of the southern plateau of Cameroon and dumped up to 260 mm of rain in 4 hours. Occurring on a relatively saturated soil, these rains caused strong floods of Kadey and Doumé. The floods were particularly damaging in the city of Batouri, where a subdivision was submerged by the Boumbé (tributary of the Sangha) with water heights in the houses reaching 1.75 m, despite the presence of a dam allowing clipping floods upstream of the basin. In this article, we present the results of the analysis of the postevent survey generated on this event with flow rates estimated on 15 sections of ungauged subbasins. These flows are then compared with those obtained from other recent postevent survey and those estimated by various regional estimations. The inventory of heavy rains around Batouri during the period 1970-2016 has led to the revision of current development standards in the region, which seem to underestimate rainfall and infrequent flows.
Attitudes towards Donor Breast Milk in an Inner City Population
Authors: Pal Abhinav , Soontarapornchai Kultida , Noble Lawrence , Hand Ivan
Published: January 2019

Objective. The purpose of our study was to identify attitudes towards donor breast milk in our population and identify barriers to its acceptance. Methods. The study sample was comprised of a convenience sample of 174 postpartum women. A questionnaire consisting of demographic information and 12 questions relating to attitudes and understanding of donor breast milk was administered. Results. Among the mothers surveyed, 34% were aware of the use of donor breast milk and donor milk banks. 62% of mothers preferred the use of formula compared to donor breast milk if they were unable to provide their own breast milk. Educational level did play a role with 64% of mothers with education beyond high school believing that donor breast milk was beneficial for newborns as opposed to 46% with a high school education or less (p=0.02). US born mothers were more likely to have heard about donor breast milk (47% versus 29%, p=0.025) than foreign born mothers although they were less likely to believe it was a better option for feeding than formula (22.7% versus 43%, p=.016). Mothers with infants in the NICU were more likely than mothers of well babies to accept milk from a milk bank rather than a relative or friend (81% versus 39%, p≤0.001). Conclusion. Although the beneficial effects of donor breast milk are well established in the scientific community, there remains a lack of awareness and a major discrepancy in the understanding and acceptance of it within our community. Education on the benefits of mother’s own milk as well as donor breast milk and milk banks is an important public health initiative needed to increase acceptance of human milk as the optimal form of nutrition in infants.
Shuang-Huang-Lian Attenuates Airway Hyperresponsiveness and Inflammation in a Shrimp Protein-Induced Murine Asthma Model
Authors: Gao Yuan , Fei Qiaoling , Qi Ruijuan , Hou Rui , Han Yixin , Cai Runlan , Sun Guibo , Qi Yun
Published: January 2019

Shuang-Huang-Lian (SHL), an herbal formula of traditional Chinese medicine, is clinically used for bronchial asthma treatment. Our previous study found that SHL prevented basophil activation to suppress Th2 immunity and stabilized mast cells through activating its mitochondrial calcium uniporter. Sporadic clinical reports that SHL was used for the treatment of bronchial asthma can be found. Thus, in this study, we systematically investigated the effects of SHL on asthmatic responses using a shrimp protein (SP)- induced mouse model. SHL significantly inhibited airway inspiratory and expiratory resistance, and histological studies suggested it reduced thickness of airway smooth muscle and infiltration of inflammation cells. It also could alleviate eosinophilic airway inflammation (EAI), including reducing the number of eosinophils and decreasing eotaxin and eosinophil peroxidase levels in the bronchoalveolar lavage fluid (BALF). Further studies indicated that SHL suppressed SP-elevated mouse mast cell protease-1 and IgE levels, prevented Th2 differentiation in mediastinal lymph nodes, and lowered Th2 cytokine (e.g., IL-4, IL-5, and IL-13) production in BALF. In conclusion, SHL attenuates airway hyperresponsiveness and EAI mainly via the inhibition of mast cell activation and Th2 immunity, which may help to elucidate the underlying mechanism of SHL on asthma treatment and support its clinical use.
Machine Learning Based Antenna Design for Physical Layer Security in Ambient Backscatter Communications
Authors: Hong Tao , Liu Cong , Kadoch Michel
Published: January 2019

Ambient backscatter employs existing radio frequency (RF) signals in the environment to support sustainable and independent communications, thereby providing a new set of applications that promote the Internet of Things (IoT). However, nondirectional forms of communication are prone to information leakage. In order to ensure the security of the IoT communication system, in this paper, we propose a machine learning based antenna design scheme, which achieves directional communication from the relay tag to the receiving reader by combining patch antenna with log-periodic dual-dipole antenna (LPDA). A multiobjective genetic algorithm optimizes the antenna side lobe, gain, standing wave ratio, and return loss, with a goal of limiting the number of large side lobes and reduce the side lobe level (SLL). The simulation results demonstrate that our proposed antenna design is well suited for practical applications in physical layer security communication, where signal-to-noise ratio of the wiretap channel is reduced, communication quality of the main channel is ensured, and information leakage is prevented.
Blow-Up Solution of Modified-Logistic-Diffusion Equation
Authors: Sitompul P. , Soeharyadi Y.
Published: January 2019

Modified-Logistic-Diffusion Equation ut=Duxx+u|1-u| with Neumann boundary condition has a global solution, if the given initial condition ψ satisfies ψ(x)≤1, for all x∈[0,1]. Other initial conditions can lead to another type of solutions; i.e., an initial condition that satifies ∫01ψ(x)dx>1 will cause the solution to blow up in a finite time. Another initial condition will result in another kind of solution, which depends on the diffusion coefficient D. In this paper, we obtained the lower bound of D, so that the solution of Modified-Logistic-Diffusion Equation with a given initial condition will have a global solution.
Influence of Preparation Reconstruction on the Compressive Strength of CAD/CAM Ceramic Inlays
Authors: Salamoni Sinhori Bruna , Vieira Luiz Clovis Cardoso , Baratieri Luiz Narciso
Published: January 2019

The aim of this study was to evaluate whether the compressive strength of lithium dissilicate ceramic inlays is influenced by the substrate (dentin or composite resin build-up) and to compare it to nonrestored teeth. Thirty freshly extracted human maxillary third molars were selected and randomly ascribed to three groups (n=10). Standardized Class II MOD preparations were made (bucco-palatal width = 2/3 of the intercuspal width and 2/3 of the width at the tooth equator for the proximal boxes), varying the extension of the preparations (Group 2: preparation limited to tooth structure; Group 3: pulpal floor of the preparation rebuilt with composite resin, IPS Empress Direct, restored with lithium dissilicate CAD/CAM ceramic inlays (e.max CAD) and cemented with a resin cement (Variolink II)). All groups were subjected to compressive strength test (1mm/min crosshead speed). The results showed that the fracture strength of G1 (control group) was significantly higher than G2 and G3, while within these groups there were no statistically significant differences. Both groups restored with lithium dissilicate restorations did not reach the fracture strength of the sound teeth but were statistically equivalent and sufficient to withstand physiologic masticatory forces.
Transmission Dynamics of Urogenital Schistosomiasis in the Rural Community of Ebonyi State, South Eastern Nigeria
Authors: Afiukwa F. N. , Nwele D. E. , Uguru O. E. , Ibiam G. A. , Onwe C. S. , Ikpo A. U. , Agumah N. B. , Odoemena O. F.
Published: January 2019

This study accessed the dynamics of urogenital schistosomiasis transmission in Nkalagu Community. A total of 500 mid-day urine samples were collected and transported to Microbiology Laboratory, Ebonyi State University, for analysis. 10ml each of the urine samples was centrifuged at 2500 rpm for 5 minutes. Transmission potential of snail intermediate host of Schistosomes collected from different sampling station at the transmission sites within the study community was equally accessed. The snail species collected were placed individually into a clean beaker with little quantity of water and then subjected to shedding light for 2 hours. Data obtained were entered in excel spread sheet and analyzed using chi square test. The result obtained shows that 205 (41%) out of 500 individuals examined were excreting S. haematobium ova in their urine. The highest prevalence of infection (23%) was found among 11-20-year age groups. Males were more infected (25.4%) than their female counterparts (15.6%), although this was not statistically significant (p > 0.05). A total of 283 snails belonging to two Bulinus species (B. globosus and B. truncatus) were collected from the four sites sampled. Bulinus globosus recorded the highest species abundance (177) with the highest occurrence in site A. 52 (18.4%) out of 283 snails collected were infected with cercariae, and the highest cercariae infection (12.0%) was recorded among B. globosus. With prevalence of 41% among the human population and the prevalence of 18.4% patent infection among the snail intermediate hosts, urogenital schistosomiasis is still a public health problem in the study area and falls within the WHO classification of endemic area. Public health campaign is recommended in order to educate the people on the mode of transmission and control of the disease.
Huangqi-Danshen Decoction Ameliorates Adenine-Induced Chronic Kidney Disease by Modulating Mitochondrial Dynamics
Authors: Liu Xinhui , Huang Shiying , Wang Fochang , Zheng Lin , Lu Jiandong , Chen Jianping , Li Shunmin
Published: January 2019

Chronic kidney disease (CKD) is a leading public health problem with high morbidity and mortality. However, the therapies remain limited. Traditional Chinese medicine (TCM) has been used for treating kidney disease for thousands of years and is an effective alternative treatment for CKD patients in China and other Asian countries. In the present study, we aimed to investigate the effect and mechanism of Huangqi-Danshen decoction (HDD), a TCM herbal decoction, on treating CKD. CKD rat model was induced by adding 0.75% adenine to the diet for 4 weeks. HDD extract was administrated orally to CKD rats at the dose of 4.7 g/kg/d for consecutive 4 weeks in adenine-induced CKD rats. Kidney function was evaluated by the levels of serum creatinine (Scr) and blood urea nitrogen (BUN). The pathological changes of kidney tissues were observed by periodic acid-Schiff (PAS) and Masson’s trichrome staining. The proteins expression of renal fibrosis and mitochondrial dynamics were determined and quantified by Western blot analysis. CKD rats showed obvious decline in renal function as evidenced by increased levels of Scr and BUN, which were blunted by HDD treatment. HDD could also improve tubular atrophy and interstitial fibrosis of CKD rats. Moreover, HDD downregulated fibronectin, type IV collagen, and α-smooth muscle actin expression in CKD rats. Furthermore, mitochondrial dynamics was disturbed in CKD rats, which manifested as increased mitochondrial fission and decreased mitochondrial fusion. HDD treatment restored mitochondrial dynamics in CKD rats by repressing dynamin-related protein 1 and Mid 49/51 expression, promoting mitofusin 2 expression, and suppressing optic atrophy 1 proteolysis. In conclusion, HDD could significantly retard CKD progression through modulating mitochondrial dynamics.
Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis
Authors: Jeong Hoibin , Kim Sehui , Hong Beom-Ju , Lee Chan-Ju , Kim Young-Eun , Bok Seoyeon , Oh Jung-Min , Gwak Seung-Hee , Yoo Min Young , Lee Min Sun , Chung Seock-Jin , Defrêne Joan , Tessier Philippe , Pelletier Martin , Jeon Hyeongrin , Roh Tae-Young , Kim Bumju , Kim Ki Hean , Ju Ji Hyeon , Kim Sungjee , Lee Yoon-Jin , Kim Dong-Wan , Kim Il Han , Kim Hak Jae , Park Jong-Wan , Lee Yun-Sang , Lee Jae Sung , Cheon Gi Jeong , Weissman Irving L. , Chung Doo Hyun , Jeon Yoon Kyung , Ahn G-One
Published: January 2019

Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non–small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFα to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy.

Significance:

These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.
Exosome-Transmitted PSMA3 and PSMA3-AS1 Promote Proteasome Inhibitor Resistance in Multiple Myeloma
Authors: Xu Hongxia , Han Huiying , Song Sha , Yi Nengjun , Qian Chen'ao , Qiu Yingchun , Zhou Wenqi , Hong Yating , Zhuang Wenyue , Li Zhengyi , Li Bingzong , Zhuang Wenzhuo
Published: January 2019

Purpose:

How exosomal RNAs released within the bone marrow microenvironment affect proteasome inhibitors' (PI) sensitivity of multiple myeloma is currently unknown. This study aims to evaluate which exosomal RNAs are involved and by which molecular mechanisms they exert this function.

Experimental Design: Exosomes were characterized by dynamic light scattering, transmission electron microscopy, and Western blot analysis. Coculture experiments were performed to assess exosomal RNAs transferring from mesenchymal stem cells (MSC) to multiple myeloma cells. The role of PSMA3-AS1 in PI sensitivity was further evaluated in vivo. To determine the prognostic significance of circulating exosomal PSMA3 and PSMA3-AS1, a cohort of patients with newly diagnosed multiple myeloma was enrolled to study. Cox regression models and Kaplan–Meier curves were used to analyze progression-free survival (PFS) and overall survival (OS).

Results:

We identified that PSMA3 and PSMA3-AS1 in MSCs could be packaged into exosomes and transferred to myeloma cells, thus promoting PI resistance. PSMA3-AS1 could form an RNA duplex with pre-PSMA3, which transcriptionally promoted PSMA3 expression by increasing its stability. In xenograft models, intravenously administered siPSMA3-AS1 was found to be effective in increasing carfilzomib sensitivity. Moreover, plasma circulating exosomal PSMA3 and PSMA3-AS1 derived from patients with multiple myeloma were significantly associated with PFS and OS.

Conclusions:

This study suggested a unique role of exosomal PSMA3 and PSMA3-AS1 in transmitting PI resistance from MSCs to multiple myeloma cells, through a novel exosomal PSMA3-AS1/PSMA3 signaling pathway. Exosomal PSMA3 and PSMA3-AS1 might act as promising therapeutic targets for PI resistance and prognostic predictors for clinical response.
Cortactin Phosphorylation by Casein Kinase 2 Regulates Actin-Related Protein 2/3 Complex Activity, Invadopodia Function, and Tumor Cell Invasion
Authors: Markwell Steven M. , Ammer Amanda G. , Interval Erik T. , Allen Jessica L. , Papenberg Brenen W. , Hames River A. , Castaño Johnathan E. , Schafer Dorothy A. , Weed Scott A.
Published: January 2019

Malregulation of the actin cytoskeleton enhances tumor cell motility and invasion. The actin-binding protein cortactin facilitates branched actin network formation through activation of the actin-related protein (Arp) 2/3 complex. Increased cortactin expression due to gene amplification is observed in head and neck squamous cell carcinoma (HNSCC) and other cancers, corresponding with elevated tumor progression and poor patient outcome. Arp2/3 complex activation is responsible for driving increased migration and extracellular matrix (ECM) degradation by governing invadopodia formation and activity. Although cortactin-mediated activation of Arp2/3 complex and invadopodia regulation has been well established, signaling pathways responsible for governing cortactin binding to Arp2/3 are unknown and potentially present a new avenue for anti-invasive therapeutic targeting. Here we identify casein kinase (CK) 2α phosphorylation of cortactin as a negative regulator of Arp2/3 binding. CK2α directly phosphorylates cortactin at a conserved threonine (T24) adjacent to the canonical Arp2/3 binding motif. Phosphorylation of cortactin T24 by CK2α impairs the ability of cortactin to bind Arp2/3 and activate actin nucleation. Decreased invadopodia activity is observed in HNSCC cells with expression of CK2α phosphorylation-null cortactin mutants, shRNA-mediated CK2α knockdown, and with the CK2α inhibitor Silmitasertib. Silmitasertib inhibits HNSCC collective invasion in tumor spheroids and orthotopic tongue tumors in mice. Collectively these data suggest that CK2α-mediated cortactin phosphorylation at T24 is critical in regulating cortactin binding to Arp2/3 complex and pro-invasive activity, identifying a potential targetable mechanism for impairing HNSCC invasion.

Implications:

This study identifies a new signaling pathway that contributes to enhancing cancer cell invasion.

Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/4/987/F1.large.jpg.
Epigenetic Suppression of SERPINB1 Promotes Inflammation-Mediated Prostate Cancer Progression
Authors: Lerman Irina , Ma Xiaoting , Seger Christina , Maolake Aerken , Garcia-Hernandez Maria de la Luz , Rangel-Moreno Javier , Ackerman Jessica , Nastiuk Kent L. , Susiarjo Martha , Hammes Stephen R.
Published: January 2019

Granulocytic myeloid infiltration and resultant enhanced neutrophil elastase (NE) activity is associated with poor outcomes in numerous malignancies. We recently showed that NE expression and activity from infiltrating myeloid cells was high in human prostate cancer xenografts and mouse Pten-null prostate tumors. We further demonstrated that NE directly stimulated human prostate cancer cells to proliferate, migrate, and invade, and inhibition of NE in vivo attenuated xenograft growth. Interestingly, reduced expression of SERPINB1, an endogenous NE inhibitor, also correlates with diminished survival in some cancers. Therefore, we sought to characterize the role of SERPINB1 in prostate cancer. We find that SERPINB1 expression is reduced in human metastatic and locally advanced disease and predicts poor outcome. SERPINB1 is also reduced in Pten-null mouse prostate tumors compared with wild-type prostates, and treatment with sivelestat (SERPINB1 pharmacomimetic) attenuates tumor growth. Knockdown of highly expressed SERPINB1 in nonmalignant prostatic epithelial cells (RWPE-1) increases proliferation, decreases apoptosis, and stimulates expression of epithelial-to-mesenchymal transition markers. In contrast, stable SERPINB1 expression in normally low-expressing prostate cancer cells (C4-2) reduces xenograft growth in vivo. Finally, EZH2-mediated histone (H3K27me3) methylation and DNA methyltransferase–mediated DNA methylation suppress SERPINB1 expression in prostate cancer cells. Analysis of The Cancer Genome Atlas and pyrosequencing demonstrate hypermethylation of the SERPINB1 promoter in prostate cancer compared with normal tissue, and the extent of promoter methylation negatively correlates with SERPINB1 mRNA expression.

Implications:

Our findings suggest that the balance between SERPINB1 and NE is physiologically important within the prostate and may serve as a biomarker and therapeutic target in prostate cancer.
Reactive Oxygen Species (ROS)-Inducing Triterpenoid Inhibits Rhabdomyosarcoma Cell and Tumor Growth through Targeting Sp Transcription Factors
Authors: Kasiappan Ravi , Jutooru Indira , Mohankumar Kumaravel , Karki Keshav , Lacey Alexandra , Safe Stephen
Published: January 2019

Methyl 2-trifluoromethyl-3,11-dioxo-18β-olean-1,12-dien-3-oate (CF3DODA-Me) is derived synthetically from glycyrrhetinic acid, a major component of licorice, and this compound induced reactive oxygen species (ROS) in RD and Rh30 rhabdomyosarcoma (RMS) cells. CF3DODA-Me also inhibited growth and invasion and induced apoptosis in RMS cells, and these responses were attenuated after cotreatment with the antioxidant glutathione, demonstrating the effective anticancer activity of ROS in RMS. CF3DODA-Me also downregulated expression of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and prooncogenic Sp-regulated genes including PAX3-FOXO1 (in Rh30 cells). The mechanism of CF3DODA-Me–induced Sp-downregulation involved ROS-dependent repression of c-Myc and cMyc-regulated miR-27a and miR-17/20a, and this resulted in induction of the miRNA-regulated Sp repressors ZBTB4, ZBTB10, and ZBTB34. The cell and tumor growth effects of CF3DODA-Me further emphasize the sensitivity of RMS cells to ROS inducers and their potential clinical applications for treating this deadly disease.

Implications:

CF3DODA-Me and HDAC inhibitors that induce ROS-dependent Sp downregulation could be developed for clinical applications in treating rhabdomyosarcoma.
Multiclonality and Marked Branched Evolution of Low-Grade Endometrioid Endometrial Carcinoma
Authors: Lazo de la Vega Lorena , Samaha Mia C. , Hu Kevin , Bick Nolan R. , Siddiqui Javed , Hovelson Daniel H. , Liu Chia-Jen , Carter Cody S. , Cho Kathleen R. , Sciallis Andrew P. , Tomlins Scott A.
Published: January 2019

The molecular events driving low-grade endometrioid endometrial carcinoma (LGEC) development—like in many cancers—are incompletely understood. Hence, here we performed multiregion, comprehensive somatic molecular profiling of routinely processed formalin-fixed, paraffin-embedded (FFPE) material from 13 cases of LGEC totaling 64 minute, spatially defined cell populations ranging from presumed precursor lesions through invasive LGEC. Shared driving PTEN, PIK3R1, or PIK3CA mutations support clonal origin of the samples in each case, except for two cases with two clonally distinct neoplastic populations, consistent with unexpected multiclonality in LGEC development. Although substantial heterogeneity in driving somatic alterations was present across populations in nearly all cases, these alterations were usually clonal in a given population, supporting continued selection and clonal sweeping of driving alterations in populations with both precursor and LGEC histology. Importantly, CTNNB1 mutational status, which has been proposed as both prognostic and predictive in LGEC, was frequently heterogeneous and subclonal, occurring both exclusively in precursor or cancer populations in different cases. Whole-transcriptome profiling of coisolated RNA from 12 lesions (from 5 cases) was robust and confirmed histologic and molecular heterogeneity, including activated Wnt signaling in CTNNB1-mutant versus wild-type populations. Taken together, we demonstrate clinically relevant multiclonality and intratumoral heterogeneity during LGEC development with important implications for diagnosis, prognosis, and therapeutic prediction. More broadly, our methodology is broadly scalable to enable high-throughput genomic and transcriptomic characterization of precursor and invasive cancer populations from routine FFPE specimens.

Implications:

Multiregion profiling of LGEC populations using a highly scalable approach demonstrates clinically relevant multiclonality and intratumoral heterogeneity.
Multidrug Resistance and the Predominance of blaCTX-M in Extended Spectrum Beta-Lactamase-Producing Enterobacteriaceae of Animal and Water Origin
Authors: Hassen Bilel , Sghaier Senda , Abbassi Mohamed Salah , Ferjani Mohamed Amine , Ben Said Meriam , Hassen Abdennaceur , Hammami Salah
Published: January 2019

The aim of this work was the genetic characterization of cefotaxime-resistant enterobacteria from animals (53 samples), the surface water of rivers (17 samples), and wastewater treatment plants (43 samples) in Tunisia. A total of 48 (42.4%) cefotaxime-resistant isolates were recovered. An extended spectrum beta-lactamase (ESBL) phenotype with a positive double-disk synergy test (DDST) was exhibited by 34 (70.8%) and 14 (29.1%) isolates from water and animal origins, respectively. Isolates from water were identified as: Escherichia coli (n = 17), Hafnia spp. (n = 13), Citrobacter spp. (n = 1), Enterobacter cloacae (n = 1), Klebsiella pneumoniae (n = 1), and K. oxytoca (n = 1). Animal isolates were identified as: E. coli (n = 11), E. cloacae (n = 1), Hafnia spp. (n = 1), and K. pneumoniae (n = 1). PCR investigation of blaCTX-M, blaTEM, and blaSHV genes showed that amongst the 48 isolates with a positive DDST, 41 (87.5%) carried the blaCTX-M gene, 1 isolate harbored the blaSHV gene, and 1 isolate coharbored blaCTX-M with blaSHV genes. The class 1 and 2 integrons were detected in 27 (56.2%) and 1 (2%) isolates, respectively. Our study showed a significant occurrence of ESBL-producing enterobacteria in animals and aquatic environments with a predominance of blaCTX-M genes.
A Mosquito Bite with Devastating Complications in an Immunocompromised Patient
Authors: Frietsch Jochen J. , Winkelmann Nils , Hunstig Friederike , Schnetzke Ulf , Hammersen Friedrich J. , Dönicke Torsten , Lenz Mark , Gras Florian , Scholl Sebastian , Hochhaus Andreas , Hilgendorf Inken
Published: January 2019

Infectious complications such as invasive aspergillosis or infection with Stenotrophomonas maltophilia (SM) in immunocompromised patients are associated with a high mortality rate. Our report concerns a 40-year-old male newly diagnosed very severe aplastic anemia (vSAA) who in consequence of a mosquito bite was suffering from skin lesion and consecutive soft tissue phlegmon subsequent to the administration of antithymocyte globulin; a full-thickness autologous meshed skin graft successfully performed to cover skin ulcera after allogeneic stem cell transplantation (SCT). This unusual case illustrates the importance of appropriate diagnosis, anti-infective therapy and close interdisciplinary diagnostic algorithms to minimalize side effects and the selection of resistant strains and to improve patients’ outcome.
Ambulatory care sensitive hospitalizations after implementation of the master plan in Minas Gerais
Authors: Arantes Luciano José , Shimizu Helena Eri , Merchán-Hamann Edgar
Published: January 2019

OBJECTIVE: To describe the rate of ambulatory care sensitive hospitalizations in groups of cities according to population size and to analyze its association with the coverage of the Family Health Strategy after the implementation of the Master Plan for Primary Health Care in Minas Gerais, Brazil. METHODS: This is an ecological study with 452 cities grouped according to population size, with data from 2004 to 2007 and 2010 to 2013. We used the Kolmogorov-Smirnov test to verify the distribution of the data in the groups. We used the Wilcoxon test for paired data or the paired Student’s t-test to compare the rate of ambulatory care sensitive hospitalizations before and after the Master Plan for Primary Health Care. We used the simple linear regression test to analyze the association between variables. We performed statistical analyses using the Statistical Package for the Social Sciences, with a significance level of 5%. RESULTS: The rate of ambulatory care sensitive hospitalizations decreased significantly after the Master Plan for Primary Health Care in the large and mid-sized groups (p < 0.05). There were positive correlations between coverage with Family Health Strategy and the rate of ambulatory care sensitive hospitalizations in the mid-sized and large groups (p < 0.05). CONCLUSIONS: Actions were carried out to implement the Master Plan for Primary Health Care. However, more investments are needed to improve the effectiveness of the Primary Health Care, with permanent confrontation of complex issues that affect the quality of services, which can lead to a significant reduction of the rates of ambulatory care sensitive hospitalizations.
Tailoring Antiplatelet Therapy Intensity to Ischemic and Bleeding Risk
Authors: Baber Usman , Leisman Daniel E. , Cohen David J. , Gibson C. Michael , Henry Timothy D. , Dangas George , Moliterno David , Kini Annapoorna , Krucoff Mitchell , Colombo Antonio , Chieffo Alaide , Sartori Samantha , Witzenbichler Bernhard , Steg Philippe Gabriel , Pocock Stuart J. , Mehran Roxana
Published: January 2019

Background:

Balancing ischemic and bleeding risk is an evolving framework.

Methods and Results:

Our objectives were to simulate changes in risks for adverse events and event-driven costs with use of ticagrelor or prasugrel versus clopidogrel according to varying levels of ischemic and bleeding risk. Using the validated PARIS risk functions, we estimated 1-year ischemic (myocardial infarction or stent thrombosis) and bleeding (Bleeding Academic Research Consortium types 3 or 5) event rates among PARIS study participants who underwent percutaneous coronary intervention with drug-eluting stent implantation for an acute coronary syndrome and were discharged with aspirin and clopidogrel (n=1497). Simulated changes in adverse events with ticagrelor or prasugrel were calculated by applying treatment effects from randomized trials for a 1-year time horizon. Event costs were estimated using National Inpatient Sample data. Net costs were calculated between antiplatelet therapy groups according to level of ischemic and bleeding risk. After weighting events for quality-of-life impact, we calculated event rates and costs for risk-tailored treatment versus clopidogrel under multiple drug pricing assumptions. One-year rates (per 1000 person-years) for ischemic events were 12.6, 24.1, and 66.1, respectively, among those at low (n=630), intermediate (n=536), and high (n=331) ischemic risk. Analogous bleeding rates were 11.0, 23.9, and 66.2, respectively, among low (n=728), intermediate (n=634), and high (n=135) bleeding risk patients. Mean per event costs were $22 174 (ischemic) and $12 203 (bleeding). When risks for ischemia matched or exceeded bleeding, simulated utility-weighted event rates favored ticagrelor/prasugrel, whereas clopidogrel reduced utility-weighted events when bleeding exceeded ischemic risk. One-year costs were sensitive to drug pricing assumptions, and risk-tailored treatment with either agent progressed from cost incurring to cost saving with increasing generic market share.

Conclusions:

Tailoring antiplatelet therapy intensity to patient risk may improve health utility and could produce cost savings in the first year after percutaneous coronary intervention.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00998127.
In-Hospital Management and Outcomes After ST-Segment–Elevation Myocardial Infarction in Medicaid Beneficiaries Compared With Privately Insured Individuals
Authors: Patel Nirav , Gupta Ankur , Doshi Rajkumar , Kalra Rajat , Bajaj Navkaranbir S. , Arora Garima , Arora Pankaj
Published: January 2019

Background:

Medicaid expansion among previously uninsured individuals has led to improved healthcare access. However, considerably lower reimbursement rates of Medicaid have raised concerns on the unintended consequence of lower utilization of life-saving therapies and inferior outcomes compared with private insurance. We examined the rates of revascularization and in-hospital mortality among Medicaid beneficiaries versus privately insured individuals hospitalized with ST-segment–elevation myocardial infarction (STEMI).

Methods and Results:

We queried the National Inpatient Sample from 2012 to 2015 for STEMI hospitalizations with Medicaid or private insurance as primary payer. Hospitalizations with the following criteria were excluded: (1) age <18 or ≥65 years, (2) transfer to another acute care facility, and (3) left against medical advice. Outcomes were compared in propensity score–matched cohort based on demographics, socioeconomic status (income based), clinical comorbidities, including drug and alcohol use, STEMI acuity (cardiac arrest and cardiogenic shock), and hospital characteristics. A total of 42 645 and 171 545 STEMI hospitalizations were identified as having Medicaid and private insurance, respectively. In unadjusted analyses, Medicaid beneficiaries with STEMI had lower rates of coronary revascularization (88.9% versus 92.3%; odds ratio, 0.67; 95% CI, 0.65–0.70) and higher rates of in-hospital mortality (4.9% versus 2.8%; odds ratio, 1.81; 95% CI, 1.72–1.91) compared with privately insured individuals (
P
<0.001 for both). In propensity-matched cohort of 40 870 hospitalizations per group, similar results for lower rates of revascularization (89.1% versus 91.1%; odds ratio, 0.80; 95% CI, 0.76–0.84) and higher in-hospital mortality (4.9% versus 3.7%; odds ratio, 1.35; 95% CI, 1.26–1.45) were observed in Medicaid compared with private insurance, despite extensive matching (
P
<0.001 for both).

Conclusions:

Medicaid beneficiaries with STEMI had lower rates of revascularization, although small absolute difference, and higher in-hospital mortality compared with privately insured individuals. Further studies are needed to identify and understand the variation in STEMI outcomes by insurance status.
Cognitive Impact of Cerebral Small Vessel Disease Changes in Patients With Hypertension
Authors: Jiménez-Balado Joan , Riba-Llena Iolanda , Abril Oscar , Garde Edurne , Penalba Anna , Ostos Elena , Maisterra Olga , Montaner Joan , Noviembre Maria , Mundet Xavier , Ventura Oriol , Pizarro Jesus , Delgado Pilar
Published: January 2019

Hypertension is one of the principal risk factors for cerebral small vessel disease progression and cognitive impairment. We aimed to investigate how changes in cerebral small vessel disease lesions relate to cognitive decline and incident mild cognitive impairment in hypertensive patients. Data were obtained from the ISSYS cohort (Investigating Silent Strokes in Hypertensives: a Magnetic Resonance Imaging Study)—a longitudinal population-based study on hypertensive patients aged 50 to 70 years without dementia and stroke at baseline. Patients underwent a brain magnetic resonance imaging, a cognitive screening test, and cognitive diagnosis (normal aging or mild cognitive impairment) at baseline and follow-up. We evaluated incident lacunar infarcts and cerebral microbleeds. Changes in the periventricular and deep white matter hyperintensities (WMH) were qualitatively defined as none, minor, or marked. We followed up 345 patients (median age, 65 [61–68]; 55.4% men) for 3.95 (3.83–4.34) years. Incident mild cognitive impairment was diagnosed in 9.1% of the sample. Considering the progression of cerebral small vessel disease, the prevalence of incident infarcts was 6.1% and that of incident cerebral microbleeds was 5.5%; progression of periventricular WMH was 22% and that of deep WMH was 48%. Patients with marked progression of periventricular WMH showed a significant decrease in global cognition compared with patients without progression (adjusted mean [SE], −0.519 [0.176] versus 0.057 [0.044], respectively;
P
value=0.004) and a higher risk of incident mild cognitive impairment (OR, 6.184; 95% CI, 1.506–25.370;
P
value=0.011). Therefore, our results indicate that hypertensive patients with progression of periventricular WMH have higher odds of cognitive impairment, even in the early stages of cognitive decline.