bluuebunny/crossref_metadata_2025 huggingface dataset:
Is the fibroblast growth factor signaling pathway a victim of receptor tyrosine kinase inhibition in pulmonary parenchymal and vascular remodeling?
Authors: El Agha Elie , Schwind Felix , Ruppert Clemens , Günther Andreas , Bellusci Saverio , Schermuly Ralph T. , Kosanovic Djuro
Published: May 2018

Idiopathic pulmonary arterial hypertension (IPAH), pulmonary hypertension (PH) due to lung disease and/or hypoxia and idiopathic pulmonary fibrosis (IPF) are increasingly recognized as important contributors to mortality and morbidity worldwide. Among others, the current treatment paradigm considers broad inhibition of receptor tyrosine kinases, a strategy that likely leads to collateral inhibition of signaling pathways that are critical for lung repair and regeneration. Fibroblast growth factor 7 (FGF7) and FGF10 signaling in the lung through FGF receptor 2 (FGFR2) are involved in epithelial cell protection and renewal, and mutations in their corresponding genes in humans are linked to increased susceptibility to lung pathologies, such as chronic obstructive pulmonary disease and bronchopulmonary dysplasia. In this report, we present data demonstrating significant upregulation of FGF7, FGF10, and FGFR2 in IPF and IPAH lungs compared with donor lungs. These ligands and their cognate receptor converged on the remodeled parenchyma and vasculature of IPF and IPAH lungs. Interestingly, the expression levels of FGFR1, which has been previously shown to play a pathological role in PH development, were not significantly changed in either disease state. Intriguingly, the expression levels of FGF7, FGF10, and FGFR2 were lower in IPF lung regions undergoing active remodeling, and inversely correlated with IPAH severity, indicating that increased expression might reflect lung repair rather than lung pathology, and warranting further research on the precise role of FGF signaling in pulmonary parenchymal and vascular remodeling.
Damage-associated molecular patterns in resuscitated hemorrhagic shock are mitigated by peritoneal fluid administration
Authors: Matheson Paul J. , Eid Mark A. , Wilson Matthew A. , Graham Victoria S. , Matheson Samuel A. , Weaver Jessica L. , Downard Cynthia D. , Smith Jason W.
Published: May 2018

Conventional resuscitation (CR) of hemorrhagic shock (HS), a significant cause of trauma mortality, is intravenous blood and fluids. CR restores central hemodynamics, but vital organ flow can drop, causing hypoperfusion, hypoxia, damage-associated molecular patterns (DAMPs), and remote organ dysfunction (i.e., lung). CR plus direct peritoneal resuscitation (DPR) prevents intestinal and hepatic hypoperfusion. We hypothesized that DPR prevents lung injury in HS/CR by altering DAMPs. Anesthetized male Sprague-Dawley rats were randomized to groups ( n = 8/group) in one of two sets: 1) sham (no HS, CR, or DPR), 2) HS/CR (HS = 40% mean arterial pressure (MAP) for 60 min, CR = shed blood + 2 volumes normal saline), or 3) HS/CR + DPR. The first set underwent whole lung blood flow by colorimetric microspheres. The second set underwent tissue collection for Luminex, ELISAs, and histopathology. Lipopolysaccharide (LPS) and DAMPs were measured in serum and/or lung, including cytokines, hyaluronic acid (HA), high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 protein (MYD88), and TIR-domain-containing adapter-inducing interferon-β (TRIF). Statistics were by ANOVA and Tukey-Kramer test with a priori P < 0.05. HS/CR increased serum LPS, HA, HMGB1, and some cytokines [interleukin (IL)-1α, IL-1β, IL-6, and interferon-γ]. Lung TLR4 and MYD88 were increased but not TRIF compared with Shams. HS/CR + DPR decreased LPS, HA, cytokines, HMGB1, TLR4, and MYD88 levels but did not alter TRIF compared with HS/CR. The data suggest that gut-derived DAMPs can be modulated by adjunctive DPR to prevent activation of lung TLR-4-mediated processes. Also, DPR improved lung blood flow and reduced lung tissue injury. Adjunctive DPR in HS/CR potentially improves morbidity and mortality by downregulating the systemic DAMP response.
Force properties of skinned cardiac muscle following increasing volumes of aerobic exercise in rats
Authors: Boldt Kevin R. , Rios Jaqueline L. , Joumaa Venus , Herzog Walter
Published: May 2018

The positive effects of chronic endurance exercise training on health and performance have been well documented. These positive effects have been evaluated primarily at the structural level, and work has begun to evaluate mechanical adaptations of the myocardium. However, it remains poorly understood how the volume of exercise training affects cardiac adaptation. To gain some understanding, we subjected 3-mo-old Sprague-Dawley rats ( n = 23) to treadmill running for 11 wk at one of three exercise volumes (moderate, high, and extra high). Following training, hearts were excised and mechanical testing was completed on skinned trabecular fiber bundles. Performance on a maximal fitness test was dose dependent on training volume, where greater levels of training led to greater performance. No differences were observed between animals from any group for maximal active stress and passive stress at a sarcomere length of 2.2 µm. Heart mass and passive stress at sarcomere lengths beyond 2.4 µm increased in a dose-dependent manner for animals in the control and moderate- and high-duration groups. However, hearts from animals in the extra high-duration group presented with inhibited responses for heart mass and passive stress, despite performing greatest on a graded treadmill fitness test. These results suggest that heart mass and passive stress adapt in a dose-dependent manner, until exercise becomes excessive and adaptation is inhibited. Our findings are in agreement with the beneficial role exercise has in cardiac adaptation. However, excessive exercise comes with risks of maladaptation, which must be weighed against the desire to increase performance.

NEW & NOTEWORTHY For the first time, we present findings on cardiac trabecular muscle passive stiffness and show the effect of excessive exercise on the heart. We demonstrated that heart mass increases with exercise until a maximum, after which greater exercise volume results in inhibited adaptation. At paraphysiological lengths, passive stiffness increases with exercise but to a lesser degree with excessive training. Despite greater performance on graded exercise tests, animals in the highest trained group exhibited possible maladaptation.
Flt3 Regulation in the Mononuclear Phagocyte System Promotes Ocular Neovascularization
Authors: Gao Yushuo , Zhong Yisheng , Zhu Yanji , Demetriades Anna M. , Cai Yujuan , Shen Jikui , Lu Qing , Shen Xi , Xie Bing
Published: May 2018

Fms-like tyrosine kinase 3 (Flt3), a tyrosine kinase receptor expressed in CD34+ hematopoietic stem/progenitor cells, is important for both normal myeloid and lymphoid differentiation. It has been implicated in mice and humans for potential multilineage differentiation. We found that mice deficient in Flt3 or mice that received an Flt3 inhibitor (AC220) showed significantly reduced areas of ischemia-induced retinal neovascularization (RNV) and laser-induced choroidal NV (CNV) (P<0.05). Increased Flt3 expression at the protein level was detected in retinas of oxygen-induced retinopathy (OIR) mice at P15 and P18 during retinal NV (RNV) progression. We subsequently found that macrophages (Mphi) polarization was regulated at the site of CNV in Flt3-deficient mice. Flow cytometry analysis demonstrated that Flt3 deficiency shifted Mphi polarization towards an M2 phenotype during RNV with significant reduction in M1 cytokine expression when compared to the wild-type controls (P<0.05). Based on the above findings, we concluded that Flt3 inhibition alleviated ocular NV by promoting a Mphi polarization shift towards the M2 phenotype. Therapies targeting Flt3 may provide a new approach for the treatment of ocular NV.
QoS‐Aware Resource Allocation for Network Virtualization in an Integrated Train Ground Communication System
Authors: Zhu Li , Wang Fei , Zhao Hongli
Published: May 2018

Urban rail transit plays an increasingly important role in urbanization processes. Communications‐Based Train Control (CBTC) Systems, Passenger Information Systems (PIS), and Closed Circuit Television (CCTV) are key applications of urban rail transit to ensure its normal operation. In existing urban rail transit systems, different applications are deployed with independent train ground communication systems. When the train ground communication systems are built repeatedly, limited wireless spectrum will be wasted, and the maintenance work will also become complicated. In this paper, we design a network virtualization based integrated train ground communication system, in which all the applications in urban rail transit can share the same physical infrastructure. In order to better satisfy the Quality of Service (QoS) requirement of each application, this paper proposes a virtual resource allocation algorithm based on QoS guarantee, base station load balance, and application station fairness. Moreover, with the latest achievement of distributed convex optimization, we exploit a novel distributed optimization method based on alternating direction method of multipliers (ADMM) to solve the virtual resource allocation problem. Extensive simulation results indicate that the QoS of the designed integrated train ground communication system can be improved significantly using the proposed algorithm.
Is There Association between Vitamin D Concentrations and Body Mass Index Variation in Women Submitted to Y-Roux Surgery?
Authors: dos Santos Maria Tereza A. , Suano-Souza Fabiola Isabel , Affonso Fonseca Fernando Luiz , Lazaretti-Castro Marise , Sarni Roseli Oselka Saccardo
Published: May 2018

Objective. To evaluate vitamin D deficiency and body composition of women submitted to bariatric surgery and relate their body mass index variation after surgery to 25(OH)D concentrations. Method. A cross-sectional and controlled study was performed including 49 obese adult volunteer women, submitted to Roux-en-Y gastric bypass (RYGB group). Collected Data. Body mass index (BMI), self-declared ethnicity, economic condition, physical activity level, serum concentrations of 25-hydroxycholecalciferol (25(OH)D; radioimmunoassay), parathormone, and body composition by dual-energy X-ray absorptiometry (Hologic DXA-QDR-1000) were collected. Results. 25(OH)D deficiency was found in 27 (55.1%) and 8 (21.1%) in the RYGB and control groups (p=0.002). Secondary hyperparathyroidism was more frequent in the RYGB group compared to the control group (15 (30.6%) versus 1 (2.6%); p=0.001). There was no relation of the studied variables and body composition with 25(OH)D deficiency. 25(OH)D concentrations were correlated (r=−0.531; p<0.001) with BMI reduction, regardless of vitamin D supplementation. Conclusion. Women submitted to bariatric surgery (RYGB) around three years ago had higher BMI and vitamin D deficiency, along with hyperparathyroidism, compared to the control group. There was no association between variables related to body composition and 25(OH)D concentrations. On the other hand, vitamin concentrations correlated negatively to BMI variation after undergoing surgery.
Inventory of Toxic Plants in Morocco: An Overview of the Botanical, Biogeography, and Phytochemistry Studies
Authors: Benzeid Hanane , Gouaz Fadma , Touré Abba Hamadoun , Bouatia Mustapha , Idrissi Mohamed Oulad Bouyahya , Draoui Mustapha
Published: May 2018

Since they are natural, plants are wrongly considered nondangerous; therefore people used them in various contexts. Each plant is used alone or in mixture with others, where knowledge and the requirements of preparation and consumption are not mastered. Thus, intoxications due to the use of plants have become more and more frequent. The reports of intoxications made at the Antipoison Center and Pharmacovigilance of Morocco (ACPM) support this finding, since the interrogations suffered by the victims show that the use of plants is practiced irrationally, anarchically, and uncontrollably. Faced by the increase of these cases of poisoning in Morocco, it seemed necessary to investigate the nature of poisonous plants, their monographs, and the chemicals responsible for this toxicity.
Septic Embolic Stroke Followed by Hemorrhage and Brain Abscess in a Patient with Systemic Infections: A Case Report and Literature Review
Authors: Mohamud Jama A. , Wu Jingtao , Jing Ye , Wang Yu
Published: May 2018

We report a case of 50-year-old man with a severe acute ischemic stroke followed by intracerebral hemorrhage and brain abscess due to systemic infection. His initial intracranial radiographic findings were normal but three days later MRI scan of the brain revealed well-defined rounded cystic lesion on the T2-weighted and T1-weighted images in the right basal ganglia; the lesion presented an area of diffusion restriction on DWI; lately the lesion was confirmed to be an early stage of cerebral abscess. A week later the patient was noted to have worsening neurological status and left extremity weakness, and emergency brain CT scan revealed massive intracerebral hemorrhage in the right occipital lobe; he underwent intracranial hematoma evacuation surgery. The hematoma was removed successfully, and the systemic infections were treated with antibiotics.
Pharmacological Properties of the Medical Maggot: A Novel Therapy Overview
Authors: Yan Litao , Chu Jin , Li Mingshu , Wang Xianfeng , Zong Junwei , Zhang Xueyang , Song Mingzhi , Wang Shouyu
Published: May 2018

In the last decade, maggot has been hailed as the miraculous “medicinal maggot” for its diverse properties, including antimicrobial, antibiofilm, anti‐inflammatory, and wound healing activities. The fact that maggots show so many beneficial properties has increased the interest in these tiny larvae dramatically. Whilst there is relatively abundant clinical evidence to demonstrate the success of maggots as debridement agents, not so much emphasis has been placed on the basic science evidence, which was a combination of physical and biochemical actions. This review differs from those earlier works in that it is undertaken to provide an update of the latest scientific basis published on maggot, particularly active ingredients within maggot excretions/secretions (ES). Further investigations should focus on the isolation, identification, recombination, transgenosis, and mass production of the beneficial molecules within maggots.
A New Dynamical Index for India-Burma Trough
Authors: Liu Kui , Zha Jinlin , Yang Ruowen , Chen Jilong
Published: May 2018

Based on the vertical velocity field of reanalysis datasets, this study defines a new dynamical index for the India-Burma trough and supports this index’s advantages by analyzing reanalysis and observational datasets. For a convenient understanding, the vertical velocities of 5 levels ranging from 700 hPa to 500 hPa within the area of 15.625°N–24.375°N and 90.625°E–100.625°E are multiplied by −1 and summed up into a time series involving each year from 1979 to 2012. The standardized value of the time series is defined as the index of India-Burma trough (IIBT). IIBT can reflect the characteristics of the annual strength and the interdecadal variation of the India-Burma trough. IIBT can also well reveal the relationship between the India-Burma trough and its upstream teleconnection. What is more, through a correlation analysis on the grid point precipitation field, respectively, with the IIBT and the India-Burma trough indices defined with vorticity and geopotential height, over southern Asia the correlation pattern between the IIBT and the precipitation field is found to nearly be the sum of the correlation patterns of the latter 2 indices with the precipitation. To the south of the TP, the correlation field between the IIBT and the grid point precipitation shows dipolar distribution, which is consistent with the correlation patterns of the IIBT with the vertical velocity, specific humidity, and the mid-level geopotential height in the same spatial location. IIBT is beneficial for more accurate study of the impact of the India-Burma trough on the associated weather and climate.
Secure Image Encryption Based on an Ideal New Nonlinear Discrete Dynamical System
Authors: Lin R. M. , Ng T. Y.
Published: May 2018

It is well known that encryption algorithms developed based on Logistic map suffer from limited key space due to the narrow regions of system parameters which can be used, potential risk of security in the presence of numerous periodic windows within the key space, and weakness in known-plain-text attack due to the inherent correlation among the chaotic sequence used for encryption. To overcome these existing problems, this paper presents a secure image encryption algorithm based on a new highly nonlinear discrete dynamical system with ideal chaotic characteristics. Transcendental functions are introduced together with modulo operations which physically represent discontinuous time-varying nonlinearities, leading to extremely complex chaotic behavior that is highly sensitive to system parameters and initial conditions, both of which are considered as the key for the cryptosystem. Extensive numerical experiment results have revealed that the proposed image encryption algorithm offers advantages of unlimited key space and high-level security, since those problematic periodic windows are no longer present within the key space, and it is extremely robust against known-plain-text attack, since the chaotic sequence generated bears no correlation whatsoever due to the folding effect of modulo operation. The algorithm makes truly efficient yet highly secure image encryption based on chaotic systems a reality.
NTRU Implementation of Efficient Privacy‐Preserving Location‐Based Querying in VANET
Authors: Mi Bo , Huang Darong , Wan Shaohua
Published: May 2018

The key for location‐based service popularization in vehicular environment is security and efficiency. However, due to the constrained resources in vehicle‐mounted system and the distributed structure of fog computation, disposing of the conflicts between real‐time implementation and user’s privacy remains an open problem. Aiming at synchronously preserving the position information for users as well as the data proprietorship of service provider, an efficient location‐based querying scheme is proposed in this paper. We argue that a recent scheme proposed by Jannati and Bahrak is time‐consuming and vulnerable against active adaptive corruptions. Thus accordingly, a postquantum secure oblivious transfer protocol is devised based on efficient NTRU cryptosystem, which then serves as the understructure of a complete location‐based querying scheme in ad hoc manner. The security of our scheme is proved under universal composability frame, while performance analysis is also carried out to testify its efficiency.
Metabolic Syndrome and Its Components in Young Adults Conceived by ICSI
Authors: Belva F. , Bonduelle M. , Provyn S. , Painter R. C. , Tournaye H. , Roelants M. , De Schepper J.
Published: May 2018

Background. Intracytoplasmic sperm injection (ICSI) conception presents the early embryo with a radically different environment, which may lead to permanent alterations to key cardiometabolic processes. Blood pressure, indicators of insulin resistance, and lipid profiles have previously been studied in offspring born after in vitro fertilisation (IVF) and ICSI, with conflicting findings. Also, results in young adults born after ICSI are lacking. Aim. We investigated if young adult men and women conceived by ICSI more frequently have metabolic syndrome and its individual features in comparison to spontaneously conceived controls. Design. Cardiometabolic and anthropometric parameters from 126 longitudinally followed young adults conceived by ICSI were compared to those of 133 controls. Results. At age 18 years, only 1 of the participants displayed the metabolic syndrome (1 control woman). Mean concentrations of total cholesterol, triglycerides, insulin, HOMA-IR, and blood pressure were comparable between the ICSI conceived and control participants. A higher proportion (19.6%) of men conceived by ICSI had low (<40 mg/dl) HDL cholesterol compared to controls (5.6%). Conclusions. While men conceived by ICSI, but not women, had lower mean HDL cholesterol concentrations in comparison to controls, other markers of the metabolic syndrome were not affected by the mode of conception.
Messaging Circumstances and Economic Pressures as Influences on Linkage to Medical Male Circumcision following Community-Based HIV Testing for Men in Rural Southwest Uganda: A Qualitative Study
Authors: Gilbert Hannah N. , Wyatt Monique A. , Asiimwe Stephen , Turyamureeba Bosco , Tumwesigye Elioda , Van Rooyen Heidi , Barnabas Ruanne V. , Celum Connie L. , Ware Norma C.
Published: May 2018

Voluntary medical male circumcision (MMC) reduces risk of HIV infection, but uptake remains suboptimal among certain age groups and locations in sub-Saharan Africa. We analysed qualitative data as part of the Linkages Study, a randomized controlled trial to evaluate community-based HIV testing and follow-up as interventions promoting linkage to HIV treatment and prevention in Uganda and South Africa. Fifty-two HIV-negative uncircumcised men participated in the qualitative study. They participated in semistructured individual interviews exploring (a) home HTC experience; (b) responses to test results; (c) efforts to access circumcision services; (d) outcomes of efforts; (e) experiences of follow-up support; and (f) local HIV education and support. Interviews were audio-recorded, translated, transcribed, and summarized into “linkage summaries.” Summaries were analysed inductively to identify the following three thematic experiences shaping men’s circumcision choices: (1) intense relief upon receipt of an unanticipated seronegative diagnosis, (2) the role of peer support in overcoming fear, and (3) anticipation of missed economic productivity. Increased attention to the timing of demand creation activities, to who delivers information about the HIV prevention benefits of MMC, and to the importance of missed income during recovery as a barrier to uptake promises to strengthen and sharpen future MMC demand creation strategies.
A New Residual Life Prediction Method for Complex Systems Based on Wiener Process and Evidential Reasoning
Authors: Zhang Xin , Tang Shuaiwen , Liu Taoyuan , Zhang Bangcheng
Published: May 2018

A new residual life prediction method for complex systems based on Wiener process and evidential reasoning is proposed to predict the residual life of complex systems effectively. Moreover, the better maintenance strategies and decision supports are provided. For the residual life prediction of complex systems, the maximum likelihood method is adopted to estimate the drift coefficient, and the Bayesian method is adopted to update the parameters of Wiener process. The process of parameters estimation and the probability density function (PDF) of the residual life are deduced. To improve the accuracy of the residual life prediction results, the evidential reasoning (ER) is used to integrate the prediction results of Wiener process. Finally, a case study of gyroscope is examined to illustrate the feasibility and effectiveness of the proposed method, compared with fuzzy theory, which provides an important reference for the optimization of the reliability of complex systems and improvement.
MIR142 Loss-of-Function Mutations Derepress ASH1L to Increase HOXA Gene Expression and Promote Leukemogenesis
Authors: Trissal Maria C. , Wong Terrence N. , Yao Juo-Chin , Ramaswamy Rahul , Kuo Iris , Baty Jack , Sun Yaping , Jih Gloria , Parikh Nishi , Berrien-Elliott Melissa M. , Fehniger Todd A. , Ley Timothy J. , Maillard Ivan , Reddy Pavan R. , Link Daniel C.
Published: May 2018

Point mutations in the seed sequence of miR-142-3p are present in a subset of acute myelogenous leukemia (AML) and in several subtypes of B-cell lymphoma. Here, we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. Mir142 loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of Mir142 increased ASH1L protein expression and consequently resulted in the aberrant maintenance of Hoxa gene expression in myeloid-committed hematopoietic progenitors. Mir142 loss also enhanced the disease-initiating activity of IDH2-mutant hematopoietic cells in mice. Together these data suggest a novel model in which miR-142, through repression of ASH1L activity, plays a key role in suppressing HOXA9/A10 expression during normal myeloid differentiation. AML-associated loss-of-function mutations of MIR142 disrupt this negative signaling pathway, resulting in sustained HOXA9/A10 expression in myeloid progenitors/myeloblasts and ultimately contributing to leukemic transformation.

Significance: These findings provide mechanistic insights into the role of miRNAs in leukemogenesis and hematopoietic stem cell function. Cancer Res; 78(13); 3510–21. ©2018 AACR.
The Autotaxin—Lysophosphatidic Acid Axis Promotes Lung Carcinogenesis
Authors: Magkrioti Christiana , Oikonomou Nikos , Kaffe Eleanna , Mouratis Marios-Angelos , Xylourgidis Nikos , Barbayianni Iliana , Megadoukas Petros , Harokopos Vaggelis , Valavanis Christos , Chun Jerold , Kosma Alexandra , Stathopoulos Georgios T. , Bouros Evangelos , Bouros Demosthenes , Syrigos Konstantinos , Aidinis Vassilis
Published: May 2018

Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor–like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. ENPP2 was genetically altered in 8% of patients with lung cancer, whereas increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in patients with lung cancer. Comparable observations were made in the two most widely used animal models of lung cancer, the carcinogen urethane–induced and the genetically engineered K-rasG12D–driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a procarcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the procarcinogenic effects of the ATX/LPA axis in K-ras-G12D–driven lung cancer pathogenesis.

Significance: These findings establish the role of ATX/LPA in lung carcinogenesis, thus expanding the mechanistic links between pulmonary fibrosis and cancer. Cancer Res; 78(13); 3634–44. ©2018 AACR.
Nintedanib Is Active in Malignant Pleural Mesothelioma Cell Models and Inhibits Angiogenesis and Tumor Growth In Vivo
Authors: Laszlo Viktoria , Valko Zsuzsanna , Kovacs Ildiko , Ozsvar Judit , Hoda Mir Alireza , Klikovits Thomas , Lakatos Dora , Czirok Andras , Garay Tamas , Stiglbauer Alexander , Helbich Thomas H. , Gröger Marion , Tovari Jozsef , Klepetko Walter , Pirker Christine , Grusch Michael , Berger Walter , Hilberg Frank , Hegedus Balazs , Dome Balazs
Published: May 2018

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor type with limited treatment options and poor prognosis. The angiokinase inhibitor nintedanib has shown promising activity in the LUME-Meso phase II MPM trial and thus is currently being evaluated in the confirmatory LUME-Meso phase III trial. However, the anti-MPM potential of nintedanib has not been studied in the preclinical setting.

Experimental Design: We have examined the antineoplastic activity of nintedanib in various in vitro and in vivo models of human MPM.

Results: Nintedanib's target receptors were (co)expressed in all the 20 investigated human MPM cell lines. Nintedanib inhibited MPM cell growth in both short- and long-term viability assays. Reduced MPM cell proliferation and migration and the inhibition of Erk1/2 phosphorylation were also observed upon nintedanib treatment in vitro. Additive effects on cell viability were detected when nintedanib was combined with cisplatin, a drug routinely used for systemic MPM therapy. In an orthotopic mouse model of human MPM, survival of animals receiving nintedanib per os showed a favorable trend, but no significant benefit. Nintedanib significantly reduced tumor burden and vascularization and prolonged the survival of mice when it was administered intraperitoneally. Importantly, unlike bevacizumab, nintedanib demonstrated significant in vivo antivascular and antitumor potential independently of baseline VEGF-A levels.

Conclusions: Nintedanib exerts significant antitumor activity in MPM both in vitro and in vivo. These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM. Clin Cancer Res; 24(15); 3729–40. ©2018 AACR.
EGFRvIII–Stat5 Signaling Enhances Glioblastoma Cell Migration and Survival
Authors: Roos Alison , Dhruv Harshil D. , Peng Sen , Inge Landon J. , Tuncali Serdar , Pineda Michael , Millard Nghia , Mayo Zachary , Eschbacher Jennifer M. , Loftus Joseph C. , Winkles Jeffrey A. , Tran Nhan L.
Published: May 2018

Glioblastoma multiforme (GBM) is the most common brain malignancies in adults. Most GBM patients succumb to the disease less than 1 year after diagnosis due to the highly invasive nature of the tumor, which prevents complete surgical resection and gives rise to tumor recurrence. The invasive phenotype also confers radioresistant and chemoresistant properties to the tumor cells; therefore, there is a critical need to develop new therapeutics that target drivers of GBM invasion. Amplification of EGFR is observed in over 50% of GBM tumors, of which half concurrently overexpress the variant EGFRvIII, and expression of both receptors confers a worse prognosis. EGFR and EGFRvIII cooperate to promote tumor progression and invasion, in part, through activation of the Stat signaling pathway. Here, it is reported that EGFRvIII activates Stat5 and GBM invasion by inducing the expression of a previously established mediator of glioma cell invasion and survival: fibroblast growth factor-inducible 14 (Fn14). EGFRvIII-mediated induction of Fn14 expression is Stat5 dependent and requires activation of Src, whereas EGFR regulation of Fn14 is dependent upon Src–MEK/ERK–Stat3 activation. Notably, treatment of EGFRvIII-expressing GBM cells with the FDA-approved Stat5 inhibitor pimozide blocked Stat5 phosphorylation, Fn14 expression, and cell migration and survival. Because EGFR inhibitors display limited therapeutic efficacy in GBM patients, the EGFRvIII–Stat5–Fn14 signaling pathway represents a node of vulnerability in the invasive GBM cell populations.

Implications: Targeting critical effectors in the EGFRvIII–Stat5–Fn14 pathway may limit GBM tumor dispersion, mitigate therapeutic resistance, and increase survival. Mol Cancer Res; 16(7); 1185–95. ©2018 AACR.
Diagnostic Accuracy of Lateral Decubitus Chest Radiography before Pleural Maneuvers for the Management of Pleurisies in the Era of Chest Ultrasound
Authors: Thiam Khady , Berbis Julie , Laroumagne Sophie , Guinde Julien , Chollet Bertrand , Dutau Hervé , Touré Nafissatou O. , Astoul Philippe
Published: May 2018

Background: Chest ultrasound (CUS) is the gold standard to detect pleural adhesions before pleural maneuvers. However, the CUS technique is not available in all countries where the assessment is only based on clinical examination and chest radiography. Objective: To assess the value of lateral decubitus chest radiography (LDCR) to detect pleural adhesions. Methods: Consecutive patients with pleural effusions undergoing LCDR followed by medical thoracoscopy the day after were identified from an institutional database. The diagnostic sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for LDCR were calculated. Results: Eighty-six patients were included in the study. The sensitivity, specificity, PPV, and NPV of LDCR for the presence of adhesions taking into account the shape of the horizontal level were 71.2% (56.7–82.5), 44.1% (27.6–61.9), 66.1% (52.1–77.8), and 50% (31.7–68.3), respectively. The accuracy to predict pleural adhesions for the sign “incomplete horizontal level” was 60.5 (49.3–70.7). The accuracy to predict pleural adhesions in case of irregular aspect of the horizontal level was 53.5 (42.5–64.2). Conclusions: The accuracy of LDCR for the detection of pleural adhesions is low in patients with pleural effusion and LDCR is not sufficient before pleural maneuvers. This has to be taken into account in countries with a high prevalence of pleural tuberculosis which usually lead to loculated pleural effusions. CUS has to be urgently included in dedicated educational programs in these areas in order to decrease the complications related to unexpected pleural adhesions and achieve better planning for the management of pleural effusions.
5-French SOFIA: Safe Access and Support in the Anterior Cerebral Artery, Posterior Cerebral Artery, and Insular Middle Cerebral Artery
Authors: Gross Bradley A. , Ares William J. , Kenmuir Cynthia L. , Jadhav Ashutosh P. , Jovin Tudor G. , Jankowitz Brian T.
Published: May 2018

Introduction: Distal access catheters are an infrequent focus of technical notes in neurointervention. The 5-French SOFIA’s unique design allows for compatibility with 6-French guide catheters, while its supple construction allows for remarkably distal access for a catheter with a 0.055-inch inner diameter. Methods: The authors reviewed a prospectively maintained endovascular database for cases utilizing the 5-French SOFIA from February 2017 through November 2017. Case type, SOFIA location, microcatheter used, and catheter-related complications were noted. Results: Over the evaluated period, the 5-French SOFIA was utilized in 33 cases, including 13 aneurysm treatments, 10 arteriovenous shunt embolizations, 5 stroke thrombectomies, and 5 other cases. Of 5 flow diversion cases, 1 was for a symptomatic cavernous internal carotid artery aneurysm necessitating transradial access, another for a ruptured A3 aneurysm, and another for a middle cerebral artery (M2) aneurysm; 2 were more proximal aneurysms. Thrombectomies were for M2 (n = 3) or A2 (n = 2) occlusions. In all cases, the 5-French SOFIA reached its anticipated distal target without complication or the need to utilize a smaller/alternative catheter. Of these 33 cases, there were 10 cases of distal SOFIA target locations: 6 M2/M3, 3 anterior cerebral arteries (ACA), and 1 posterior cerebral artery (PCA). M2/M3 and PCA catheterization was achieved over 2.1-Fr microcatheters; ACA catheterization employed a 2.9-Fr microcatheter for pipeline embolization and a deployed stentriever in the setting of two thrombectomies. Conclusion: The 5-French SOFIA can be safely utilized for distal, superselective catheterization in the context of complex neurointervention, including aneurysm and arteriovenous shunt embolization and distal thrombectomy.
Animal Models of Proliferative Vitreoretinopathy and Their Use in Pharmaceutical Investigations
Authors: Hou Huiyuan , Nudleman Eric , Weinreb Robert N.
Published: May 2018

Animal models are indispensable for pharmaceutical investigations. However, investigators often have difficulty choosing the appropriate modal for their research. To provide a comprehensive and convenient source of information about animal models of proliferative vitreoretinopathy (PVR), the current review sorted and analyzed representative animal models for pharmacotherapy of PVR since 1976.
Chilblain Lupus with Nail Involvement: A Case Report and a Brief Overview
Authors: Lambertini Martina , Vincenzi Colombina , Dika Emi , La Placa Michelangelo
Published: May 2018

Chilblain lupus erythematosus is a rare, chronic variant of cutaneous lupus erythematosus that occurs during cold or damp periods on the hands, fingers, or feet. It is often associated with other forms of cutaneous lupus and about 20% of patients develop systemic lupus erythematosus. Various medications have been put forward, including steroids, mycophenolate mofetil, calcium channel blockers, and hydroxychloroquine, but the symptoms do not remit completely.
Diagnostic Value of Nineteen Different Imaging Methods for Patients with Breast Cancer: a Network Meta-Analysis
Authors: Zhang Xiao-Hong , Xiao Can
Published: May 2018

Background/Aims: We performed a network meta-analysis (NMA) to investigate and compare the diagnostic value of 19 different imaging methods used for breast cancer (BC). Methods: Cochrane Library, PubMed and EMBASE were searched to collect the relevant literature from the inception of the study until November 2016. A combination of direct and indirect comparisons was performed using an NMA to evaluate the combined odd ratios (OR) and draw the surface under the cumulative ranking curves (SUCRA) of the diagnostic value of different imaging methods for BC. Results: A total of 39 eligible diagnostic tests regarding 19 imaging methods (mammography [MG], breast-specific gamma imaging [BSGI], color Doppler sonography [CD], contrast-enhanced magnetic resonance imaging [CE-MRI], digital breast tomosynthesis [DBT], fluorodeoxyglucose positron-emission tomography/computed tomography [FDG PET/CT], fluorodeoxyglucose positron-emission tomography [FDG-PET], full field digital mammography [FFDM], handheld breast ultrasound [HHUS], magnetic resonance imaging [MRI], automated breast volume scanner [ABUS], magnetic resonance mammography [MRM], scintimammography [SMM], single photon emission computed tomography scintimammography [SPECT SMM], ultrasound elastography [UE], ultrasonography [US], mammography + ultrasonography [MG + US], mammography + scintimammography [MG + SMM], and ultrasound elastography + ultrasonography [UE + US]) were included in the study. According to this network meta-analysis, in comparison to the MG method, the CE-MRI, MRI, MRM, MG + SMM and UE + US methods exhibited relatively higher sensitivity, and the specificity of the FDG PET/CT method was higher, while the BSGI and MRI methods exhibited higher accuracy. Conclusion: The results from this NMA indicate that the diagnostic value of the BSGI, MG + SMM, MRI and CE-MRI methods for BC were relatively higher in terms of sensitivity, specificity and accuracy.
Epigallocatechin-3-Gallate Regulates Anti-Inflammatory Action Through 67-kDa Laminin Receptor-Mediated Tollip Signaling Induction in Lipopolysaccharide-Stimulated Human Intestinal Epithelial Cells
Authors: Byun Eui-Baek , Kim Woo Sik , Sung Nak-Yun , Byun Eui-Hong
Published: May 2018

Background/Aims: Inflammatory bowel disease (IBD) is a condition that involves chronic inflammation in all or part of the digestive tract. Often painful and debilitating, IBD can lead to life-threatening complications and increase the risk for colon cancer. In this study, we investigated the epigallocatechin-3-gallate (EGCG) mediated anti-inflammation response in lipopolysaccharide (LPS)-stimulated human colorectal cells through the negative regulator of Toll-like receptor (TLR) signaling. Methods: human intestinal epithelial cells (HT-29) were used in all experiments. Cell cytotoxicity and nitric oxide (NO) were evaluated by WST-1 and the Griess reagent. Western blot analysis and ELISA were used to determine inflammatory mediators and 67-kDa laminin receptor (67LR)-mediated Tollip signaling pathways. Results: Treatment of EGCG and LPS did not affect the cytotoxicity in HT-29 cells. LPS treatment dose-dependently increased the pro-inflammatory cytokine, such as interleukin (IL)-8, whereas EGCG significantly reduced the LPS-stimulated IL-8 production. Additionally, EGCG treatment markedly increased the Toll-interacting protein (Tollip) expression, which negatively regulates the TLR signaling in a dose and time-dependent manner. In particular, in the result from an RNA interference-mediated assay, our finding showed that silencing of Tollip resulted in abrogation of the inhibitory action of EGCG on LPS-induced production of pro-inflammatory mediators (inducible nitric oxide synthase-mediated NO/COX2, and IL-8) and activation of MAPKs and NF-κB signaling pathways. Interestingly, we also found that Tollip expression induced by EGCG could be modulated through 67LR expressed on the surface of HT-29 cells. Conclusions: Our novel finding indicates that 67LR and Tollip signaling activated by EGCG treatment is essential for inhibition of inflammation in human intestinal epithelial cells.
Upregulation of NOX2 and NOX4 Mediated by TGF-β Signaling Pathway Exacerbates Cerebral Ischemia/Reperfusion Oxidative Stress Injury
Authors: Lou Zheng , Wang Ai-Ping , Duan Xiao-Ming , Hu Guo-Huang , Song Gui-Lin , Zuo Mei-Ling , Yang Zhong-Bao
Published: May 2018

Background/Aims: Ischemic stroke is still one of the leading debilitating diseases with high morbidity and mortality. NADPH oxidase (NOX)-derived reactive oxygen species (ROS) play an important role in cerebral ischemia/reperfusion (I/R) injury. However, the mechanism underlying the regulation of ROS generation is still not fully elucidated. This study aims to explore the role of transforming growth beta (TGF-β) signals in ROS generation. Methods: Sprague–Dawley rats were subjected to I/R injury, and PC-12 cells were challenged by hypoxia/reoxygenation (H/R) and/or treated with activin receptor-like kinase (ALK5) inhibitor Sb505124 or siRNA against ALK5. Brain damage was evaluated using neurological scoring, triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, infarct volume measurement, TUNEL staining, and caspase-3 activity measurement. Expression of TGF-β and oxidative stress-related genes was analyzed by real-time polymerase chain reaction and Western blot; NOX activity and ROS level were measured using spectrophotometry and fluorescence microscopy, respectively. Results: I/R contributed to severe brain damage (impaired neurological function, brain infarction, tissue edema, apoptosis), TGF-β signaling activation (upregulation of ALK5, phosphorylation of SMAD2/3) and oxidative stress (upregulation of NOX2/4, rapid release of ROS [oxidative burst]). However, Sb505124 significantly reversed these alterations and protected rats against I/R injury. As in the animal results, H/R also contributed to TGF-β signaling activation and oxidative stress. Likewise, the inhibition of ALK5 or ALK5 knockdown significantly reversed these alterations in PC-12 cells. Other than ALK5 knockdown, ALK5 inhibition had no effect on the expression of ALK5 in PC-12 cells. Conclusions: Our studies demonstrated that TGF-β signaling activation is involved in the regulation of NOX2/NOX4 expression and exacerbates cerebral I/R injury.
Establishing the Transient Mass Balance of Thrombosis
Authors: Zhu Shu , Chen Jason , Diamond Scott L.
Published: May 2018

Objective—

We investigated the coregulation of thrombin and fibrin as blood flows over a procoagulant surface.

Approach and Results—

Using microfluidic perfusion of factor XIIa-inhibited human whole blood (200 s
−1
wall shear rate) over a 250-μm long patch of collagen/TF (tissue factor; ≈1 molecule per μm
2
) and immunoassays of the effluent for F1.2 (prothrombin fragment 1.2), TAT (thrombin–antithrombin complex), and D-dimer (post–end point plasmin digest), we sought to establish the transient mass balance for clotting under venous flow. F1.2 (but almost no free thrombin detected via TAT assay) continually eluted from clots when fibrin was allowed to form. Low-dose fluorescein-Phe-Pro-Arg-chloromethylketone stained fibrin-bound thrombin—a staining ablated by anti–γ′-fibrinogen or the fibrin inhibitor glypro-arg-pro but highly resistant to 7-minute buffer rinse, demonstrating tight binding of thrombin to γ′-fibrin. With fibrin polymerizing for 500 seconds, 92 000 thrombin molecules and 203 000 clot-associated fibrin monomer equivalents were generated per TF molecule (or per μm
2
). Fibrin reached 15 mg/mL in the pore space (porosity ≈0.5) of a 15-μm-thick thrombus core by 500 seconds and 30 mg/mL by 800 seconds. For a known rate of ≈60 FPA (fibrinopeptide-A) per thrombin per second, each thrombin molecule generated only 3 fibrin monomer equivalents during 500 seconds, indicating an intraclot thrombin half-life of ≈70 ms, much shorter than its diffusional escape time (≈10 seconds). By 800 seconds, gly-pro-arg-pro allowed 4-fold more F1.2 generation, consistent with gly-pro-arg-pro ablating fibrin’s antithrombin-I activity and facilitating thrombin-mediated FXIa activation.

Conclusions—

Under flow, fibrinogen continually penetrates the clot, and γ′-fibrin regulates thrombin.
Coronary and Peripheral Vasomotor Responses to Mental Stress
Authors: Hammadah Muhammad , Kim Jeong Hwan , Al Mheid Ibhar , Samman Tahhan Ayman , Wilmot Kobina , Ramadan Ronnie , Alkhoder Ayman , Khayata Mohamed , Mekonnen Girum , Levantsevych Oleksiy , Bouchi Yasir , Kaseer Belal , Choudhary Fahad , Gafeer Mohamad M. , Corrigan Frank E. , Shah Amit J. , Ward Laura , Kutner Michael , Bremner J. Douglas , Sheps David S. , Raggi Paolo , Vaccarino Viola , Samady Habib , Mavromatis Kreton , Quyyumi Arshed A.
Published: May 2018

Background

Coronary microvascular dysfunction may contribute to myocardial ischemia during mental stress (
MS
). However, the role of coronary epicardial and microvascular function in regulating coronary blood flow (
CBF
) responses during
MS
remains understudied. We hypothesized that coronary vasomotion during
MS
is dependent on the coronary microvascular endothelial function and will be reflected in the peripheral microvascular circulation.

Methods and Results

In 38 patients aged 59±8 years undergoing coronary angiography, endothelium‐dependent and endothelium‐independent coronary epicardial and microvascular responses were measured using intracoronary acetylcholine and nitroprusside, respectively, and after
MS
induced by mental arithmetic testing. Peripheral microvascular tone during
MS
was measured using peripheral arterial tonometry (Itamar Inc, Caesarea, Israel) as the ratio of digital pulse wave amplitude compared to rest (peripheral arterial tonometry ratio).
MS
increased the rate‐pressure product by 22% (±23%) and constricted epicardial coronary arteries by −5.9% (−10.5%, −2.6%) (median [interquartile range]),
P
=0.001, without changing
CBF
. Acetylcholine increased
CBF
by 38.5% (8.1%, 91.3%),
P
=0.001, without epicardial coronary diameter change (0.1% [−10.9%, 8.2%],
P
=not significant). The
MS
‐induced
CBF
response correlated with endothelium‐dependent
CBF
changes with acetylcholine (
r
=0.38,
P
=0.03) but not with the response to nitroprusside. The peripheral arterial tonometry ratio also correlated with the demand‐adjusted change in
CBF
during
MS
(
r
=−0.60,
P
=0.004), indicating similarity between the microcirculatory responses to
MS
in the coronary and peripheral microcirculation.

Conclusions

The coronary microvascular response to
MS
is determined by endothelium‐dependent, but not endothelium‐independent, coronary microvascular function. Moreover, the coronary microvascular responses to
MS
are reflected in the peripheral microvascular circulation.