bluuebunny/crossref_metadata_2025 huggingface dataset:
Using Graph Theory to Assess the Interaction between Cerebral Function, Brain Hemodynamics, and Systemic Variables in Premature Infants
Authors: Hendrikx Dries , Thewissen Liesbeth , Smits Anne , Naulaers Gunnar , Allegaert Karel , Van Huffel Sabine , Caicedo Alexander
Published: August 2018

Graphs can be used to describe a great variety of real‐world situations and have therefore been used extensively in different fields. In the present analysis, we use graphs to study the interaction between cerebral function, brain hemodynamics, and systemic variables in premature neonates. We used data from a propofol dose‐finding and pharmacodynamics study as a model in order to evaluate the performance of the graph measures to monitor signal interactions. Concomitant measurements of heart rate, mean arterial blood pressure, arterial oxygen saturation, regional cerebral oxygen saturation—measured by means of near‐infrared spectroscopy—and electroencephalography were performed in 22 neonates undergoing INSURE (intubation, surfactant administration, and extubation). The graphs used to study the interaction between these signal modalities were constructed using the RBF kernel. Results indicate that propofol induces a decrease in the signal interaction up to 90 minutes after propofol administration, which is consistent with clinical observations published previously. The clinical recovery phase is mainly determined by the EEG dynamics, which were observed to recover much slower compared to the other modalities. In addition, we found a more pronounced loss in cerebral‐systemic interactions with increasing propofol dose.
Research on Roles of Mongolian Medical Warm Acupuncture in Inhibiting p38 MAPK Activation and Apoptosis of Nucleus Pulposus Cells
Authors: Li Sha , Bao Lidao , Si Lengge , Wang Xiaohui , Bo Agula
Published: August 2018

Background. Mongolian medical warm acupuncture has a desirable therapeutic effect on sciatica. Apoptosis of the nucleus pulposus cells is considered to play an important role in sciatica. Evidence has demonstrated that oxidative stress and its induced activation of the signaling pathways play important roles in sciatica. However, further research is expected to reveal whether Mongolian medical warm acupuncture can inhibit the apoptosis of nucleus pulposus cells and oxidative stress. Objective. To study the effect of the p38 MAPK pathway activated by the generated ROS on apoptosis and the expression of the genes related to the balance of the extracellular matrix metabolism during treatment of sciatica with Mongolian medical warm acupuncture. Method. The volume of the active oxygen generated in the nucleus pulposus cells was detected following intervention of Mongolian medical warm acupuncture. The p38 MAPK phosphorylation level was detected with Western blot. The genes are related to the metabolism of the nucleus pulposus extracellular matrix. Result. Mongolian medical warm acupuncture reduced the active oxygen within the nucleus pulposus cells and inhibited the activation of the p38 MAPK pathway (P=0.013). Meanwhile, it upregulated the gene expression of Type II collagen, aggrecan, Sox‐9, and tissue matrix metalloproteinase reagent 1 (P‐0.015; P=0.025; P=0.031; P=0.045) and downregulated the gene expression of matrix metalloproteinase 3 (P=0.015). Conclusion. Mongolian medical warm acupuncture may inhibit apoptosis of nucleus pulposus cells and activation of the extracellular matrix decomposition metabolism pathway and promote its anabolism. This process may rely on the oxidative stress matrix of the p38 MAPK pathway.
Effect of Modulation of the Inlet Velocity and Equivalence Ratio Gradients on the Stabilization of Stratified Axisymmetric Bluff-Body Flames
Authors: Paterakis G. , Koutmos P.
Published: August 2018

An investigation of ultralean stratified, disk stabilized, propane flames operated with acoustic modulation of the inlet velocity and fuel-air mixture profiles is presented. Transverse acoustic forcing was applied to the air, upstream of a double-cavity premixer section, formed along three concentric disks, which fueled the stabilization region with a radial mixture gradient. Measurements and supporting Large Eddy Simulations with a nine-step mechanism for propane combustion were performed to evaluate variations in the ultralean flame characteristics under forced and unforced conditions. The effects of forcing on the heat release profiles and on the interaction of the toroidal flame with the recirculation region are examined and discussed. The impact of the acoustic excitation of inlet conditions on the local extinction behavior is, also, assessed by monitoring a local stability criterion and by analyzing phase-resolved chemiluminescence images.
Functional Modification Effect of Epoxy Oligomers on the Structure and Properties of Epoxy Hydroxyurethane Polymers
Authors: Stroganov Victor , Stoyanov Oleg , Stroganov Ilya , Kraus Eduard
Published: August 2018

We introduce different ways to solve the actual fragility problem of the epoxy‐amine polymers by curing epoxidian oligomers with aliphatic amines without additional heat input. The pathways are the oligomer‐oligomeric modification of epoxy resins‐epoxy oligomers (EO), with their conversion to oligoethercyclocarbonates (OECC) by carbonization with carbon dioxide. The cocuring of these oligomers as a result of aminolysis competing reactions is “epoxide‐amine” (forming a network polymer) and “cyclocarbonate‐amine” (forming the linear hydroxyurethane, extending the internodal chains). Formation of internal and intermolecular hydrogen bonds was established on hydroxycarbonates (HA) and linear polyhydroxyurethanes (PHU) model compounds by IR and NMR spectroscopy. The results of the hydrogen bond system formation processes explain the change in the relaxation and physicomechanical properties of hard polymers modified by the epoxy‐amine compositions (OECC), containing aromatic and aliphatic links. This paper presents a possible OECC modificator, the optimal EO:OECC ratio and its influence on the cross‐link frequency, the polarity, the fragment and chain flexibilities and, as a consequence, the possible stiffness regulation for selected epoxy polymers. Thus, the causes of the increase in deformation‐strength and adhesion characteristics were established by a factor of 1.5 to 3.0 due to an increase in cohesive strength (as a result of the combined network operation with covalent and physical bonds), as well as reduction of residual stresses (by adding the aliphatic fragments as additional relaxants), and reducing the defectiveness of the boundary layers (polymer‐substrate).
Energy Definition and Dark Energy: A Thermodynamic Analysis
Authors: Moradpour H. , Graça J. P. Morais , Lobo I. P. , Salako I. G.
Published: August 2018

Accepting the Komar mass definition of a source with energy-momentum tensor Tμν and using the thermodynamic pressure definition, we find a relaxed energy-momentum conservation law. Thereinafter, we study some cosmological consequences of the obtained energy-momentum conservation law. It has been found out that the dark sectors of cosmos are unifiable into one cosmic fluid in our setup. While this cosmic fluid impels the universe to enter an accelerated expansion phase, it may even show a baryonic behavior by itself during the cosmos evolution. Indeed, in this manner, while Tμν behaves baryonically, a part of it, namely, Tμν(e) which is satisfying the ordinary energy-momentum conservation law, is responsible for the current accelerated expansion.
Hygiene Quality and Consumer Safety of Traditional Short- and Long-Ripened Cheeses from Poland
Authors: Pyz-Łukasik Renata , Knysz Przemysław , Gondek Michał
Published: August 2018

The aim of this study was the assessment of the microbiological quality of three types of traditional cheeses which are produced from raw and pasteurized cow’s milk. Two types of cheeses were of the short-ripened type, and one cheese was long-ripened. A microbial examination was conducted for the presence of Salmonella spp. and Listeria monocytogenes microorganisms and the count of aerobic, psychrotrophic, lactic acid bacteria, and coliform bacteria, as well as Escherichia coli, Enterobacteriaceae, Enterococcus spp., Staphylococcus spp., and yeasts. The examined cheeses did not fulfill the microbial criteria for food safety (presence of L. monocytogenes) and process hygiene (exceeded allowable levels of E. coli and coagulase-positive Staphylococcus). The levels of coliform bacteria, E. coli, and Enterobacteriaceae and the presence of Enterococcus faecalis determined in the three examined cheese types indicated that insufficient hygiene procedures were used during the production process. The results of the study indicate that the examined cheeses did not fulfill the microbial criteria for food safety and process hygiene according to the legislation. It is necessary to introduce correction procedures as indicated in the current report.
Expanded (G/G2) Expansion Method to Solve Separated Variables for the 2+1-Dimensional NNV Equation
Authors: Meng Yong
Published: August 2018

The traditional (G/G2) expansion method is modified to extend the symmetric extension to the negative power term in the solution to the positive power term. The general traveling wave solution is extended to a generalized solution that can separate variables. By using this method, the solution to the detached variables of the symmetric extended form of the 2+1-dimensional NNV equation can be solved, also the soliton structure and fractal structure of Dromion can be studied well.
Single-Cell Analyses of Prostate Cancer Liquid Biopsies Acquired by Apheresis
Authors: Lambros Maryou B. , Seed George , Sumanasuriya Semini , Gil Veronica , Crespo Mateus , Fontes Mariane , Chandler Rob , Mehra Niven , Fowler Gemma , Ebbs Berni , Flohr Penny , Miranda Susana , Yuan Wei , Mackay Alan , Ferreira Ana , Pereira Rita , Bertan Claudia , Figueiredo Ines , Riisnaes Ruth , Rodrigues Daniel Nava , Sharp Adam , Goodall Jane , Boysen Gunther , Carreira Suzanne , Bianchini Diletta , Rescigno Pasquale , Zafeiriou Zafeiris , Hunt Joanne , Moloney Deirdre , Hamilton Lucy , Neves Rui P. , Swennenhuis Joost , Andree Kiki , Stoecklein Nikolas H. , Terstappen Leon W.M.M. , de Bono Johann S.
Published: August 2018

Purpose: Circulating tumor cells (CTCs) have clinical relevance, but their study has been limited by their low frequency.

Experimental Design: We evaluated liquid biopsies by apheresis to increase CTC yield from patients suffering from metastatic prostate cancer, allow precise gene copy-number calls, and study disease heterogeneity.

Results: Apheresis was well tolerated and allowed the separation of large numbers of CTCs; the average CTC yield from 7.5 mL of peripheral blood was 167 CTCs, whereas the average CTC yield per apheresis (mean volume: 59.5 mL) was 12,546 CTCs. Purified single CTCs could be isolated from apheresis product by FACS sorting; copy-number aberration (CNA) profiles of 185 single CTCs from 14 patients revealed the genomic landscape of lethal prostate cancer and identified complex intrapatient, intercell, genomic heterogeneity missed on bulk biopsy analyses.

Conclusions: Apheresis facilitated the capture of large numbers of CTCs noninvasively with minimal morbidity and allowed the deconvolution of intrapatient heterogeneity and clonal evolution. Clin Cancer Res; 24(22); 5635–44. ©2018 AACR.
Role of the RANK/RANKL Pathway in Multiple Myeloma
Authors: Raje Noopur S. , Bhatta Sumita , Terpos Evangelos
Published: August 2018

Receptor activator of nuclear factor-kappa B (RANK) and its ligand, RANKL, are expressed in a variety of tissues throughout the body; their primary role is in the regulation of bone remodeling and development of the immune system. Consistent with these functions, evidence exists for a role of RANK/RANKL in all stages of tumorigenesis, from cell proliferation and carcinogenesis to epithelial–mesenchymal transition to neoangiogenesis and intravasation to metastasis to bone resorption and tumor growth in bone. Results from current studies also point to a role of RANK/RANKL signaling in patients with multiple myeloma, who have increased serum levels of soluble RANKL and an imbalance in RANKL and osteoprotegerin. Current therapies for patients with multiple myeloma demonstrate that RANKL may be released by tumor cells or osteoprogenitor cells. This article will review currently available evidence supporting a role for RANK/RANKL signaling in tumorigenesis, with a focus on patients with multiple myeloma.
The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation
Authors: Reiff Sean D. , Mantel Rose , Smith Lisa L. , Greene J.T. , Muhowski Elizabeth M. , Fabian Catherine A. , Goettl Virginia M. , Tran Minh , Harrington Bonnie K. , Rogers Kerry A. , Awan Farrukh T. , Maddocks Kami , Andritsos Leslie , Lehman Amy M. , Sampath Deepa , Lapalombella Rosa , Eathiraj Sudharshan , Abbadessa Giovanni , Schwartz Brian , Johnson Amy J. , Byrd John C. , Woyach Jennifer A.
Published: August 2018

Targeted inhibition of Bruton tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has improved outcomes for patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here, we describe preclinical investigations of ARQ 531, a potent, reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses. In vitro treatment of patient CLL cells with ARQ 531 decreases BTK-mediated functions including B-cell receptor (BCR) signaling, viability, migration, CD40 and CD86 expression, and NF-κB gene transcription. In vivo, ARQ 531 was found to increase survival over ibrutinib in a murine Eμ-TCL1 engraftment model of CLL and a murine Eμ-MYC/TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 mutants, which facilitate clinical resistance to ibrutinib.

Significance: This study characterizes a rationally designed kinase inhibitor with efficacy in models recapitulating the most common mechanisms of acquired resistance to ibrutinib. Reversible BTK inhibition is a promising strategy to combat progressive CLL, and multikinase inhibition demonstrates superior efficacy to targeted ibrutinib therapy in the setting of Richter transformation. Cancer Discov; 8(10); 1300–15. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1195
Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations
Authors: Drilon Alexander , Ou Sai-Hong Ignatius , Cho Byoung Chul , Kim Dong-Wan , Lee Jeeyun , Lin Jessica J. , Zhu Viola W. , Ahn Myung-Ju , Camidge D. Ross , Nguyen Judy , Zhai Dayong , Deng Wei , Huang Zhongdong , Rogers Evan , Liu Juliet , Whitten Jeff , Lim John K. , Stopatschinskaja Shanna , Hyman David M. , Doebele Robert C. , Cui J. Jean , Shaw Alice T.
Published: August 2018

The use of tyrosine kinase inhibitors (TKI) with activity against ALK, ROS1, or TRKA–C can result in significant clinical benefit in patients with diverse tumors harboring ALK, ROS1, or NTRK1–3 rearrangements; however, resistance invariably develops. The emergence of on-target kinase domain mutations represents a major mechanism of acquired resistance. Solvent-front substitutions such as ALKG1202R, ROS1G2032R or ROS1D2033N, TRKAG595R, and TRKCG623R are among the most recalcitrant of these mechanisms. Repotrectinib (TPX-0005) is a rationally designed, low-molecular-weight, macrocyclic TKI that is selective and highly potent against ROS1, TRKA–C, and ALK. Importantly, repotrectinib exhibits activity against a variety of solvent-front substitutions in vitro and in vivo. As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with ROS1 or NTRK3 fusion–positive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance.

Significance: Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1–3, and ALK. Repotrectinib may represent an effective therapeutic option for patients with ROS1-, NTRK1–3-, or ALK-rearranged malignancies who have progressed on earlier-generation TKIs. Cancer Discov; 8(10); 1227–36. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1195
The Head Turning Sign in Dementia and Mild Cognitive Impairment: Its Relationship to Cognition, Behavior, and Cerebrospinal Fluid Biomarkers
Authors: Durães João , Tábuas-Pereira Miguel , Araújo Rui , Duro Diana , Baldeiras Inês , Santiago Beatriz , Santana Isabel
Published: August 2018

Background/Aims: The head turning sign (HTS) is frequently noticed in clinical practice, but few studies have investigated its etiological and neuropsychological correlates. Methods: The presence and frequency of the HTS was operationalized and prospectively evaluated in patients with Alzheimer’s disease (AD), amnestic mild cognitive impairment (MCI), and behavioral-variant frontotemporal dementia (bvFTD). Cerebrospinal fluid (CSF) samples for AD biomarkers were collected. Mini-Mental State Examination, Montreal Cognitive Assessment, Geriatric Depression Scale (GDS), and insight scale scores were ascertained. Results: A total of 84 patients were included. The HTS was more prevalent in AD than in MCI or bvFTD. It correlated negatively with cognitive measures and depression. It also had a positive correlation with CSF total tau and hyperphosphorylated tau proteins. Total tau protein and GDS score were the only variables independently associated with the HTS. Conclusions: The presence of the HTS in a cognitively impaired individual suggests a diagnosis of AD. A higher HTS frequency correlates with higher CSF total tau levels, a smaller GDS score, and worse cognitive measures. In the MCI subgroup, the HTS may suggest a higher risk of progression.
Impact of CYP2C19 Polymorphism on Antiplatelet Potency of Prasugrel 5 and 10 mg Daily Maintenance
Authors: Li JiaXin , Kim Moo Hyun , Guo LongZhe , Song Kai , Shin Eun-Seok , Ann Soe Hee , Kim Soo Jin , Cho Yong-Rak , Park Kyungil , Park Tae Ho , Kim Young Dae , Lomakin Nikita , Serebruany Victor
Published: August 2018

Background: Whether genetic polymorphisms (GP) impact residual platelet aggregation (RPA) following prasugrel is unclear, especially during maintenance phase. We assessed the influence of CYP2C19 GP carriers on RPA in the prospective observational cohort study. Methods and Results: All post-stent patients (n = 206) received prasugrel 60 mg loading and either 5 or 10 mg daily maintenance with aspirin100 mg. RPA levels by light transmission aggregometry (LTA), multiplate electrode aggregometry (MEA), and VerifyNow (P2Y12 reaction units, PRU) with CYP2C19 GP were measured simultaneously. Demographics and clinical characteristics were not useful for predicting response after prasugrel. GP carriers exhibited higher RPA (PRU: p = 0.001, LTA: p = 0.001, MEA: p = 0.023) than noncarriers. CYP2C19 carriers had higher RPA for 5 mg (n = 35; LTA: p = 0.043, MEA: p = 0.023) and reached significance for 10 mg (n = 27; LTA: p = 0.001, PRU: p = 0.001) prasugrel. When divided into extensive, intermediate, and poor metabolizers, all exhibited statistical differences among the 3 groups (LTA: 14.9 ± 12.3%, 22.6 ± 14.9%, 22.9 ± 15.6%, p = 0.002; PRU: 104.1 ± 70.8%, 141.8 ± 78.0%, 151.0 ± 84.8%, p = 0.003; MEA: 19.7 ± 8.9%, 24.4 ± 12.2%, 28.1 ± 14.7%, p = 0.002). Conclusion: CYP2C19 GP impacts RPA during maintenance phase prasugrel in Korean outpatients. This effect is consistent for both of the approved prasugrel doses potentially affecting long-term outcomes including bleeding risks. However, the clinical utility of these findings is still uncertain, and requires more evidence from larger randomized trials beyond East Asians.
Factors Associated with Stroke Misdiagnosis in the Emergency Department: A Retrospective Case-Control Study
Authors: Venkat Abhay , Cappelen-Smith Cecilia , Askar Shabeel , Thomas Peter R. , Bhaskar Sonu , Tam Amanda , McDougall Alan J. , Hodgkinson Suzanne J. , Cordato Dennis J.
Published: August 2018

Background: Failure to recognise acute stroke may result in worse outcomes due to missed opportunity for acute stroke therapies. Our study examines factors associated with stroke misdiagnosis in patients admitted to a large comprehensive stroke centre. Methods: Retrospective review comparing 156 consecutive stroke patients misdiagnosed in emergency department (ED) with 156 randomly selected stroke controls matched for age, gender, language spoken and stroke subtype for the period 2014–2016. Results: There were 141 ischemic and 15 hemorrhagic misdiagnosed strokes (median age: 77 years, male:female = 1.3: 1). Symptom resolution, altered mental status, nausea/vomiting, dizziness and vertigo favored misdiagnosis (p < 0.05). Hemiparesis and dysarthria favored an accurate diagnosis (p < 0.05). Misdiagnosed patients were more commonly triaged into a lower ED category (62 vs. 42%, p = 0.001), clinically assessed as Face, Arm, Speech and Time (FAST) – negative (78 vs. 22%, p < 0.001) and underwent delayed CT imaging (median 4.1 vs. 1.5 h, p < 0.001). Misdiagnosed patients were more likely to have posterior circulation stroke (PCS; 39 vs. 22%, p = 0.01) and be admitted under non-neurological services (35 vs. 11%, p < 0.001) with worse discharge outcomes including increased mortality. Conclusions: Patients with stroke misdiagnosis were commonly FAST-negative with nonspecific symptoms including altered mental status, dizziness and nausea/vomiting often associated with PCS. Improved diagnostic accuracy may increase access to acute therapies.
Pili Annulati with Severe Trichorrhexis Nodosa: A Case Report and Review of the Literature
Authors: Gonzalez Adrianna M. , Borda Luis J. , Tosti Antonella
Published: August 2018

Pili annulati is generally classified as a hair shaft disorder without fragility. However, increased susceptibility to weathering is common. Severe breakage due to trichorrhexis nodosa is uncommon. We report a case and review the literature on this topic.
Delayed Intravenous Thrombolysis in Patients with Minor Stroke
Authors: Yoo Joonsang , Sohn Sung-Il , Kim Jinkwon , Ahn Seong Hwan , Lee Kijeong , Baek Jang-Hyun , Kim Kyoungsub , Hong Jeong-Ho , Koo Jaseong , Kim Young Dae , Kwak Jaehyuk , Nam Hyo Suk , Heo Ji Hoe
Published: August 2018

Background: The actions and responses of the hospital personnel during acute stroke care in the emergency department (ED) may differ according to the severity of a patient’s stroke symptoms. We investigated whether the time from arrival at ED to various care steps differed between patients with minor and non-minor stroke who were treated with intravenous tissue plasminogen activator (IV tPA). Methods: We included consecutive patients who received IV tPA during a 1.5 year-period in 5 hospitals. Minor stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score < 5. We compared various intervals from arrival at the ED to treatment between patients with minor stroke and those with non-minor stroke (NIHSS score ≥5). Delayed treatment was defined as a door-to-needle time > 40 min. Results: During the study period, 356 patients received IV tPA treatment. The median door-to-needle time was significantly longer in the minor stroke group than it was in the non-minor stroke group (43 min [interquartile range [IQR] 35.5–55.5] vs. 37 min [IQR 30–46], p < 0.001). The minor stroke group had a significantly longer door-to-notification time (7 min [IQR 4.5–12] vs. 5 min [IQR 3–8], p < 0.001) and door-to-imaging time (20 min [IQR 15–26.5] vs. 16 min [IQR 11–21], p < 0.001) than did the non-minor stroke group. However, the imaging-to-needle time was not different between the groups. Multivariable analyses revealed that minor stroke was associated with delayed treatment (OR 2.54 [95% CI 1.52–4.30], p = 0.001). Conclusions: Our findings show that the door-to-needle time was longer in patients with minor stroke than it was in those with non-minor stroke, mainly owing to delayed action in the initial steps of neurology notification and imaging. Our findings suggest that some quality improvement initiatives are necessary for patients with suspected stroke with minor symptoms.
Liver Transplantation in Acute-on-Chronic Liver Failure: Considerations for a Systematic Approach to Decision Making
Authors: Heise Michael , Weiler Nina , Iken Sonja , Welker Martin-Walter , Zeuzem Stefan , Bechstein Wolf O. , Schnitzbauer Andreas A.
Published: August 2018

Background: Acute-on-chronic liver failure (ACLF) is a complex disease with deteriorating liver and kidney function and associated organ failure in patients with chronic liver disease. Methods: This is a concise overview for bedside and algorithmic decision making in patients with ACLF based on the most recent literature. Results: Diagnosis and dynamics of ACLF can be easily monitored with the CLIF-C-ACLF calculator, which delivers grading for ACLF and estimates the risk of mortality, as the natural transplant-free course of ACLF is often fatal. Transplantation offers the best results in patients with ACLF that do not recover spontaneously. However, marginal donor organs should be avoided. Conclusion: ACLF is an increasingly relevant indication with good outcome after liver transplantation. Adequate donor rates may reduce the incidence by means of timely transplantation of acute decompensated patients in lower stages of urgency. Future challenges comprise specific allocation of donor organs to this group of patients that are at a similar risk of mortality when compared to acute liver failure.
Order of Treatment Matters in Ischemic Stroke: Mechanical Thrombectomy First, Then Carotid Artery Stenting for Tandem Lesions of the Anterior Circulation
Authors: Maus Volker , Borggrefe Jan , Behme Daniel , Kabbasch Christoph , Abdullayev Nuran , Barnikol Utako Birgit , Yeo Leonard Leong Litt , Brouwer Patrick A. , Söderman Michael , Möhlenbruch Markus , Liebig Thomas , Fink Gereon Rudolf , Mpotsaris Anastasios
Published: August 2018

Background: One endovascular treatment option of acute ischemic stroke due to tandem occlusion (TO) comprises intracranial thrombectomy and acute extracranial carotid artery stenting (CAS). In this setting, the order of treatment may impact the clinical outcome in this stroke subtype. Methods: Retrospective analysis was performed on data prospectively collected in 4 international stroke centers between 2013 and 2017. One hundred sixty-five patients with anterior TO were treated by endovascular therapy. Clinical and procedural data were evaluated. Favorable clinical outcome was defined as modified Rankin Scale (mRS) ≤2 at 90 days. Propensity score matching was performed for different treatment strategies. Results: Patients’ mean age was 65 ± 11 years and 118 were male (69%). The median admission National Institutes of Health Stroke Scale was 15 (interquartile range 8). In 59% of the patients (n = 101), the antegrade strategy (first stenting, then thrombectomy) was ­performed, in 41% (n = 70) retrograde treatment (first thrombectomy, then stenting). Successful reperfusion (mTICI ≥2b) was achieved in 128 patients (75%). Fifty-nine patients (39%) showed a favorable clinical outcome after 90 days. After propensity score matching, data of 100 patients could be analyzed. Analysis revealed that the retrograde strategy yielded a significantly higher rate of successful reperfusion compared to the antegrade strategy (92 vs. 56%; p < 0.001). The rate of favorable clinical outcome after 90 days (mRS ≤2) was consistently higher (44 vs. 30%; p < 0.05) in the retrograde strategy group. Conclusion: Mechanical thrombectomy prior to acute CAS in TO is a predictive factor for favorable clinical outcome at 90 days.
Roles of Exosome-Like Vesicles Released from Inflammatory C2C12 Myotubes: Regulation of Myocyte Differentiation and Myokine Expression
Authors: Kim Sujin , Lee Min-Jae , Choi Ji-Young , Park Dong-Ho , Kwak Hyo-Bum , Moon Sohee , Koh Je-Woo , Shin Hun-Kyu , Ryu Ji-Kan , Park Chang-Shin , Park Jai Hyung , Kang Ju-Hee
Published: August 2018

Background/Aims: The complicated differentiation processes of cells in skeletal muscle against inflammation that induce muscle atrophy are not fully elucidated. Given that skeletal muscle is a secretory organ, we evaluated the effects of inflammation on myogenic signals and myokine expression, and the roles of inflammatory exosomes released by myotubes in myogenic differentiation. Methods: Inflammation was induced by treatment of fully differentiated C2C12 myotubes with a cytokine mixture of TNF-α and INF-γ. Exosome-like vesicles (ELVs) were isolated from conditioned media of control or inflamed myotubes and incubated with myoblasts. The expression of molecular switches that contribute to myogenic differentiation, including several kinases, their downstream targets, and myokines, were evaluated using immunoblot analysis in inflamed myotubes and in myoblasts treated with ELVs. Results: Inflammation activated molecular mechanisms contributing to muscle atrophy, including AMPK, p-38 MAPK and JNK, while inhibiting Akt-mediated myogenic signals. In addition, inflammation induced myostatin expression with suppression of a myostatin-counteracting myokine, decorin. Well-characterized ELVs released from inflamed myotubes induced myoblast inflammation and inhibited myogenic mechanisms while stimulating atrophic signals. Conclusion: Inflammation of skeletal muscle induces muscle atrophy via multiple mechanisms, including the regulation of myokines and kinases. Inflammatory ELVs are likely to contribute to inflammation-induced muscle atrophy.
Aldehyde Dehydrogenase-2 Attenuates Myocardial Remodeling and Contractile Dysfunction Induced by a High-Fat Diet
Authors: Li Chuanbao , Li Xiaoxing , Chang Ying , Zhao Lang , Liu Baoshan , Wei Shujian , Xu Feng , Zhang Yun , Chen Yuguo
Published: August 2018

Background/Aims: Consumption of a high-fat (HF) diet exacerbates metabolic cardiomyopathy through lipotoxic mechanisms. In this study, we explored the role of aldehyde dehydrogenase-2 (ALDH2) in myocardial damage induced by a HF diet. Methods: Wild-type C57 BL/6J mice were fed a HF diet or control diet for 16 weeks. ALDH2 overexpression was achieved by injecting a lentiviral ALDH2 expression vector into the left ventricle. Results: Consumption of a HF diet induced metabolic syndrome and myocardial remodeling, and these deleterious effects were attenuated by ALDH2 overexpression. In addition, ALDH2 overexpression attenuated the cellular apoptosis and insulin resistance associated with a HF diet. Mechanistically, ALDH2 overexpression inhibited the expression of c-Jun N-terminal kinase (JNK)-1, activated protein 1 (AP-1), insulin receptor substrate 1 (IRS-1), 4- hydroxynonenal, caspase 3, transforming growth factor β1, and collagen I and III, and enhanced Akt phosphorylation. Conclusion: ALDH2 may effectively attenuate myocardial remodeling and contractile defects induced by a HF diet through the regulation of the JNK/AP-1 and IRS-1/Akt signaling pathways. Our study demonstrates that ALDH2 plays an essential role in protecting cardiac function from lipotoxic cardiomyopathy.
Identification of Potential Prognostic Long Non-Coding RNA Biomarkers for Predicting Survival in Patients with Hepatocellular Carcinoma
Authors: Liao Xiwen , Yang Chengkun , Huang Rui , Han Chuangye , Yu Tingdong , Huang Ketuan , Liu Xiaoguang , Yu Long , Zhu Guangzhi , Su Hao , Wang Xiangkun , Qin Wei , Deng Jianlong , Zeng Xianmin , Ye Xinping , Peng Tao
Published: August 2018

Background/Aims: The aim of the current study was to identify potential prognostic long non-coding RNA (lncRNA) biomarkers for predicting survival in patients with hepatocellular carcinoma (HCC) using The Cancer Genome Atlas (TCGA) dataset and bioinformatics analysis. Methods: RNA sequencing and clinical data of HCC patients from TCGA were used for prognostic association assessment by univariate Cox analysis. A prognostic signature was built using stepwise multivariable Cox analysis, and a comprehensive analysis was performed to evaluate its prognostic value. The prognostic signature was further evaluated by functional assessment and bioinformatics analysis. Results: Thirteen differentially expressed lncRNAs (DELs) were identified and used to construct a single prognostic signature. Patients with high risk scores showed a significantly increased risk of death (adjusted P < 0.0001, adjusted hazard ratio = 3.522, 95% confidence interval = 2.307–5.376). In the time-dependent receiver operating characteristic analysis, the prognostic signature performed well for HCC survival prediction with an area under curve of 0.809, 0.782 and 0.79 for 1-, 3- and 5-year survival, respectively. Comprehensive survival analysis of the 13-DEL prognostic signature suggested that it serves as an independent factor in HCC, showing a better performance for prognosis prediction than traditional clinical indicators. Functional assessment and bioinformatics analysis suggested that the prognostic signature was associated with the cell cycle and peroxisome proliferator-activated receptor signaling pathway. Conclusions: The novel lncRNA expression signature identified in the present study may be a potential biomarker for predicting the prognosis of HCC patients.
Characterization of Recombinant Adeno-Associated Viral Transduction and Safety Profiles in Cardiomyocytes
Authors: Ai Jianzhong , He Yong , Zheng Mingxia , Wen Yi , Zhang Huan , Huang Fangyang , Zhu Ye
Published: August 2018

Background/Aims: Cardiovascular diseases (CVD) are the leading causes for human mortality. However, the effective treatment for these diseases are still lacking. Currently, gene therapy could be a potential way for efficiently treating heart diseases. The aim of our study is to analyze the transduction efficacy and safety profile of recombinant adeno associated virus (AAV) serotype 9 for cardiomyocytes in vivo and in vitro. Methods: We produced rAAV serotype 9 expressing enhanced green fluorescence protein (EGFP) driven by a cardiac troponin T (cTNT) promoter, and characterized its transduction efficiency in primary cultured cardiomyocytes in vitro, and in wild-type mouse heart tissue in vivo. Results: Our data showed that rAAV9 efficiently transduced mouse cardiomyocytes in vitro. Following intravenous injection, rAAV9 could efficiently and safely transduce cardiomyocytes that are involved in heart diseases. Conclusion: Our findings suggested that rAAV9 can efficiently and safely transduce cardiomyocytes in vitro and/or in vivo. The rAAV9 serotype vector could constitute a powerful toolbox for future gene therapy of heart diseases.
lncRNA TUG1-Mediated Mir-142-3p Downregulation Contributes to Metastasis and the Epithelial-to-Mesenchymal Transition of Hepatocellular Carcinoma by Targeting ZEB1
Authors: He Chuan , Liu Zhigang , Jin Li , Zhang Fang , Peng Xinhao , Xiao Yaqin , Wang Xi , Lyu Qian , Cai XiaoJun
Published: August 2018

Background/Aims: MicroRNA-142-3p (miR-142-3p) is dysregulated in many malignancies and may function as a tumor suppressor or oncogene in tumorigenesis and tumor development. However, few studies have investigated the clinical significance and biological function of miR-142-3p in hepatocellular carcinoma (HCC). Methods: The expression levels of taurine upregulated gene 1 (TUG1), miR-142-3p, and zinc finger E-box-binding homeobox 1 (ZEB1) were evaluated in HCC tissues and cell lines by quantitative real-time PCR. MTT and colony formation assays were used to detect cell proliferation ability, transwell assays were used to assess cell migration and invasion, and luciferase reporter assays were used to examine the interaction between the long noncoding RNA TUG1 and miR-142-3p. Tumor formation was evaluated through in vivo experiments. Results: miR-142-3p was significantly downregulated in HCC tissues, but TUG1 was upregulated in HCC tissues. Knockdown of TUG1 and upregulation of miR-142-3p inhibited cell proliferation, cell migration, cell invasion, and the epithelial-mesenchymal transition (EMT). miR-142-3p was found to be a prognostic factor of HCC, and the mechanism by which TUG1 upregulated ZEB1 was via direct binding to miR-142-3p. In vivo assays showed that TUG1 knockdown suppressed cell proliferation and the EMT in nude mice. Conclusion: The results of this study suggest that the TUG1/miR-142-3p/ ZEB1 axis contributes to the formation of malignant behaviors in HCC.
Bioactive Peptide Improves Diet-Induced Hepatic Fat Deposition and Hepatocyte Proinflammatory Response in SAMP8 Ageing Mice
Authors: Dumeus Stanley , Shibu Marthandam Asokan , Lin Wan-Teng , Wang Ming-Fu , Lai Chao-Hung , Shen Chia-Yao , Lin Yueh-Min , Viswanadha Vijaya Padma , Kuo Wei-Wen , Huang Chih-Yang
Published: August 2018

Background/Aims: High-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) poses therapeutic challenges in elderly subjects. Due to lack of efficient drug therapy, plant-based bioactive peptides have been studied as alternative strategy in NAFLD and for less toxicity in elderly. To mimic fatty liver in aging conditions, researchers highly commended the genetically engineered strains SAMP8 (senescence-accelerated mice prone 8). However, there is a paucity of reports about the anti-steatosis effects of bioactive peptides against fatty liver development under a combined action of high-fat diet exposure and aging process. This study was conducted to evaluate the activity of DIKTNKPVIF peptide synthesized from alcalase-generated potato protein hydrolysate (PH), on reducing HFD-driven and steatosis-associated proinflammatory reaction in ageing model. Methods: Five groups of six-month-old SAMP8 mice (n=4, each) were fed either a normal chow (NC group) for 14 weeks upon sacrifice, or induced with a 6-week HFD feeding, then treated without (HCO group) or with an 8-week simultaneous administration of peptide (HPEP group), protein (HPH group) or probucol (HRX group). Liver organs were harvested from each group for histological analysis and immunoblot assay. Results: In contrast to NC, extensive fat accumulation was visualized in the liver slides of HCO. Following the trends of orally administered PH, intraperitoneally injected peptide reduces hepatic fat deposition and causes at protein level, a significant decrease in HFD-induced proinflammatory mediators p-p38 MAPK, FGF-2, TNF-α, IL-6 with concomitant reactivation of AMPK. However, p-Foxo1 and PPAR-α levels were slightly changed. Conclusion: Oral supplementation of PH and intraperitoneal injection of derived bioactive peptide alleviate proinflammatory reaction associated with hepatosteatosis development in elderly subjects, through activation of AMPK.
WBP2 Downregulation Inhibits Proliferation by Blocking YAP Transcription and the EGFR/PI3K/Akt Signaling Pathway in Triple Negative Breast Cancer
Authors: Song Hongming , Wu Tianqi , Xie Dan , Li Dengfeng , Hua Kaiyao , Hu Jiashu , Fang Lin
Published: August 2018

Background/Aims: Dysregulated expression of WW domain-binding protein 2 (WBP2) is associated with poor prognosis in ER+ breast cancer patients. However, its role in triple negative breast cancer (TNBC) has not been previously assessed. Therefore, we aimed to elucidate the functional mechanism of WBP2 in TNBC cells. Methods: qRT-PCR, western blotting, and immunohistochemical staining were used to evaluate WBP2 expression in TNBC patient tumors and cell lines. HCC1937 and MDA-MB-231 cells transiently transfected with WBP2 small interfering RNA (siRNA), miR-613 mimics, or miR-613 inhibitors were subject to assays for cell viability, apoptosis and cell cycle distribution. Co-immunoprecipitation, western blotting or qRT-PCR were employed to monitor changes in signaling pathway-related genes and proteins. Luciferase assays were performed to assess whether WBP2 is a direct target of miR-613. The effect of miR-613 on tumor growth was assessed in vivo using mouse xenograft models. Results: The expression of WBP2 was upregulated in TNBC tissues and cells. Expression of WBP2 was significantly correlated with Ki67 in TNBC patients. Knockdown of WBP2 inhibited cellular proliferation, promoted apoptosis, and induced cell cycle arrest of TNBC cells. miR-613 directly bound to the 3’-untranslated region (3’-UTR) of WBP2 and regulated the expression of WBP2. Moreover, miR-613 reduced the expression of WBP2 and suppressed tumor growth of TNBC cells in vivo. Knockdown of WBP2 inhibited YAP transcription and the EGFR/PI3K/Akt signaling pathway in TNBC cells, and these effects were reversed by inhibition of miR-613. Conclusion: WBP2 overexpression is associated with the poor prognosis of TNBC patients and the miR-613-WBP2 axis represses TNBC cell growth by inactivating YAP-mediated gene expression and the EGFR/PI3K/Akt signaling pathway.
Analysis of Circulating Tumor Cells in Ovarian Cancer and Their Clinical Value as a Biomarker
Authors: Zhang Xuehui , Li Hui , Yu Xiuyan , Li Shanxin , Lei Zhen , Li Chang , Zhang Qun , Han Qing , Li Yuan , Zhang Kun , Wang Yuxiang , Liu Congrong , Mao Yiqing , Wang Xi , Irwin David M. , Guo Hongyan , Niu Gang , Tan Huanran
Published: August 2018

Background/Aims: Monitoring the appearance and progression of tumors are important for improving the survival rate of patients with ovarian cancer. This study aims to examine circulating tumor cells (CTCs) in epithelial ovarian cancer (EOC) patients to evaluate their clinical significance in comparison to the existing biomarker CA125. Methods: Immuomagnetic bead screening, targeting epithelial antigens on ovarian cancer cells, combined with multiplex reverse transcriptase-polymerase chain reaction (Multiplex RT-PCR) was used to detect CTCs in 211 samples of peripheral blood (5 ml) from 109 EOC patients. CTCs and CA125 were measured in serial from 153 blood and 153 serum samples from 51 patients and correlations with treatment were analyzed. Immunohistochemistry was used to detect the expression of tumor-associated proteins in tumor tissues and compared with gene expression in CTCs from patients. Results: CTCs were detected in 90% (98/109) of newly diagnosed patients. In newly diagnosed patients, the number of CTCs was correlated with stage (p=0.034). Patients with stage IA-IB disease had a CTC positive rate of 93% (13/14), much higher than the CA125 positive rate of only 64% (9/14) for the same patients. The numbers of CTCs changed with treatment, and the expression of EpCAM (p=0.003) and HER2 (p=0.035) in CTCs was correlated with resistance to chemotherapy. Expression of EpCAM in CTCs before treatment was also correlated with overall survival (OS) (p=0.041). Conclusion: Detection of CTCs allows early diagnose and expression of EpCAM in CTC positive patients predicts prognosis and should be helpful for monitoring treatment.
Rochas intrusivas básicas no sudeste do Cinturão Dom Feliciano, RS: petrografia e geoquímica das associações I e II
Authors: Barbosa Laércio Dal Olmo , Koester Edinei , Gastal Maria do Carmo Pinto
Published: August 2018

Intrusões dioríticas, gabroicas e outras rochas máficas-ultramáficas registram tanto os processos de extração e transporte de magmas do manto, resultando na acresção vertical de material à crosta, quanto os processos de interação entre esses dois componentes. Recentemente, essas rochas têm sido apontadas como importantes marcadores petrogenéticos, quando associadas ao magmatismo intermediário a ácido, em ambientes orogênicos a pós-colisionais. Na porção sudeste do Cinturão Dom Feliciano, no Rio Grande do Sul, constituído majoritariamente por granitoides, ocorrem intrusões dioríticas e gabroicas de pequeno porte e caráter dominantemente básico, na região compreendida entre Pinheiro Machado e Pedro Osório. Este artigo apresenta a caracterização geológica, mineralógica, petrográfica e geoquímica dessas rochas, propondo assim a separação de duas associações principais. A Associação I (AI), constituída por rochas gabroicas, comumente cumuladas e por vezes estratificadas, engloba os corpos do Passo da Fabiana, Passo da Olaria, Arroio Santa Fé e Desvio Herval. A Associação II (AII), diorítica a gabroica, compreende rochas maciças a localmente foliadas, nas ocorrências do Alto Alegre, Passo dos Machados e Campo Bonito. As duas associações são subalcalinas, com afinidade cálcio-alcalina médio-K (AI) e médio a alto-K (AII), com altos teores de alumina (Al2O3 > 17%), mesmo para os termos não cumulados. Diferenças quanto aos elementos maiores (CaO, Mg# e álcalis), menores e traços (P2O5, Zr, Nb, Y, total e padrões de ETR) referendam a separação proposta. As assinaturas magnéticas sugerem o controle no posicionamento das intrusões por descontinuidades litosféricas, que teriam possibilitado a ascensão e a colocação desses magmas em níveis superiores da crosta. Processos petrogenéticos envolvendo a participação de líquidos derivados do manto em reservatórios supracrustais e a sua evolução nas deep crustal hot zones são propostos.
Concentração de elementos traços, terras raras e escândio em perfil de intemperismo de rocha metaultramáfica (Bom Jesus da Penha, Minas Gerais)
Authors: Faria Júnior Ilio Rodarte , Luvizotto George Luiz , Rosolen Vania Silvia
Published: August 2018

O processo de formação dos horizontes lateríticos é responsável pela reorganização química e mineralógica dos litotipos preexistentes. Esse arranjo é controlado pela mineralogia primária da rocha e pelas características de desenvolvimento do processo intempérico. Este artigo apresenta um estudo em um clorita-anfibólio xisto, a partir do qual se desenvolveram dois horizontes de intemperismo. No topo se observou solo caulinítico vermelho argiloso, enquanto abaixo se desenvolve um horizonte saprolítico verde com plintitas de cor ocre, o qual contém montmorillonita neoformada. Os elementos químicos analisados tiveram variações nos teores ao longo desse perfil, sendo que todos os metais tiveram, em determinadas amostras, picos de acúmulos superiores a 100% em relação à rocha. Al2O3, U, Th, Zr e TiO2 mostram concentração residual no topo do horizonte de solos, junto a caulinita e óxidos e hidróxidos de ferro; Fe2O3, V e Co tiveram maior acúmulo na base do horizonte de solos, próximo à transição para o saprolito; Mn, Cr2O3, Ni, Zn, Cu e elementos terras raras (ETR) apresentaram máximos de enriquecimento no horizonte plintificado, junto a montmorillonita; CaO, MgO e SiO2 tiveram redução dos teores ao longo de todo o perfil estudado. Tomando o litotipo metaultramáfico, destacam-se os enriquecimentos dos elementos terras raras e ítrio (ETRY) e escândio (Sc) no perfil de intemperismo, os quais são compatíveis com modelos de mineralização laterítica.