bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of novel metabolomic biomarkers in an experimental model of septic acute kidney injury
Authors: Izquierdo-Garcia Jose L. , Nin Nicolás , Cardinal-Fernandez Pablo , Rojas Yenny , de Paula Marta , Granados Rosario , Martínez-Caro Leticia , Ruíz-Cabello Jesús , Lorente José A.
Published: October 2018

The aim of this study is the identification of metabolomic biomarkers of sepsis and sepsis-induced acute kidney injury (AKI) in an experimental model. Pigs were anesthetized and monitored to measure mean arterial pressure (MAP), systemic blood flow (QT), mean pulmonary arterial pressure, renal artery blood flow (QRA), renal cortical blood flow (QRC), and urine output (UO). Sepsis was induced at t = 0 min by the administration of live Escherichia coli ( n = 6) or saline ( n = 8). At t = 300 min, animals were killed. Renal tissue, urine, and serum samples were analyzed by nuclear magnetic resonance (NMR) spectroscopy. Principal component analyses were performed on the processed NMR spectra to highlight kidney injury biomarkers. Sepsis was associated with decreased QT and MAP and decreased QRA, QRC, and UO. Creatinine serum concentration and neutrophil gelatinase-associated lipocalin (NGAL) serum and urine concentrations increased. NMR-based metabolomics analysis found metabolic differences between control and septic animals: 1) in kidney tissue, increased lactate and nicotinuric acid and decreased valine, aspartate, glucose, and threonine; 2) in urine, increased isovaleroglycine, aminoadipic acid, N-acetylglutamine, N-acetylaspartate, and ascorbic acid and decreased myoinositol and phenylacetylglycine; and 3) in serum, increased lactate, alanine, pyruvate, and glutamine and decreased valine, glucose, and betaine concentrations. The concentration of several metabolites altered in renal tissue and urine samples from septic animals showed a significant correlation with markers of AKI (i.e., creatinine and NGAL serum concentrations). NMR-based metabolomics is a potentially useful tool for biomarker identification of sepsis-induced AKI.
A muscle-activity-dependent gain between motor cortex and EMG
Authors: Naufel Stephanie , Glaser Joshua I. , Kording Konrad P. , Perreault Eric J. , Miller Lee E.
Published: October 2018

Whether one is delicately placing a contact lens on the surface of the eye or lifting a heavy weight from the floor, the motor system must produce a wide range of forces under different dynamical loads. How does the motor cortex, with neurons that have a limited activity range, function effectively under these widely varying conditions? In this study, we explored the interaction of activity in primary motor cortex (M1) and muscles (electromyograms, EMGs) of two male rhesus monkeys for wrist movements made during three tasks requiring different dynamical loads and forces. Despite traditionally providing adequate predictions in single tasks, in our experiments, a single linear model failed to account for the relation between M1 activity and EMG across conditions. However, a model with a gain parameter that increased with the target force remained accurate across forces and dynamical loads. Surprisingly, this model showed that a greater proportion of EMG changes were explained by the nonlinear gain than the linear mapping from M1. In addition to its theoretical implications, the strength of this nonlinearity has important implications for brain-computer interfaces (BCIs). If BCI decoders are to be used to control movement dynamics (including interaction forces) directly, they will need to be nonlinear and include training data from broad data sets to function effectively across tasks. Our study reinforces the need to investigate neural control of movement across a wide range of conditions to understand its basic characteristics as well as translational implications.

NEW & NOTEWORTHY We explored the motor cortex-to-electromyogram (EMG) mapping across a wide range of forces and loading conditions, which we found to be highly nonlinear. A greater proportion of EMG was explained by a nonlinear gain than a linear mapping. This nonlinearity allows motor cortex to control the wide range of forces encountered in the real world. These results unify earlier observations and inform the next-generation brain-computer interfaces that will control movement dynamics and interaction forces.
Human manual control precision depends on vestibular sensory precision and gravitational magnitude
Authors: Rosenberg Marissa J. , Galvan-Garza Raquel C. , Clark Torin K. , Sherwood David P. , Young Laurence R. , Karmali Faisal
Published: October 2018

Precise motion control is critical to human survival on Earth and in space. Motion sensation is inherently imprecise, and the functional implications of this imprecision are not well understood. We studied a “vestibular” manual control task in which subjects attempted to keep themselves upright with a rotational hand controller (i.e., joystick) to null out pseudorandom, roll-tilt motion disturbances of their chair in the dark. Our first objective was to study the relationship between intersubject differences in manual control performance and sensory precision, determined by measuring vestibular perceptual thresholds. Our second objective was to examine the influence of altered gravity on manual control performance. Subjects performed the manual control task while supine during short-radius centrifugation, with roll tilts occurring relative to centripetal accelerations of 0.5, 1.0, and 1.33 GC(1 GC = 9.81 m/s2). Roll-tilt vestibular precision was quantified with roll-tilt vestibular direction-recognition perceptual thresholds, the minimum movement that one can reliably distinguish as leftward vs. rightward. A significant intersubject correlation was found between manual control performance (defined as the standard deviation of chair tilt) and thresholds, consistent with sensory imprecision negatively affecting functional precision. Furthermore, compared with 1.0 GCmanual control was more precise in 1.33 GC(−18.3%, P = 0.005) and less precise in 0.5 GC(+39.6%, P < 0.001). The decrement in manual control performance observed in 0.5 GCand in subjects with high thresholds suggests potential risk factors for piloting and locomotion, both on Earth and during human exploration missions to the moon (0.16 G) and Mars (0.38 G).

NEW & NOTEWORTHY The functional implications of imprecise motion sensation are not well understood. We found a significant correlation between subjects’ vestibular perceptual thresholds and performance in a manual control task (using a joystick to keep their chair upright), consistent with sensory imprecision negatively affecting functional precision. Furthermore, using an altered-gravity centrifuge configuration, we found that manual control precision was improved in “hypergravity” and degraded in “hypogravity.” These results have potential relevance for postural control, aviation, and spaceflight.
Cortical neural modulation by previous trial outcome differentiates fast- from slow-learning rats on a visuomotor directional choice task
Authors: Mao Hongwei , Yuan Yuan , Si Jennie
Published: October 2018

To better understand the neural cortical underpinnings that explain behavioral differences in learning rate, we recorded single-unit activity in primary motor (M1) and secondary motor (M2) areas while rats learned to perform a directional (left or right) operant visuomotor association task. Analysis of neural activity during the early portion of the cue period showed that neural modulation in the motor cortex was most strongly associated with two task factors: the previous trial outcome (success or error) and the current trial’s directional choice (left or right). Furthermore, the fast learners, defined as those who had steeper learning curves and required fewer learning sessions to reach criterion performance, encoded the previous trial outcome factor more strongly than the directional choice factor. Conversely, the slow learners encoded directional choice more strongly than previous trial outcome. These differences in task factor encoding were observed in both the percentage of neurons and the neural modulation depth. These results suggest that fast learning is accompanied by a stronger component of previous trial outcome in the modulation representation present in motor cortex, which therefore may be a contributing factor to behavioral differences in learning rate.

NEW & NOTEWORTHY We chronically recorded neural activity as rats learned a visuomotor directional choice task from a naive state. Learning rates varied. Single-unit neural modulation of two motor areas revealed that the fast learners encoded previous trial outcome more strongly than directional choice, whereas the reverse was true for slow learners. This finding provides novel evidence that rat learning rate is strongly correlated with the strength of neural modulation by previous trial outcome in motor cortex.
Konjac Sponge Derived Carbon Flakes with Optimized Pore Structure for High-Performance Supercapacitor
Authors: Han Bing , Geng Chongchong , Cheng Gong
Published: October 2018

Lamellar activated carbons derived from Konjac sponges (KACs) have been successfully fabricated through a facile KOH activation method. By manipulating the activation temperature and KOH/C ratio, the achieved KACs exhibit ultrahigh specific surface area up to ∼3000 m2/g and hierarchical pore structure with tunable micro/mesopore distribution. Notably, KACs possess plenty of worm-shaped micropores formed by graphene stacking layers with the lateral distance close to size of hydrated electrolyte ions. Owing to optimized pore structure, high graphitization, and extra O/N doping, KACs exhibited much enhanced specific capacitance (253.0 F/g), superior rate ability (77% retention of capacitance at 10 A/g), and remarkable cycling stability (0.4% decay under 5 A/g after 2000 cycles) in the acid electrolyte. The mass production ability of KAC materials and the knowledge of correlation between texture properties and capacitive performance open new opportunities for the application of such novel biomass-derived carbons in supercapacitor devices.
Corneal Epithelial Damage and Impaired Tear Functions in Patients with Inflamed Pinguecula
Authors: Küçük Erkut , Yılmaz Uğur , Zor Kürsad Ramazan
Published: October 2018

Purpose. In this study, we evaluated corneal epithelial integrity and tear film parameters in patients with inflamed pinguecula and compared these findings with their fellow eyes and with healthy controls. Methods. We evaluated the fluorescein staining properties and performed the tear break-up time (TBUT) test and Schirmer 2 test (ST2) measurements of 32 patients who had symptomatic unilateral inflamed pinguecula and compared the results with their fellow eyes and also with an age- and sex-matched control group. Results. Twenty-three eyes (72%) in the inflamed pinguecula group and 1 eye (3.1%) in the fellow eyes group had punctate epithelial staining (PES) or epithelial defect on the nasal cornea (p<0.001). There was no PES or epithelial defect in the control group. Eyes with inflamed pinguecula (n = 32) had lower TBUT and ST2 values compared to the control group (n = 32) (p<0.001 for both). Fellow eyes (n = 32) also had lower TBUT and ST2 values compared to the control group (p=0.003 for both). There was no difference in the TBUT and ST2 results between the eyes with inflamed pinguecula and fellow eyes (p=0.286 and p=0.951, respectively). Conclusion. A high percentage of eyes with inflamed pinguecula had nasal corneal epithelial staining or epithelial defect. We also found lower TBUT and ST2 results in eyes with inflamed pinguecula and the fellow eyes compared to the control group. These findings may be important in pathogenesis of pinguecula and pterygium and also in uncovering their relation.
Rhabdomyolysis-Induced Acute Kidney Injury in Diabetic Emergency: Underdiagnosed and an Important Association to Be Aware of
Authors: Amin Ami , Gandhi Bhavika , Torre Steven , Amirpour Alireza , Cheng Jennifer , Patel Mayurkumar , Hossain Mohammad A.
Published: October 2018

Rhabdomyolysis is a potentially life-threatening clinical syndrome associated with muscle injury which can cause a leakage of intracellular contents, manifested from the range of being asymptomatic to a life-threatening condition causing acute kidney injury and severe electrolyte abnormalities. Rhabdomyolysis has been associated with both diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic nonketotic syndrome, though there is an increased association with rhabdomyolysis and acute kidney injury with hyperosmolar nonketonic state compared with patients with diabetic ketoacidosis. Common clinical manifestations are muscle pain, dark urine, and generalized weakness. The causes of rhabdomyolysis are broadly categorized into three groups: traumatic, nontraumatic exertional, and nontraumatic nonexertional. Here, we present a case of rhabdomyolysis-induced acute kidney injury in a patient with hyperosmolar hyperglycemic state. The patient was discharged on insulin and needed intermittent dialysis for two months. Our case highlights the importance of the rare association of rhabdomyolysis causing acute kidney injury in a diabetic emergency.
A Case of Unusual Vascularization of Upper Abdominal Cavity’ Organs
Authors: Mazuruc Natalia , Covantev Serghei , Belic Olga
Published: October 2018

We describe a case report of multiple arterial variations of internal organs of upper abdominal cavity in a cadaver of 63-year-old female. There were several developmental variations of the vascular supply of the stomach, pancreas, spleen, and liver. There were several accessory arteries: left gastric, left hepatic, and posterior gastric artery as well as several arteries that had abnormal origin. The variations were discovered during macroscopical dissection at the department of human anatomy. It should be noted that multiple developmental variation can be common in clinical practice and clinicians should be aware of them during diagnostic and interventional procedures.
Pose Estimation in Noncontinuous Video Sequences Using Evolutionary Correlation Filtering
Authors: Picos Kenia , Orozco-Rosas Ulises , Díaz-Ramírez Victor H. , Montiel Oscar
Published: October 2018

In this paper, we propose an evolutionary correlation filtering approach for solving pose estimation in noncontinuous video sequences. The proposed algorithm computes the linear correlation between the input scene containing a target in an unknown environment and a bank of matched filters constructed from multiple views of the target and estimates of statistical parameters of the scene. An evolutionary approach for finding the optimal filter that produces the highest matching score in the correlator is implemented. The parameters of the filter bank evolve through generations to refine the quality of pose estimation. The obtained results demonstrate the robustness of the proposed algorithm in challenging image conditions such as noise, cluttered background, abrupt pose changes, and motion blur. The performance of the proposed algorithm yields high accuracy in terms of objective metrics for pose estimation in noncontinuous video sequences.
Cyanin Chloride Inhibits Hyperbaric Pressure-Induced Decrease of Intracellular Glutamate-Aspartate Transporter in Rat Retinal Müller Cells
Authors: Chen Xiaomin , Wang Yue , Han Fangfang , Ke Min
Published: October 2018

Purpose. Glaucoma is the leading cause of irreversible blindness throughout the world. The pathogenesis of glaucoma is complex, and neuroprotection is a crucial aspect of therapy. High concentrations of extracellular glutamate are toxic to the optic nerve. The glutamate-aspartate transporter (GLAST) in retinal Müller cells is involved in the development of glaucoma. Anthocyanin has been reported to protect retinal neurons. We hypothesize that cyanin chloride, a type of anthocyanin, can inhibit hyperbaric pressure-induced GLAST decreases in cultured rat retinal Müller cells and may serve as a potential neuroprotective agent in glaucoma treatment.Materials and Methods. Sprague Dawley rat Müller cells were cultured in a hyperbaric pressure device at 60 mmHg additional pressure and treated with cyanin chloride (10 μmol/L, 30 μmol/L, or 50 μmol/L) or vehicle for 2 hours. Cell survival rates (SRs) were evaluated by an MTT assay. GLAST mRNA and protein expression were determined by western blot and RT-PCR analyses, respectively.Results. Cell SR was significantly decreased in the 60 mmHg additional hyperbaric pressure group compared to the control group (P<0.01). Cyanin chloride treatment significantly improved SR under 60 mmHg additional pressure (P<0.01). GLAST mRNA and protein expression levels in Müller cells were significantly reduced in the 60 mmHg hyperbaric pressure group compared to the control group (P<0.01), but cyanin chloride significantly inhibited hyperbaric pressure-induced decreases in GLAST expression (P<0.01).Conclusion. Our results support our hypothesis and demonstrate that cyanin chloride can protect rat retinal Müller cells from hyperbaric pressure-induced decreases of GLAST.
Therapeutic Modulation of Virus‐Induced Oxidative Stress via the Nrf2‐Dependent Antioxidative Pathway
Authors: Lee Choongho
Published: October 2018

Virus‐induced oxidative stress plays a critical role in the viral life cycle as well as the pathogenesis of viral diseases. In response to reactive oxygen species (ROS) generation by a virus, a host cell activates an antioxidative defense system for its own protection. Particularly, a nuclear factor erythroid 2p45‐related factor 2 (Nrf2) pathway works in a front‐line for cytoprotection and detoxification. Recently, a series of studies suggested that a group of clinically relevant viruses have the capacity for positive and negative regulations of the Nrf2 pathway. This virus‐induced modulation of the host antioxidative response turned out to be a crucial determinant for the progression of several viral diseases. In this review, virus‐specific examples of positive and negative modulations of the Nrf2 pathway will be summarized first. Then a number of successful genetic and pharmacological manipulations of the Nrf2 pathway for suppression of the viral replication and the pathogenesis‐associated oxidative damage will be discussed later. Understanding of the interplay between virus‐induced oxidative stress and antioxidative host response will aid in the discovery of potential antiviral supplements for better management of viral diseases.
Pubococcygeal Sling versus Refixation of the Pubocervical Fascia in Vesicovaginal Fistula Repair: A Retrospective Review
Authors: Pope Rachel , Ganesh Prakash , Wilkinson Jeffrey
Published: October 2018

Urethral incontinence is an issue for approximately 10–15% of women with an obstetric fistula. Various surgical interventions to prevent this exist, including the pubococcygeal sling and refixation of the pubocervical fascia. Neither has been evaluated in comparison to one another. Therefore, this retrospective evaluation for superiority was performed. The primary outcome was urinary stress incontinence, and secondary outcomes were operative factors. There were 185 PC slings, but 12 were excluded because of urethral plications. There were 50 RPCF procedures, but 3 were excluded because of urethral plications. Finally, there were 32 cases with both PC sling and RPCF procedures. All groups demonstrated a higher than expected fistula repair rate with negative dye tests in 84% of the PC sling group, 89.9% in the RPCF group, and 93.8% in the RPCF and PC groups. There were no statistically significant differences found in continence status between the three groups. Of those who underwent PC slings, 49% were found to have residual stress incontinence. Of those who underwent RPCF, 47.8% had stress incontinence. Of those with both techniques, 43.8% had residual stress incontinence. Pad weight was not significantly different between the groups. As there is no statistically significant difference, we cannot recommend one procedure over the other as an anti-incontinence procedure. The use of both simultaneously is worth investigating.
Scalable Deposition of Nanomaterial-Based Temperature Sensors for Transparent and Pervasive Electronics
Authors: Albrecht Andreas , Rivadeneyra Almudena , Bobinger Marco , Calia Jacopo Bonaccini , Loghin Florin C. , Salmeron Jose F. , Becherer Markus , Lugli Paolo , Falco Aniello
Published: October 2018

This work presents a comparative analysis of materials for planar semitransparent thermocouples fabricated by spray deposition on a flexible substrate. Three different materials are employed to build such devices, analyzing also the effect of the spray order in their final performance. The highest Seebeck coefficient (50.4 μV/K) is found for a junction made of carbon nanotubes (CNTs) on top of silver nanowires (AgNWs) whereas its efficiency in terms of power is the lowest because of the higher sheet resistance of the CNTs. In this case, the best combination for energy-harvesting purposes would be poly (3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) and AgNWs, with a power factor of 219 fW/K2. These results prove the feasibility of developing large-scale and cost-effective thermocouples that could be used for sensing or energy-harvesting applications.
Dynamic Characteristics and Load Sharing of Herringbone Wind Power Gearbox
Authors: Mo Shuai , Zhang Ting , Jin Guoguang , Feng Zhanyong , Gong Jiabei , Zhu Shengping
Published: October 2018

In this study, the dynamic model for the herringbone planetary gear transmission system is established by the lumped parameter method based on the system dynamics and the Lagrange equation, and the impact of the support stiffness and the torsional stiffness on dynamic characteristics is studied. The research results have a guiding significance for the design of the herringbone gear transmission system. In this model, the herringbone gear is treated as a special gear coupled by 2 opposite helical gears, where the stagger angle, comprehensive meshing error, support stiffness, support damping, and load inertia are considered in the analysis of dynamics. Moreover, the dynamic characteristic of the carrier is considered as well. By calculating the meshing force curve of the transmission system, the impact of the stagger angle, supporting stiffness, and the torsional stiffness on meshing force and load sharing coefficient is analyzed. The results show that the stagger angle has an obvious impact on load sharing coefficient while it has little impact on maximum meshing force. And the support stiffness has a more obvious impact on the dynamic characteristics of the system. The recommendary support stiffness of the system is that all of the support stiffness of the sun gear, planetary gear, ring gear, and carrier is 107 N/m. The torsional stiffness has little impact on the dynamic characteristics of transmission system, except the torsional stiffness of planetary gear, and carrier has an obvious impact on load sharing coefficient. The commercial software ADAMS carried out dynamics analysis of the transmission system to verify the necessity validity of the theoretical analysis.
Azithromycin Promotes the Osteogenic Differentiation of Human Periodontal Ligament Stem Cells after Stimulation with TNF-α
Authors: Meng Tingting , Zhou Ying , Li Jingkun , Hu Meilin , Li Xiaomeng , Wang Pingting , Jia Zhi , Li Liyu , Liu Dayong
Published: October 2018

Background and Objective. This study investigated the effects and underlying mechanisms of azithromycin (AZM) treatment on the osteogenic differentiation of human periodontal ligament stem cells (PDLSCs) after their stimulation with TNF-α in vitro. Methods. PDLSCs were isolated from periodontal ligaments from extracted teeth, and MTS assay was used to evaluate whether AZM and TNF-α had toxic effects on PDLSCs viability and proliferation. After stimulating PDLSCs with TNF-α and AZM, we analyzed alkaline phosphatase staining, alkaline phosphatase activity, and alizarin red staining to detect osteogenic differentiation. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis was performed to detect the mRNA expression of osteogenic-related genes, including RUNX2, OCN, and BSP. Western blotting was used to measure the NF-κB signaling pathway proteins p65, phosphorylated p65, IκB-α, phosphorylated IκB-α, and β-catenin as well as the apoptosis-related proteins caspase-8 and caspase-3. Annexin V assay was used to detect PDLSCs apoptosis. Results. TNF-α stimulation of PDLSCs decreased alkaline phosphatase and alizarin red staining, alkaline phosphatase activity, and mRNA expression of RUNX2, OCN, and BSP in osteogenic-conditioned medium. AZM enhanced the osteogenic differentiation of PDLSCs that were stimulated with TNF-α. Western blot analysis showed that β-catenin, phosphorated p65, and phosphorylated IκB-α protein expression decreased in PDLSCs treated with AZM. In addition, pretreatment of PDLSCs with AZM (10 μg/ml, 20 μg/ml) prevented TNF-α-induced apoptosis by decreasing caspase-8 and caspase-3 expression. Conclusions. Our results showed that AZM promotes PDLSCs osteogenic differentiation in an inflammatory microenvironment by inhibiting the WNT and NF-κB signaling pathways and by suppressing TNF-α-induced apoptosis. This suggests that AZM has potential as a clinical therapeutic for periodontitis.
Transient Pressure and Rate Decline Analysis for Horizontal Well in Stress-Sensitive Composite Reservoir
Authors: Huang Yu , Li Xiaoping , Tan Xiaohua
Published: October 2018

The existence of stress sensitivity effect made the percolation mechanism of low-permeability reservoirs significantly complex. Further, numerous reservoirs have composite stratum properties in actual development procedure. This paper based on the concept of permeability stress sensitivity presents an unsteady flow model for horizontal well taking both stress sensitivity and composite reservoir into account. Analytic solutions for the transient pressure and the rate decline behaviors are obtained by comprehensive utilization of regular perturbation method, Laplace transformation, orthogonal transformation, and Stehfest numerical inversion. The example analysis verifies that the proposed model is reliable and practical. Likewise, there is a discussion of the influence of permeability modulus and other relevant parameters on the transient pressure and the rate decline for horizontal well in stress-sensitive composite reservoir. The work of this paper improved the previous researches and provided a more accurate basis for transient flow analysis and formation evaluation of this typical reservoir.
Synthesis of Controllable Carboxylated Polystyrene Microspheres by Two-Step Dispersion Polymerization with Hydrocarbon Alcohols
Authors: Zhang Bin , Lu Jiazhen , Liu Xin , Jin Haibo , He Guangxiang , Guo Xiaoyan
Published: October 2018

Carboxylated polystyrene (PS) microspheres were synthesized by the two-step dispersion polymerization of styrene in hydrocarbon alcohols (CnH2n+1OH,n=1–5) in the presence of acrylic acid (AA) as a functional comonomer, 2,2′-azobis-(2-methylbutyronitrile) (AMBN) as the initiator and polyvinylpyrrolidone (PVP55) as the dispersant. The effects of solvent type, AA concentration, and first reaction time on the carboxyl content on the microsphere surfaces were investigated. The PS microspheres were characterized by scanning electron microscopy, infrared spectroscopy, nuclear magnetic resonance, and gel permeation chromatography. The results showed that the first reaction time of the two-stage dispersion polymerization had a great influence on the nucleation process, and appropriately prolonging the first-step reaction time had a great influence on the surface carboxyl content. The effect of the solvent on the surface carboxyl content of PS microspheres was significant. With n-butanol as the solvent, the carboxyl group content on the surface of the microspheres reached 57.05 mg/g.
Simulations of Gamma-Ray Emission from Magnetized Microquasar Jets
Authors: Kosmas Odysseas , Smponias Theodoros
Published: October 2018

In this work, we simulate γ-rays created in the hadronic jets of the compact object in binary stellar systems known as microquasars. We utilize as the main computational tool the 3D relativistic magnetohydrodynamical code PLUTO combined with in-house derived codes. Our simulated experiments refer to the SS433 X-ray binary, a stellar system in which hadronic jets have been observed. We examine two new model configurations that employ hadron-based emission mechanisms. The simulations aim to explore the dependence of the γ-ray emissions on the dynamical as well as the radiative properties of the jet (hydrodynamic parameters of the mass-flow density, gas-pressure, temperature of the ejected matter, high energy proton population inside the jet plasma, etc.). The results of the two new scenarios of initial conditions for the microquasar stellar system studied are compared to those of previously considered scenarios.
Diclofenac Sodium Treatment Ameliorates Extrapancreatic Organ Injuries in a Murine Model of Acute Pancreatitis Induced by Caerulein
Authors: Ozer Cakir Ozlem , Findik Siddika
Published: October 2018

Aim. We determined the effects of diclofenac sodium, octreotide, and their combination on extrapancreatic organ injuries in caerulein-induced acute pancreatitis in mice. Methods. A total of 58 BALB-C male mice (25 g) were divided into seven groups and used to create a caerulein-induced acute pancreatitis model. Diclofenac sodium, octreotide, and their combination were given for treatment of caerulin-induced acute pancreatitis in mice. At the end of the experiment, the lung, liver, kidney, and stomach were removed for histopathologic assessment. Results. Histopathologic investigation revealed a statistically significant difference between the groups in mean congestion, edema, tubular injury, perirenal fat tissue inflammation, and tubular stasis scores in kidney tissue (P<0.001, P<0.001, P<0.001, P<0.001, and P=0.048, respectively); mean congestion, edema, neutrophil inflammation, mononuclear inflammation, and emphysematous change scores in the lung (P<0.001, P<0.001, P<0.001, P=0.030, and P<0.001, respectively); mean congestion, edema, and neutrophil inflammation scores in the stomach (P=0.008, P=0.014, and P<0.001, respectively); and mean congestion and hydropic degeneration scores in the liver (P=0.029 and P=0.002, respectively). Conclusion. Diclofenac sodium alone ameliorates lung edema due to caerulin-induced acute pancreatitis.
Nicotine-N′-Oxidation by Flavin Monooxygenase Enzymes
Authors: Perez-Paramo Yadira X. , Chen Gang , Ashmore Joseph H. , Watson Christy J. W. , Nasrin Shamema , Adams-Haduch Jennifer , Wang Renwei , Gao Yu-Tang , Koh Woon-Puay , Yuan Jian-Min , Lazarus Philip
Published: October 2018

Background:

The major mode of metabolism of nicotine is by hydroxylation via cytochrome P450 (CYP) 2A6, but it can also undergo glucuronidation by UDP-glucuronosyltransferases and oxidation by flavin monooxygenases (FMO). The goal of this study was to examine the potential importance of FMOs in nicotine metabolism and assess the potential impact of missense polymorphisms in active FMOs on nicotine-N′-oxide (NOX) formation.

Methods:

Urine samples from 106 current Chinese smokers were analyzed for nicotine metabolites by mass spectrometry. Wild-type FMOs 1–5 and their most prevalent nonsynonymous variants were cloned and overexpressed in HEK293 cells, and were tested in oxidation reactions against nicotine.

Results:

A strong inverse correlation was observed between the ratio of urinary 3′-hydroxycotinine/cotinine, a measure of CYP2A6 activity, and the urinary levels of NOX alone (r = −0.383; P < 0.001) or NOX measured as a ratio of total nicotine metabolites (r = −0.414; P < 0.001) in smokers. In addition to FMO1 and FMO3, the functional FMO2427Q isoform was active against nicotine, whereas FMO4 and FMO5 exhibited low activity against nicotine (Km > 5.0 mmol/L). Significant (P < 0.05) decreases in N′-oxidation activity (Vmax/Km) were observed for the FMO1I303V, FMO3N61S, FMO3D132H, FMO3V257M, and FMO3E308G variants in vitro when compared with their respective wild-type isoforms; the truncated FMO2Q472stop isoform exhibited no enzyme activity.

Conclusions:

These data indicate that increases in nicotine-N′-oxidation occur in subjects with deficient CYP2A6 activity, and that several FMO enzymes are active in nicotine-N′-oxidation.

Impact:

Several common missense FMO variants are associated with altered enzyme activity against nicotine and may play an important role in nicotine metabolism in low-CYP2A6 activity subjects.
Glycoprotein-130 Expression Is Associated with Aggressive Bladder Cancer and Is a Potential Therapeutic Target
Authors: Martin Darryl T. , Shen Hongliang , Steinbach-Rankins Jill M. , Zhu Xi , Johnson Katelyn K. , Syed Jamil , Saltzman W. Mark , Weiss Robert M.
Published: October 2018

Predicting bladder cancer progression is important in selecting the optimal treatment for bladder cancer. Because current diagnostic factors regarding progression are lacking, new factors are needed to further stratify the curative potential of bladder cancer. Glycoprotein-130 (GP130), a transmembrane protein, is central to a number of signal transduction pathways involved in tumor aggressiveness, making it an attractive target. We hypothesize that if GP130 is found in an aggressive population of bladder tumors, then blocking GP130 expression may inhibit bladder cancer growth. Herein, we quantitatively show, using 11 patient samples and four bladder cancer cell lines, that GP130 is expressed in the aggressive human bladder tumors and in high-grade bladder cancer cell lines. Moreover, GP130 is significantly correlated with tumor grade, node category, tumor category, and patient outcome. We demonstrated a tumor-specific GP130 effect by blocking GP130 expression in bladder tumor cells, which resulted in decreased cell viability and reduced cell migration. Furthermore, we reduced tumor volume by approximately 70% compared with controls by downregulating GP130 expression using chitosan-functionalized nanoparticles encapsulating GP130 siRNA in an in vivo bladder cancer xenograft mouse model. Our results indicate that GP130 expression is linked to the aggressiveness of bladder tumors, and blocking GP130 has therapeutic potential in controlling tumor growth.
Identification of the Novel Role of CD24 as an Oncogenesis Regulator and Therapeutic Target for Triple-Negative Breast Cancer
Authors: Chan Shih-Hsuan , Tsai Kuo-Wang , Chiu Shu-Yi , Kuo Wen-Hung , Chen Heng-Yi , Jiang Shih Sheng , Chang King-Jen , Hung Wen-Chun , Wang Lu-Hai
Published: October 2018

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with unfavorable prognosis and 5-year survival. The purpose of this study was to investigate the underlying mechanisms involved in TNBC progression. We determined that CD24 expression was elevated in highly lung and lymph node metastatic TNBC cells. CD24 depletion inhibited primary tumor growth and lymph node and lung metastasis and reduced the number of blood and lymphatic vessels in the tumor microenvironment. CD24 knockdown impaired EGFR/Met-mediated signaling and reduced lymphangiogenesis- and angiogenesis-related molecules, including vascular endothelial growth factors A and C, by promoting EGFR and Met protein instability via the lysosomal degradation pathway. CD24 monoclonal antibody treatment reduced lung metastasis and prolonged the survival in a lung metastasis mouse model. Clinical analyses revealed that the CD24high/METhigh “double-positive” signature identified a subset of TNBC patients with worst outcomes. We conclude that CD24 could be a therapeutic target by itself and in combination with the Met expression could be a good prognostic biomarker for TNBC patients.
CD3-Bispecific Antibody Therapy Turns Solid Tumors into Inflammatory Sites but Does Not Install Protective Memory
Authors: Benonisson Hreinn , Altıntaş Işıl , Sluijter Marjolein , Verploegen Sandra , Labrijn Aran F. , Schuurhuis Danita H. , Houtkamp Mischa A. , Verbeek J. Sjef , Schuurman Janine , van Hall Thorbald
Published: October 2018

Immunotherapy of cancer with CD3-targeting bispecific antibodies (CD3 bsAb) is a fast developing field, and multiple tumor-associated antigens (TAA) are evaluated for hematologic and solid malignancies. The efficacy of these CD3 bsAb is usually examined in xenograft mouse tumor models with human T cells or in genetically engineered mouse models, where human TAA are introduced. These models often fail to fully recapitulate the natural tumor environment, especially for solid cancers, because of interspecies differences. Here, we investigated the systemic and intratumoral effects of a mouse CD3 bsAb in a fully immune-competent mouse melanoma model. Systemic administration of 0.5 mg/kg antibody induced a brief overall T-cell activation that was selectively sustained in the tumor microenvironment for several days. A fast subsequent influx of inflammatory macrophages into the tumor microenvironment was observed, followed by an increase in the number of CD4+ and CD8+ T cells. Although the capacity to directly kill melanoma cells in vitro was very modest, optimal tumor elimination was observed in vivo, even in the absence of CD8+ T cells, implying a redundancy in T-cell subsets for therapeutic efficacy. Finally, we took advantage of the full immune competence of our mouse model and tested immune memory induction. Despite a strong initial immunity against melanoma, treatment with the CD3 bsAb did not install protective memory responses. The observed mechanisms of action revealed in this immune-competent mouse model might form a rational basis for combinatorial approaches.
Combined Cellular and Biochemical Profiling to Identify Predictive Drug Response Biomarkers for Kinase Inhibitors Approved for Clinical Use between 2013 and 2017
Authors: Uitdehaag Joost C.M. , Kooijman Jeffrey J. , de Roos Jeroen A.D.M. , Prinsen Martine B.W. , Dylus Jelle , Willemsen-Seegers Nicole , Kawase Yusuke , Sawa Masaaki , de Man Jos , van Gerwen Suzanne J.C. , Buijsman Rogier C. , Zaman Guido J.R.
Published: October 2018

Kinase inhibitors form the largest class of precision medicine. From 2013 to 2017, 17 have been approved, with 8 different mechanisms. We present a comprehensive profiling study of all 17 inhibitors on a biochemical assay panel of 280 kinases and proliferation assays of 108 cancer cell lines. Drug responses of the cell lines were related to the presence of frequently recurring point mutations, insertions, deletions, and amplifications in 15 well-known oncogenes and tumor-suppressor genes. In addition, drug responses were correlated with basal gene expression levels with a focus on 383 clinically actionable genes. Cell lines harboring actionable mutations defined in the FDA labels, such as mutant BRAF(V600E) for cobimetinib, or ALK gene translocation for ALK inhibitors, are generally 10 times more sensitive compared with wild-type cell lines. This sensitivity window is more narrow for markers that failed to meet endpoints in clinical trials, for instance CDKN2A loss for CDK4/6 inhibitors (2.7-fold) and KRAS mutation for cobimetinib (2.3-fold). Our data underscore the rationale of a number of recently opened clinical trials, such as ibrutinib in ERBB2- or ERBB4-expressing cancers. We propose and validate new response biomarkers, such as mutation in FBXW7 or SMAD4 for EGFR and HER2 inhibitors, ETV4 and ETV5 expression for MEK inhibitors, and JAK3 expression for ALK inhibitors. Potentially, these new markers could be combined to improve response rates. This comprehensive overview of biochemical and cellular selectivities of approved kinase inhibitor drugs provides a rich resource for drug repurposing, basket trial design, and basic cancer research.
Successful Use of Pembrolizumab to Treat Refractory Thymic Carcinoma with High PD-L1 Expression
Authors: Isshiki Takuma , Isobe Kazutoshi , Tochigi Naobumi , Sunakawa Motoko , Nakamura Yasuhiko , Shibuya Kazutoshi , Sakamoto Susumu , Takai Yujiro , Homma Sakae
Published: October 2018

Thymic carcinoma is a relatively rare and aggressive thymic epithelial tumor. Herein, we report successful treatment of thymic carcinoma with pembrolizumab. A 68-year-old woman was admitted to our hospital for evaluation of chest pain. Chest computed tomography showed a mass in the anterior mediastinum and lymphadenopathy in the left cervical lymph node. Analysis of biopsy specimens detected squamous cell carcinoma in the left cervical lymph node, and immunohistochemical analysis showed 100% expression of programmed death-ligand 1 (PD-L1). Masaoka-Koga stage IVb thymic carcinoma was ultimately diagnosed. Since 3 cycles of first-line chemotherapy did not result in improvement, pembrolizumab was administered as second-line treatment every 3 weeks at a dosage of 200 mg. After 3 cycles of pembrolizumab treatment, the size of the anterior mediastinal tumor and metastatic lesions had notably decreased. Pembrolizumab may prove to be an effective therapy for thymic carcinoma with high PD-L1 expression.
The Differential Diagnosis in Nonlymphoproliferative Malignant Pleural Effusion Cytopathology and Its Correlation with Patients’ Demographics
Authors: Rodriguez Erika F. , Chowsilpa Sayanan , Maleki Zahra
Published: October 2018

Background: We report our experience with malignant pleural effusion (MPE) and the impact of patients’ demographics on the differential diagnosis at the primary site. Methods: After IRB approval, we searched our pathology database from January 2013 to January 2017 for patients with positive pleural effusions (PEs). Patients’ demographics and clinical histories were noted. Results: 474 patients were identified (288 females [61%] and 186 males [39%]), ranging in age from 19 to 64 years old. Ethnicity was distributed as follows: Caucasian (n = 330, 70%), African American (n = 114, 24%) and Asian (n = 30, 6%). The most common primary sites were the lung (n = 180, 37%), followed by the breast (n = 81, 17%), and the gynecologic system (67, 13%). The lung was the most common primary for all ethnicities (n = 190, 40%). The second-most common primary site was the breast in African Americans and Caucasians and upper gastrointestinal (GI) tract in Asians. In 5 cases (1%), the primary tumor could not be determined. Conclusion: Cytology examination is a useful method to diagnose primary sites of PE. Pulmonary primary is the most common cause of effusion in all ethnicities. In African American and Caucasian patients, the breast was the second-most common site of MPE, while in Asian patients it was the upper GI tract.
In vivo Human Skin Penetration of the UV Filter Ethylhexyl Triazone: Effect of Lipid Microparticle Encapsulation
Authors: Scalia Santo , Battaglioli Sarah , Bianchi Anna
Published: October 2018

Background/Aims: The data available on the skin permeability of ethylhexyl triazone (EHT), a widely used high-molecular-weight (823.1-Da) UV filter, are scarce and obtained only via in vitro studies. Therefore, we evaluated in vivo the penetration of EHT in human stratum corneum by the tape stripping technique. Moreover, the effect of EHT encapsulation in lipid microparticles (LMs) on its diffusion through the stratum corneum was examined. Methods: LMs loaded with EHT were prepared using glyceryl behenate and phosphatidylcholine. Creams containing EHT free or encapsulated in LMs in conjunction with the two most commonly used UV filters, octyl methoxycinnamate (OMC) and butyl methoxydibenzoylmethane (BMDBM), were applied to human volunteers and the fraction of the applied sunscreen dose having penetrated into different stratum corneum layers was measured. Results and Conclusion: For the cream with the nonencapsulated sunscreen agent, the percentage of the applied EHT dose diffused into the stratum corneum was 21.9 ± 4.9%, not significantly different from that of the smaller-molecular-weight OMC (22.2 ± 7.6%) and BMDBM (20.5 ± 3.7%). A marked (45.7%) and statistically significant reduction in the in vivo skin penetration of EHT was attained with the cream containing microencapsulated EHT. The decreased percutaneous penetration provided by the LMs should favor the efficacy of EHT and limit potential toxicological risks.
Diagnostic Accuracy of Fine-Needle Aspiration Cytology for Discrimination of Squamous Cell Carcinoma from Adenocarcinoma in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis
Authors: Layfield Lester J. , Pearson Lauren , Walker Brandon S. , White Sandra K. , Schmidt Robert L.
Published: October 2018

Objective: To determine the accuracy with which morphology alone can distinguish adenocarcinoma and squamous cell carcinoma in non-small cell lung cancer. Methods: We performed a systematic review and meta-analysis. Three data bases (MEDLINE, EMBASE, Scopus) were searched for studies on the diagnostic accuracy of subtyping non-small cell lung cancer. Accuracy data was abstracted and synthesized using bivariate mixed effects logistic regression as implemented in the midas package in Stata 14. Heterogeneity was assessed using the Higgins I2. Results: We included 17 studies (2,235 cases). Most studies had a low risk of bias. The pooled diagnostic accuracy for cytological diagnosis of adenocarcinoma resulted in a sensitivity of 63% (48–76%) and specificity of 95% (87–98%). The I2 values were 93 and 88% for sensitivity and specificity, respectively. The pooled diagnostic accuracy for the cytological diagnosis of squamous cell carcinoma resulted in a sensitivity of 84% (79–88%) and a specificity of 90% (84–94%). The I2 values were 69 and 86% for sensitivity and specificity, respectively. Conclusion: Accuracy varies widely by study and summary estimates do not provide a useful representation of accuracy. Squamous cell carcinoma was diagnosed more accurately than adenocarcinoma.
On the Concept of Praecox Feeling
Authors: Pallagrosi Mauro , Fonzi Laura
Published: October 2018

Despite the development and widespread diffusion of modern nosographic systems, the diagnosis of schizophrenia continues to raise several epistemological issues. To address these issues, a number of researchers are currently pursuing the possibility of an integration between reliable, objective approaches and the intersubjective perspective in the clinical encounter. In the present article, we discuss Rümke’s popular concept of praecox feeling, as introduced in 1941 and re-elaborated over the following 20 years. Our aim was to thoroughly analyze the author’s original formulation and to identify the connections between his thinking and certain psychopathological developments, epistemological issues, and research perspectives on schizophrenia. The praecox feeling is presented by Rümke as a sensitive diagnostic tool for schizophrenia that is rooted in the peculiar subjective experience of the clinician when encountering a schizophrenic patient. This experience seems to be characterized by two essential dimensions: a subjective one, which reflects the failure of a clinician’s empathic effort due to a fundamental alteration of the intersubjective space, a phenomenon related to schizophrenic autism, and a gestaltic, objective one, which is grounded in the clinician’s implicit typifying process as a consequence of collecting recurrent clinical observations over the course of his/her professional experience. According to Rümke, the diagnostic use of the praecox feeling should be limited to the acute phases of the schizophrenic process, as the clinician’s experience of an intersubjective struggle is attenuated in interactions with older, chronic patients. The multifaceted nature of Rümke’s proposal seems to have contributed to some theoretical critiques and to inconclusive results from empirical investigations, leading to a progressive devaluation of the scientific and diagnostic validity of praecox feeling. The present analysis of the original concept suggests that a renewed research interest in the role of the clinician’s subjective experience with regard to the schizophrenic patient could be helpful.