bluuebunny/crossref_metadata_2025 huggingface dataset:
RESEARCH OF MAXILLARY IMPACTED CANINE IN ORTHODONTIC TREATMENT BASED ON NANOINDENTATION EXPERIMENTS
Authors: WU BIN , ZHU YUNYUN , LU RUXIN , YAN BIN , FU YIPENG , ZHAO SIYU , HUANG HUIXIANG
Published: October 2017

This study selected the maxillary labial impacted canine as the research object to build the model of periodontal ligament (PDL) and simulate the process of orthodontic treatment. This paper obtained stress–strain curve by calculating and analyzing the data of nanoindentation experiments. The parameters were identified through curve fittings by ABAQUS. The fitting results show that the third-order Ogden model is in good agreement with the experimental data which demonstrate that the third-order Ogden model is able to reflect the material properties of the PDL. In this paper, orthodontic process of the maxillary labial impacted canine was simulated. The results show that inside and outside surfaces of PDL all have stress variation, the stress on the root apex and dental cervix of PDL is relatively large, the maximum appears at dental cervix and the minimum appears close to tooth impedance center.
Hydromagnetic Nanofluids Flow through a Porous Medium with Thermal Radiation, Chemical Reaction and Viscous Dissipation using the Spectral Relaxation Method
Authors: Haroun Nageeb A. H. , Mondal Sabyasachi , Sibanda Precious
Published: October 2017

We investigate the convective heat and mass transfer in a magnetohydrodynamic nanofluid flow through a porous medium over a stretching sheet subject to heat generation, thermal radiation, viscous dissipation and chemical reaction effects. We have assumed that the nanoparticle volume fraction at the wall may be actively controlled. Two types of nanofluids, namely Cu-water and Al2O3-water are studied. The physical problem is modeled using systems of nonlinear differential equations which have been solved numerically using the spectral relaxation method. Comparing the results with those previously published results in the literature shows excellent agreement. The impact of porosity, heat generation, thermal radiation, magnetic field, viscous dissipation and chemical reaction on the flow field is evaluated and explained.
Innovations in Mobile Value-Added Services: Findings from Cases in India
Authors: Gupta Dharmesh , Gupta Ruchita , Jain Karuna , Momaya Kirankumar S.
Published: October 2017

Convergence of internet and mobile technologies has fueled growth in service innovations in the telecommunication sector. Digitization has transformed telecommunication value chain from linear to nonlinear web, presenting the role of telecom operators in a dilemma. Objective of the research is to understand the dynamics of technology and service innovation for development of mobile value-added services (VAS). We study the process of service innovation in select mobile VAS in India and map their delivery process on enhanced telecom operations map (eTOM) framework. Our findings indicate challenges in managing sector-crossing service innovations effectively, presenting an opportunity to extend the existing framework.
Norepinephrine enhances song responsiveness and encoding in the auditory forebrain of male zebra finches
Authors: Lee Vanessa , Pawlisch Benjamin A. , Macedo-Lima Matheus , Remage-Healey Luke
Published: October 2017

Norepinephrine (NE) can dynamically modulate excitability and functional connectivity of neural circuits in response to changes in external and internal states. Regulation by NE has been demonstrated extensively in mammalian sensory cortices, but whether NE-dependent modulation in sensory cortex alters response properties in downstream sensorimotor regions is less clear. Here we examine this question in male zebra finches, a songbird species with complex vocalizations and a well-defined neural network for auditory processing of those vocalizations. We test the hypothesis that NE modulates auditory processing and encoding, using paired extracellular electrophysiology recordings and pattern classifier analyses. We report that a NE infusion into the auditory cortical region NCM (caudomedial nidopallium; analogous to mammalian secondary auditory cortex) enhances the auditory responses, burst firing, and coding properties of single NCM neurons. Furthermore, we report that NE-dependent changes in NCM coding properties, but not auditory response strength, are transmitted downstream to the sensorimotor nucleus HVC. Finally, NE modulation in the NCM of males is qualitatively similar to that observed in females: in both sexes, NE increases auditory response strengths. However, we observed a sex difference in the mechanism of enhancement: whereas NE increases response strength in females by decreasing baseline firing rates, NE increases response strength in males by increasing auditory-evoked activity. Therefore, NE signaling exhibits a compensatory sex difference to achieve a similar, state-dependent enhancement in signal-to-noise ratio and coding accuracy in males and females. In summary, our results provide further evidence for adrenergic regulation of sensory processing and modulation of auditory/sensorimotor functional connectivity.

NEW & NOTEWORTHY This study documents that the catecholamine norepinephrine (also known as noradrenaline) acts in the auditory cortex to shape local processing of complex sound stimuli. Moreover, it also enhances the coding accuracy of neurons in the auditory cortex as well as in the downstream sensorimotor cortex. Finally, this study shows that while the sensory-enhancing effects of norepinephrine are similar in males and females, there are sex differences in the mode of action.
Eye-hand coordination during flexible manual interception of an abruptly appearing, moving target
Authors: Li Yuhui , Wang Yong , Cui He
Published: October 2017

As a vital skill in an evolving world, interception of moving objects relies on accurate prediction of target motion. In natural circumstances, active gaze shifts often accompany hand movements when exploring targets of interest, but how eye and hand movements are coordinated during manual interception and their dependence on visual prediction remain unclear. Here, we trained gaze-unrestrained monkeys to manually intercept targets appearing at random locations and circularly moving with random speeds. We found that well-trained animals were able to intercept the targets with adequate compensation for both sensory transmission and motor delays. Before interception, the animals' gaze followed the targets with adequate compensation for the sensory delay, but not for extra target displacement during the eye movements. Both hand and eye movements were modulated by target kinematics, and their reaction times were correlated. Moreover, retinal errors and reaching errors were correlated across different stages of reach execution. Our results reveal eye-hand coordination during manual interception, yet the eye and hand movements may show different levels of prediction based on the task context.

NEW & NOTEWORTHY Here we studied the eye-hand coordination of monkeys during flexible manual interception of a moving target. Eye movements were untrained and not explicitly associated with reward. We found that the initial saccades toward the moving target adequately compensated for sensory transmission delays, but not for extra target displacement, whereas the reaching arm movements fully compensated for sensorimotor delays, suggesting that the mode of eye-hand coordination strongly depends on behavioral context.
Novel and Unexpected Functions of SGLTs
Authors: Wright Ernest M. , Ghezzi Chiara , Loo Donald D. F.
Published: October 2017

It has been 30 years since the intestinal sodium glucose cotransporter SGLT1 was cloned, and, in the intervening years, there have been many advances that have influenced physiology and medicine. Among the first was that SGLT1 is the founding member of the human gene family SLC5, containing 11 diverse transporters and a glucose sensor. Equally surprising was that SGLTs are members of a structural family of cotransporters and exchangers in different gene families. This led to the conclusion that these proteins operate by a mechanism where transport involves the opening and closing of external and internal gates. The mechanism is shared by a wide variety of transporters in different structural families, e.g., the human facilitated glucose transporters (SLC2) in the huge major facilitator superfamily (MFS). Not surprising is the finding that mutations in Sglt genes cause the rare diseases glucose-galactose-malabsorption (GGM) and familial renal glucosuria (FRG). However, it was not envisaged that SGLT inhibitors would be used to treat diabetes mellitus, and these drugs may be able to treat cancer. Finally, in 2017, we have just learned that SGLT1 may be required to resist infection and to avoid recurrent pregnancy loss.
Liver Metastases in Pancreatic Acinar Cell Carcinoma Treated with Selective Internal Radiation Therapy with Y-90 Resin Microspheres
Authors: Nasser Felipe , Motta Leal Filho Joaquim Maurício , Affonso Breno Boueri , Galastri Francisco Leonardo , Cavalcante Rafael Noronha , Martins Diego Lima Nava , Segatelli Vanderlei , Yamaga Lilian Yuri Itaya , Gansl Rene Claudio , Tranchesi Junior Bernardino , Macedo Antônio Luiz de Vasconcellos
Published: October 2017

Background. Pancreatic acinar cell carcinoma (PACC) is a rare tumor. Surgical resection is the treatment of choice when feasible, but there are no clear recommendations for patients with advanced disease. Liver-directed therapy with Y-90 selective internal radiation therapy (SIRT) has been used to treat hepatic metastases from pancreatic tumors. We describe a case of PACC liver metastases treated with SIRT. Case Report. 59-year-old man was admitted with an infiltrative, solid lesion in pancreatic tail diagnosed as PACC. Lymph nodes in the hepatic hilum were enlarged, and many metastatic liver nodules were observed. After partial pancreatectomy, the left and right lobes of the liver were separately treated with Y-90 resin microspheres. Follow-up imaging revealed that all hepatic nodules shrank by at least 50%, and 3 nodules disappeared completely. Lipase concentration was 8407 U/L at baseline, rose to 12,705 U/L after pancreatectomy, and declined to 344 U/L after SIRT. Multiple rounds of chemotherapy in the subsequent year shrank the hepatic tumors further; disease then progressed, but a third line of chemotherapy shrank the tumors again, 16 months after SIRT treatment. Conclusion. SIRT had a positive effect on liver metastases from PACC. In conjunction with systemic therapy, SIRT can achieve sustained disease control.
Ocular Rosacea Causing Corneal Melt in an African American Patient and a Hispanic Patient
Authors: Saade Joanna S. , Abiad Bachir , Jan Jonathan , Saadeh Dana , McCulley James P. , Bartley Jeremy
Published: October 2017

Purpose. To discuss two rare presentations of ocular rosacea in a Hispanic patient and an African American patient with unusual ocular manifestations. Case Report. Case  1: a 43-year-old Hispanic woman presented with right eye corneal perforation. Her prior medical history was significant for rosacea only, diagnosed clinically by a dermatologist. Her eye exam showed signs of bilateral ocular rosacea. An emergent full thickness tectonic corneal patch graft was done. The patient’s bilateral eye symptoms improved one month after initiating rosacea treatment. Case  2: a 51-year-old African American man with long standing history of untreated rosacea presented with bilateral peripheral corneal thinning with neovascularization that led to right eye corneal perforation. Glue and bandage contact lens were applied. The patient did well 4 weeks after starting antibacterial, oral steroids, and rosacea treatment. Discussion. Ocular rosacea can present in Hispanic and African American patients with severe manifestations such as corneal perforation.
Effectiveness of Chinese Herbal Medicine Combined with Antibiotics for Extensively Drug-Resistant Enterobacteria and Nonfermentative Bacteria Infection: Real-Life Experience in a Retrospective Cohort
Authors: Cai Yangping , Zhang Qing , Fu Yuefeng , Li Li , Zhao Ning , Lu Aiping , Liu Qingquan , Jiang Miao
Published: October 2017

Chinese herbal medicines (CHMs) have been successfully used in the treatment of infectious diseases, yet the effectiveness of CHMs for extensively drug-resistant enterobacteria (XDRE) infection remains unclear. Herein we developed a retrospective multicenter study including 766 patients with XDRE and nonfermentative bacteria (NFB) infection to investigate the effectiveness of CHMs combined with antibiotics in the treatment of XDRE infections in clinical daily practice in a cohort of patients and compared the regular antibiotics monotherapy. After 14-day treatment, the 547 patients accepted CHMs combined with antibiotics therapy indicating a more desirable effectiveness compared to the 219 patients treated with antibiotics monotherapy. The primary evaluation indexes included white blood cell count (WBC) and percentage of neutrophil (N%) in blood test. Secondary evaluation indexes consisted of body temperature, breath, heart rate, platelets, hemoglobin, red blood cell, albumin, creatinine, glucose, and 28-day survival rates. Briefly speaking, in our experience, CHMs combined with antibiotics therapy achieved more desirable effectiveness in treating XDRE infections compared with antibiotics monotherapy, and CHMs might be a potential huge resource in the field of XDRE infection management and enlighten the new antibiotics research and development. This trial is registered withChiCTR-ORC-17011760.
Lipodystrophy among HIV-Infected Patients Attending Care and Treatment Clinics in Dar es Salaam
Authors: Njelekela Marina , Mpembeni Rose , Muhihi Alfa , Ulenga Nzovu , Aris Eric , Kakoko Deodatus
Published: October 2017

Background. HIV infection and long-term HAART use are associated with metabolic and morphological changes. We assessed prevalence, types, and risk factors associated with lipodystrophy among HIV-infected adults attending CTC in Dar es Salaam, Tanzania. Methods. Analysis included 466 HIV-infected patients. Study protocol involved administration of structured questionnaire to collect sociodemographic and clinical information. Diagnosis of lipodystrophy was based on physician clinical assessment. Results. Lipodystrophy was present in 95 (20.4%) of the study participants, with lipoatrophy being the most common (49.5%) followed by mixed lipodystrophy (37.9%), and lipohypertrophy was the least prevalent (12.6%). Male gender, older age, long duration on HAART, and use of Stavudine containing regimen were associated with lipodystrophy (all p<0.05). The risk for lipodystrophy was 1.6 times (AOR = 1.66, 95% CI = 1.01–2.72) for male participants and 13.3 times (AOR = 13.3, 95% CI = 6.4–27.7) for those on HAART. Long duration on HAART and use of Stavudine containing regimen were also associated with increased risk for lipodystrophy. Lipodystrophy was associated with poor perception about own body image and decreased social interactions. Conclusions. Lipodystrophy is common among HIV-infected patients in Tanzania, especially among male patients and those on HAART. Regular screening, monitoring, and patient awareness are needed for early identification and appropriate management.
Analysis of Economic Burden of Seasonal Influenza: An Actuarial Based Conceptual Model
Authors: Perera S. S. N.
Published: October 2017

Analysing the economic burden of the seasonal influenza is highly essential due to the large number of outbreaks in recent years. Mathematical and actuarial models can be considered as management tools to understand the dynamical behavior, predict the risk, and compute it. This study is an attempt to develop conceptual model to investigate the economic burden due to seasonal influenza. The compartment SIS (susceptible-infected-susceptible) model is used to capture the dynamical behavior of influenza. Considering the current investment and future medical care expenditure as premium payment and benefit (claim), respectively, the insurance and actuarial based conceptual model is proposed to model the present economic burden due to the spread of influenza. Simulation is carried out to demonstrate the variation of the present economic burden with respect to model parameters. The sensitivity of the present economic burden is studied with respect to the risk of disease spread. The basic reproduction is used to identify the risk of disease spread. Impact of the seasonality is studied by introducing the seasonally varying infection rate. The proposed model provides theoretical background to investigate the economic burden of seasonal influenza.
Kinematics Analysis of Cervical Rotation‐Traction Manipulation Measured by a Motion Capture System
Authors: Liguo Zhu , Minshan Feng , Xunlu Yin , Shangquan Wang , Jie Yu
Published: October 2017

Objectives. To analyze the kinematics of cervical rotation‐traction manipulation (CRTM). Methods. An experimental study measuring the kinematics of CRTM was conducted. A total of 18 healthy volunteers participated in the study. A single manipulator operated the CRTM for all subjects. Motion capture technology was adopted to track the trajectory during the CRTM operation. Results. The manipulated side did not influence the cervical spine motion. The motion ranges obtained during CRTM were well below the active range of motion reported in the literature. The head rotation angle after thrusting was less than the angle of the rotary‐position (P < 0.05). There was no significant difference in the head rotation angle between pretraction and upward‐thrust. The thrust direction of CRTM was mainly upward. The thrust operation was of high‐velocity and low‐amplitude (thrust velocity: 203.06 ± 49.95 mm/s; thrust acceleration: 3836.27 ± 1262.28 mm/s2; thrust displacement: 3.25 ± 1.30 mm). Conclusions. CRTM has clear operation steps and repeatability that is suitable for clinical application.
Posttransplant Lymphoproliferative Disease Presenting as an Extracranial Mass
Authors: Arasaratnam Reuben J. , Restrepo Alejandro
Published: October 2017

Posttransplant lymphoproliferative disease is a serious complication following stem cell and solid organ transplantation. Early recognition of the disease is important in facilitating timely therapy and improving long-term outcomes. We report a renal transplant recipient presenting with an extracranial frontoparietal soft tissue mass that was subsequently diagnosed as a B-cell lymphoma. The patient was treated successfully with immunosuppression reduction, anti-CD20 monoclonal antibody therapy, and cytotoxic chemotherapy. Our case highlights the importance of recognizing soft tissue masses in the head and neck as a potential clinical manifestation of PTLD in solid organ transplant recipients.
Numerical Simulation of Wind Turbine Rotors Autorotation by Using the Modified LS-STAG Immersed Boundary Method
Authors: Marchevsky Ilia K. , Puzikova Valeria V.
Published: October 2017

A software package is developed for numerical simulation of wind turbine rotors autorotation by using the modified LS-STAG level-set/cut-cell immersed boundary method. The level-set function is used for immersed boundaries description. Algorithm of level-set function construction for complex-shaped airfoils, based on Bézier curves usage, is proposed. Also, algorithm for the level-set function recalculation at any time without reconstructing the Bézier curve for each new rotor position is described. The designed second-order Butterworth low-pass filter for aerodynamic torque filtration for simulations using coarse grids is presented. To verify the modified LS-STAG method, the flow past autorotating Savonius rotor with two blades was simulated at Re=1.96·105.
Supercritical Extraction Process of Allspice Essential Oil
Authors: Andrade-Avila Yasvet Y. , Cruz-Olivares Julian , Pérez-Alonso César , Ortiz-Estrada Ciro Humberto , Chaparro-Mercado María del Carmen
Published: October 2017

Allspice essential oil was extracted with supercritical carbon dioxide (SC-CO2) in a static process at three different temperatures (308.15, 313.15, and 318.15 K) and four levels of pressure (100, 200, 300, and 360 bar). The amount of oil extracted was measured at intervals of 1, 2, 3, 4, 5, and 6 h; the most extraction yield reached was of 68.47% at 318.15 K, 360 bar, and 6 h of contact time. In this supercritical extraction process, the distribution coefficient (KD), the mean effective diffusion coefficient (Def), the energy of activation (Ea), the thermodynamic properties (ΔG0, ΔH0, and ΔS0), and the apparent solubility (S) expressed as mass fraction (w/w) were evaluated for the first time. At the equilibrium the experimental apparent solubility data were successfully correlated with the modified Chrastil equation.
Connatal Urinary Ascites in a Female Preterm
Authors: Brunner Barbara , Ralser Elisabeth , D’Costa Elisabeth , Maurer Kathrin , Kiechl-Kohlendorfer Ursula , Griesmaier Elke
Published: October 2017

Background. Connatal urinary ascites is rare in females without associated malformations and occurs following bladder rupture. Case Presentation. A female very preterm was delivered by caesarean section because of abnormal Doppler findings. The mother suffered from viral pneumonia requiring intensive care in the third trimester of pregnancy. Serial fetal ultrasound examinations showed a megacystis and ascites. Postnatally, pronounced isolated ascites was drained and its urinary nature was confirmed. The bladder leak was demonstrated when blue dye, instilled via a Foley catheter, appeared in the ascitic drain. After removal of the catheter spontaneous micturition was unremarkable. A micturating cystourethrogram showed spontaneous closure of the bladder leak. Conclusion. The female infant experienced fetal bladder rupture and connatal urinary ascites due to maternal pneumonia and intensive care. The use of blue dye is an effective alternative method to any contrast media radiography and should be considered, especially in very preterm infants.
On the Feasibility of High Speed Railway mmWave Channels in Tunnel Scenario
Authors: Li Guangkai , Ai Bo , He Danping , Zhong Zhangdui , Hui Bing , Kim Junhyeong
Published: October 2017

Rail traffic is widely acknowledged as an efficient and green transportation pattern and its evolution attracts a lot of attention. However, the key point of the evolution is how to develop the railway services from traditional handling of the critical signaling applications only to high data rate applications, such as real-time videos for surveillance and entertainments. The promising method is trying to use millimeter wave which includes dozens of GHz bandwidths to bridge the high rate demand and frequency shortage. In this paper, the channel characteristics in an arched railway tunnel are investigated owing to their significance of designing reliable communication systems. Meantime, as millimeter wave suffers from higher propagation loss, directional antenna is widely accepted for designing the communication system. The specific changes that directional antenna brings to the radio channel are studied and compared to the performances of omnidirectional antenna. Note that the study is based on enhanced wide-band ray tracing tool where the electromagnetic and scattering parameters of the main materials of the tunnel are measured and fitted with predicting models.
A Genetic Algorithm Approach for Expedited Crossing of Emergency Vehicles in Connected and Autonomous Intersection Traffic
Authors: Lu Qiang , Kim Kyoung-Dae
Published: October 2017

This paper proposes an intersection control algorithm which aims to determine an efficient vehicle-passing sequence that allows the emergency vehicle to cross an intersection as soon as possible while the travel times of other vehicles are minimally affected. When there are no emergency vehicles within the intersection area, the vehicles are controlled by the DICA that we proposed in our earlier work. When there are emergency vehicles entering the communication range, we prioritize emergency vehicles through optimal ordering of vehicles. Since the number of possible vehicle-passing sequences increases rapidly with the number of vehicles, finding an efficient sequence of vehicles in a short time is the main challenge of the study. A genetic algorithm is proposed to solve the optimization problem which finds the optimal vehicle sequence that gives the emergency vehicles the highest priority. The efficiency of the proposed approach for expedited crossing of emergency vehicles is validated through comparisons with DICA and a reactive traffic light algorithm through extensive simulations. The results show that the proposed genetic algorithm is able to decrease the travel times of emergency vehicles significantly in light and medium traffic volumes without causing any noticeable performance degradation of normal vehicles.
Analysis of Chemical Constituents Changing in Physical Process and Nutritional Components of Malus halliana Koehne Tea
Authors: Yin Zhenhua , Zhang Yong , Zhang Juanjuan , Kang Wenyi
Published: October 2017

This study aimed to establish a HPLC method for simultaneous determination of the changing of quercitrin, 3-hydroxyphloridzin, and phloridzin in physical process of M. halliana tea. Meanwhile, the nutritional compositions were determined, using anthrone-sulfuric acid colorimetry and direct titration determination of total sugar and reducing sugar, respectively, in order to provide theoretical basis for quality control and tea production. The results showed that the regression equations for quercitrin, 3-hydroxyphloridzin, and phloridzin were linear in the range of 0.0972–12.15 μg (r=0.999 8), 0.0932~11.65 μg (r=0.999 1), and 0.9~112.5 μg (r=0.999 6), respectively. The average recoveries ranged from 98.19% to 99.35%. The contents of crude protein and the crude fat were measured by spectrophotometric detection and soxhlet extraction detection, respectively. The contents of total sugar, reducing sugar, the fat, and protein were 6.8 g/100 g, 8.5 mg/100 g, 2.399 g/100 g, and 4.362 g/100 g, respectively, in M. halliana tea.
Prescription Function Prediction Using Topic Model and Multilabel Classifiers
Authors: Wang Lidong , Zhang Yin , Zhang Yun , Xu Xiaodong , Cao Shihua
Published: October 2017

Determining a prescription’s function is one of the challenging problems in Traditional Chinese Medicine (TCM). In past decades, TCM has been widely researched through various methods in computer science, but none concentrates on the prediction method for a new prescription’s function. In this study, two methods are presented concerning this issue. The first method is based on a novel supervised topic model named Label‐Prescription‐Herb (LPH), which incorporates herb‐herb compatibility rules into learning process. The second method is based on multilabel classifiers built by TFIDF features and herbal attribute features. Experiments undertaken reveal that both methods perform well, but the multilabel classifiers slightly outperform LPH‐based method. The prediction results can provide valuable information for new prescription discovery before clinical test.
The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation
Authors: Samy Kannan P. , Butler James R. , Li Ping , Cooper David K. C. , Ekser Burcin
Published: October 2017

Pig-to-human xenotransplantation offers a potential bridge to the growing disparity between patients with end-stage organ failure and graft availability. Early studies attempting to overcome cross-species barriers demonstrated robust humoral immune responses to discordant xenoantigens. Recent advances have led to highly efficient and targeted genomic editing, drastically altering the playing field towards rapid production of less immunogenic porcine tissues and even the discussion of human xenotransplantation trials. However, as these humoral immune barriers to cross-species transplantation are overcome with advanced transgenics, cellular immunity to these novel xenografts remains an outstanding issue. Therefore, understanding and optimizing immunomodulation will be paramount for successful clinical xenotransplantation. Costimulation blockade agents have been introduced in xenotransplantation research in 2000 with anti-CD154mAb. Most recently, prolonged survival has been achieved in solid organ (kidney xenograft survival > 400 days with anti-CD154mAb, heart xenograft survival > 900 days, and liver xenograft survival 29 days with anti-CD40mAb) and islet xenotransplantation (>600 days with anti-CD154mAb) with the use of these potent experimental agents. As the development of novel genetic modifications and costimulation blocking agents converges, we review their impact thus far on preclinical xenotransplantation and the potential for future application.
Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients with Unresectable Hepatocellular Carcinoma Lesions
Authors: Tak Won Young , Lin Shi-Ming , Wang Yijun , Zheng Jiasheng , Vecchione Aldo , Park Soo Young , Chen Min Hua , Wong Stephen , Xu Ruocai , Peng Cheng-Yuan , Chiou Yi-You , Huang Guan-Tarn , Cai Jianqiang , Abdullah Basri Johan Jeet , Lee June Sung , Lee Jae Young , Choi Jong-Young , Gopez-Cervantes Julieta , Sherman Morris , Finn Richard S. , Omata Masao , O'Neal Michael , Makris Lukas , Borys Nicholas , Poon Ronnie , Lencioni Riccardo
Published: October 2017

Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm.

Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy.

Results: The primary endpoint was not met; in intention-to-treat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P = 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76–1.20; P = 0.67). Among 285 patients with a solitary HCC lesion who received ≥45 minutes RFA dwell time, the OS HR was 0.63 (95% CI, 0.41–0.96; P < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin.

Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes. Clin Cancer Res; 24(1); 73–83. ©2017 AACR.
Functional Genomics Approach Identifies Novel Signaling Regulators of TGFα Ectodomain Shedding
Authors: Wilson Jennifer L. , Kefaloyianni Eirini , Stopfer Lauren , Harrison Christina , Sabbisetti Venkata S. , Fraenkel Ernest , Lauffenburger Douglas A. , Herrlich Andreas
Published: October 2017

Ectodomain shedding of cell-surface precursor proteins by metalloproteases generates important cellular signaling molecules. Of importance for disease is the release of ligands that activate the EGFR, such as TGFα, which is mostly carried out by ADAM17 [a member of the A-disintegrin and metalloprotease (ADAM) domain family]. EGFR ligand shedding has been linked to many diseases, in particular cancer development, growth and metastasis, as well as resistance to cancer therapeutics. Excessive EGFR ligand release can outcompete therapeutic EGFR inhibition or the inhibition of other growth factor pathways by providing bypass signaling via EGFR activation. Drugging metalloproteases directly have failed clinically because it indiscriminately affected shedding of numerous substrates. It is therefore essential to identify regulators for EGFR ligand cleavage. Here, integration of a functional shRNA genomic screen, computational network analysis, and dedicated validation tests succeeded in identifying several key signaling pathways as novel regulators of TGFα shedding in cancer cells. Most notably, a cluster of genes with NFκB pathway regulatory functions was found to strongly influence TGFα release, albeit independent of their NFκB regulatory functions. Inflammatory regulators thus also govern cancer cell growth–promoting ectodomain cleavage, lending mechanistic understanding to the well-known connection between inflammation and cancer.

Implications: Using genomic screens and network analysis, this study defines targets that regulate ectodomain shedding and suggests new treatment opportunities for EGFR-driven cancers. Mol Cancer Res; 16(1); 147–61. ©2017 AACR.
Zoned phosphosiderite-metavariscite crystals from Eduardo Mine, Conselheiro Pena, Minas Gerais, Brazil
Authors: Lamoso Ingrid Souto Maia , Atencio Daniel
Published: October 2017

Zoned phosphosiderite-metavariscite crystals are recorded for the first time, in a phosphate-rich granitic pegmatite, at the Eduardo mine, Conselheiro Pena, Minas Gerais, Brazil. Metavariscite is described for the first time in Brazil. Phosphosiderite and metavariscite occur as small friable, globular agglomerates, up to 2 mm, with purple to lilac color, in miarolitic cavities up to 1 cm in the pegmatite. Phosphosiderite, ideally Fe3+(PO4).2H2O, and metavariscite, ideally Al(PO4).2H2O, are isostructural. Empirical formulae from EDS analysis (H2O by difference) are, respectively, (Fe3+0.65Al0.24)Ʃ0.89[PO3.67(OH)0.33].0.96H2O and (Al0.61Fe3+ 0.23)Ʃ0.84[PO3.52(OH)0.48].0.97H2O. The differences between ideal and empirical formulae are attributed to the instability of the crystals under the electron beams. Only the peaks for phosphosiderite were observed in the X-ray powder diffraction pattern due to the small proportion of metavariscite in the mixture. Unit cell parameters calculated for phosphosiderite are: a 5.368(7), b 9.778(10), c 8.710(9) Å, β 90.9(1)º, V 457.1(9) Å³.
Higher Adiposity Is Associated With Slower Cognitive Decline in Hypertensive Patients: Secondary Analysis of the China Stroke Primary Prevention Trial
Authors: Zhang Jun , Tang Genfu , Xie Haiqun , Wang Binyan , He Mingli , Fu Jia , Shi Xiuli , Zhang Chengguo , Huo Yong , Xu Xiping , Wang Kai
Published: October 2017

Background

Obesity is a risk factor for many diseases. However, the potential association between adiposity and cognitive decline in hypertensive patients is inconclusive. We performed a secondary data analysis of the CSPPT (China Stroke Primary Prevention Trial) to examine whether adiposity is correlated with longitudinal cognitive performance in hypertensive adults.

Methods and Results

The analysis included 16 791 patients in the
CSPPT
who received at least 2 cognitive assessments by the Mini‐Mental State Examination (
MMSE
) during the follow‐up (median, 4.5 years; interquartile range, 4.2–4.8 years). Outcomes included changes in
MMSE
scores and cognitive impairment (defined as
MMSE
score less than education‐specific cutoff point). A marked reduction in
MMSE
scores at the final (compared with at the 1‐year) follow‐up was apparent in both men (n=4838; mean [
SD
] score, 0.41 [3.62]) and women (n=7190; mean [SD] score, 1.07 [4.61]; both
P
<0.001). Analysis using a mixed‐effects model revealed an association between higher body mass index with less
MMSE
decline, even after controlling for demographics and comorbidities (men, β=0.0134 [
SE
, 0.0036]; women, β=0.0133 [SE, 0.0034]; both
P
<0.001). A total of 1037 men (15.3%) and 3317 women (33.1%) developed cognitive impairment. In multivariable Cox regression analyses, being obese in men (11.3% versus 18.0%; hazard ratio, 0.75; 95% confidence interval, 0.60–0.94) and women (30.1% versus 36.5%; hazard ratio, 0.82; 95% confidence interval, 0.74–0.91) was a protective factor against cognitive impairment compared with normal body mass index.

Conclusions

Higher adiposity is independently associated with slower cognitive decline in Chinese hypertensive adults.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
00794885
CSPPT
.
Mortality and Disability According to Baseline Blood Pressure in Acute Ischemic Stroke Patients Treated by Thrombectomy: A Collaborative Pooled Analysis
Authors: Maïer Benjamin , Gory Benjamin , Taylor Guillaume , Labreuche Julien , Blanc Raphaël , Obadia Michael , Abrivard Marie , Smajda Stanislas , Desilles Jean‐Philippe , Redjem Hocine , Ciccio Gabriele , Lukaszewicz Anne Claire , Turjman Francis , Riva Roberto , Labeyrie Paul Emile , Duhamel Alain , Blacher Jacques , Piotin Michel , Lapergue Bertrand , Mazighi Mikael , Decroix Jean‐Pierre , Wang Adrien , Evrard Serge , Tchikviladzé Maya , Bourdin Frederic , Gonzalez‐Valcarcel Jaime , Di Maria Federico , Pico Fernando , Rakotoharinandrasana Haja , Tassan Philippe , Poll Roxanna , Corabianu Ovide , de Broucker Thomas , Smadja Didier , Alamowitch Sonia , Ille Olivier , Manchon Eric , Garcia Pierre‐Yves
Published: October 2017

Background

High blood pressure (
BP
) is associated with worse clinical outcomes in the setting of acute ischemic stroke, but the optimal blood pressure target is still a matter of debate. We aimed to study the association between baseline
BP
and mortality in acute ischemic stroke patients treated by mechanical thrombectomy.

Methods and Results

A total of 1332 acute ischemic stroke patients treated by mechanical thrombectomy were enrolled (from January 2012 to June 2016) in the
ETIS
(Endovascular Treatment in Ischemic Stroke) registry. Linear and polynomial logistic regression models were used to assess the association between
BP
and mortality and functional outcome at 90 days. Highest mortality was found at lower and higher baseline systolic blood pressure (
SBP
) values following a J‐ or U‐shaped relationship, with a nadir at 157 mm Hg (95% confidence interval 143‐170). When
SBP
values were categorized in 10–mm Hg increments, the odds ratio for all‐cause mortality was 3.78 (95% confidence interval 1.50‐9.55) for
SBP
<110 mm Hg and 1.81 (95% confidence interval 1.01‐3.36) for
SBP
≥180 mm Hg using
SBP
≥150 to 160 mm Hg as reference. The rate of favorable outcome was the highest at low
SBP
values and lowest at high
SBP
values, with a nonlinear relationship; in unplanned exploratory analysis, an optimal threshold
SBP
≥177 mm Hg was found to predict unfavorable outcome (adjusted odds ratio 0.47; 95% confidence interval 0.31‐0.70).

Conclusion

In acute ischemic stroke patients treated by mechanical thrombectomy, baseline
SBP
is associated with all‐cause mortality and favorable outcome. In contrast to mortality, favorable outcome rate was the highest at low
SBP
values and lowest at high
SBP
values. Further studies are warranted to confirm these findings.
Circulatory Dynamics During Pulmonary Vein Isolation Using the Second‐Generation Cryoballoon
Authors: Kajiyama Takatsugu , Miyazaki Shinsuke , Watanabe Tomonori , Yamao Kazuya , Kusa Shigeki , Igarashi Miyako , Nakamura Hiroaki , Hachiya Hitoshi , Iesaka Yoshito
Published: October 2017

Background

Circulatory dynamics change during pulmonary vein (PV) isolation using cryoballoons. This study sought to investigate the circulatory dynamics during cryoballoon‐based PV isolation procedures and the contributing factors.

Methods and Results

This study retrospectively included 35 atrial fibrillation patients who underwent PV isolation with 28‐mm second‐generation cryoballoons and single 3‐minute freeze techniques. Blood pressures were continuously monitored via arterial lines. The left ventricular function was evaluated with intracardiac echocardiography throughout the procedure in 5 additional patients. Overall, 126 cryoapplications without interrupting freezing were analyzed. Systolic blood pressure (
SBP
) significantly increased during freezing (138.7±28.0 to 148.0±27.2 mm Hg,
P
<0.001) and sharply dropped (136.3±26.0 to 95.0±17.9 mm Hg,
P
<0.001) during a mean of 21.0±8.0 seconds after releasing the occlusion during thawing. In the multivariate analyses, the left
PV
s (
P
=0.008) and lower baseline
SBP
(
P
<0.001) correlated with a larger
SBP
rise, whereas a higher baseline
SBP
(
P
<0.001), left
PV
s (
P
=0.017), lower balloon nadir temperature (
P
=0.027), and female sex (
P
=0.045) correlated with larger
SBP
drops. These changes were similarly observed regardless of preprocedural atropine administration and the target
PV
order.
PV
occlusions without freezing exhibited no
SBP
change.
PV
antrum freezing without occlusions similarly increased the
SBP
, but the
SBP
drop was significantly smaller than that with occlusions (
P
<0.001). The
SBP
drop time‐course paralleled the left ventricular ejection fraction increase (66.8±8.1% to 79.3±6.7%,
P
<0.001) and systemic vascular resistance index decrease (2667±1024 to 1937±513 dynes‐sec/cm
2
per m
2
,
P
=0.002).

Conclusions

With second‐generation cryoballoon‐based PV isolation,
SBP
significantly increased during freezing owing to atrial tissue freezing and dropped sharply after releasing the occlusion, presumably because of the peripheral vascular resistance decrease mainly by circulating chilled blood.
Inflammation and Aortic Stiffness: An Individual Participant Data Meta‐Analysis in Patients With Inflammatory Bowel Disease
Authors: Zanoli Luca , Boutouyrie Pierre , Fatuzzo Pasquale , Granata Antonio , Lentini Paolo , Oztürk Kadir , Cappello Maria , Theocharidou Eleni , Tuttolomondo Antonino , Pinto Antonio , Cammà Calogero , Licata Anna , Blanco Julien , Rastelli Stefania , Inserra Gaetano , Castellino Pietro , Laurent Stephane
Published: October 2017

Background

The recent finding that aortic pulse wave velocity (
aPWV
) is increased in patients with inflammatory bowel disease may explain why the cardiovascular risk is increased despite the low prevalence of traditional cardiovascular risk factors. We aimed to test whether inflammation is associated with aortic stiffening in this setting after adjustment for major confounders and to perform subgroup analyses.

Methods and Results

A systematic literature search for
aPWV
in inflammatory bowel disease was performed using PubMed, Scopus, Web of Science, and Google Scholar databases (last accessed May 7, 2017). Inclusion criterion was peer‐reviewed publications on clinical studies reporting original data. This study followed the Preferred Reporting Items for Systematic Review and Meta‐Analyses of individual participant data 2015 guidelines. Data were provided for 4 cohorts in 3 countries (151 participants with ulcerative colitis, 159 with Crohn's disease, and 227 control patients). Using
aPWV
, cohort‐specific
z
scores were calculated after log
e
‐transform and combined in meta‐analysis to form pooled effects using a random‐effects model. Compared with controls,
aPWV
was increased in patients with Crohn's disease (mean difference 0.78
z
score; 95% confidence interval, 0.56–1.00
z
score [
P
<0.001]) and ulcerative colitis (mean difference 0.75
z
score; 95% confidence interval, 0.52–0.97
z
score [
P
<0.001]). In an outlier‐robust multivariate linear regression model adjusted for prespecified confounders,
aPWV
was associated with disease duration (years, β=0.05
z
score; 95% confidence interval, 0.02–0.08
z
score [
P
<0.001]) and white blood cell count (billion cells/L, β=0.07
z
score; 95% confidence interval, 0.02–0.11
z
score [
P
=0.002]) but not with markers of acute inflammation (C‐reactive protein and erythrocyte sedimentation rate), cardiovascular risk factors, and therapy.

Conclusions

The increased
aPWV
reported in patients with inflammatory bowel disease is associated with inflammation.

Clinical Trial Registration

URL
:
http://www.crd.york.ac.uk
. Unique identifier:
PROSPERO
2016:
CRD
42016053070.
Bosutinib Attenuates Inflammation via Inhibiting Salt-Inducible Kinases in Experimental Model of Intracerebral Hemorrhage on Mice
Authors: Ma Li , Manaenko Anatol , Ou Yi-Bo , Shao An-Wen , Yang Shu-Xu , Zhang John H.
Published: October 2017

Background and Purpose—

Intracerebral hemorrhage (ICH) is a subtype of stroke with highest mortality and morbidity. Pronounced inflammation plays a significant role in the development of the secondary brain injury after ICH. Recently, SIK-2 (salt-inducible kinase-2) was identified as an important component controlling inflammatory response. Here we sought to investigate the role of SIK-2 in post-ICH inflammation and potential protective effects of SIK-2 inhibition after ICH.

Methods—

Two hundred and ninety-three male CD-1 mice were used. ICH was induced via injection of 30 μL of autologous blood. Recombinant SIK-2 was administrated 1 hour after ICH intracerebroventricularly. SIK-2 small interfering RNA was injected intracerebroventricularly 24 hours before ICH. Bosutinib, a clinically approved tyrosine kinase inhibitor with affinity to SIK-2, was given intranasally 1 hour or 6 hours after ICH. Effects of treatments were evaluated by neurological tests and brain water content calculation. Molecular pathways were investigated by Western blots and immunofluorescence studies.

Results—

Endogenous SIK-2 was expressed in microglia and neurons. SIK-2 expression was reduced after ICH. Exogenous SIK-2 aggravated post-ICH inflammation, leading to brain edema and the neurobehavioral deficits. SIK-2 inhibition attenuated post-ICH inflammation, reducing brain edema and ameliorating neurological dysfunctions. Bosutinib inhibited SIK-2–attenuating ICH-induced brain damage. Protective effects of Bosutinib were mediated, at least partly, by CRTC3 (cyclic amp-response element binding protein-regulated transcription coactivator 3)/cyclic amp-response element binding protein/NF-κB (nuclear factor-κB) pathway.

Conclusions—

SIK-2 participates in inflammation induction after ICH. SIK-2 inhibition via Bosutinib or small interfering RNA decreased inflammation, attenuating brain injury. SIK-2 effects are, at least partly, mediated by CRTC3-cyclic amp-response element binding protein-NF-κB signaling pathway.
Dietary Sodium to Potassium Ratio and Risk of Stroke in a Multiethnic Urban Population
Authors: Willey Joshua , Gardener Hannah , Cespedes Sandino , Cheung Ying K. , Sacco Ralph L. , Elkind Mitchell S.V.
Published: October 2017

Background and Purpose—

There is growing evidence that increased dietary sodium (Na) intake increases the risk of vascular diseases, including stroke, at least in part via an increase in blood pressure. Higher dietary potassium (K), seen with increased intake of fruits and vegetables, is associated with lower blood pressure. The goal of this study was to determine the association of a dietary Na:K with risk of stroke in a multiethnic urban population.

Methods—

Stroke-free participants from the Northern Manhattan Study, a population-based cohort study of stroke incidence, were followed-up for incident stroke. Baseline food frequency questionnaires were analyzed for Na and K intake. We estimated the hazard ratios and 95% confidence intervals for the association of Na:K with incident total stroke using multivariable Cox proportional hazards models.

Results—

Among 2570 participants with dietary data (mean age, 69±10 years; 64% women; 21% white; 55% Hispanic; 24% black), the mean Na:K ratio was 1.22±0.43. Over a mean follow-up of 12 years, there were 274 strokes. In adjusted models, a higher Na:K ratio was associated with increased risk for stroke (hazard ratio, 1.6; 95% confidence interval, 1.2–2.1) and specifically ischemic stroke (hazard ratio, 1.6; 95% confidence interval, 1.2–2.1).

Conclusions—

Na:K intake is an independent predictor of stroke risk. Further studies are required to understand the joint effect of Na and K intake on risk of cardiovascular disease.