bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance Analysis and Maintenance Planning of Evaporation System in the Sugar Industry by Using Supplementary Variable Technique
Authors: Kumar Ramesh , Kadyan M. S.
Published: March 2018

In this paper, a reliability model for evaporation system in sugar industry is developed to accomplish performance evolution. This system consists of three subsystems, namely evaporator, syrup sulphitor and sulphited syrup. These subsystems are working in series. Failure time distribution of subsystems is exponential, whereas repair time distribution of subsystems is arbitrary. The differential difference equations associated with state changeover model of the system are developed by using supplementary variable technique and solved to get state probabilities of the system model. The results for some measures (availability and profit) of system performance are obtained in steady state. A particular case is also considered to show the behavior of availability and profit analysis of the evaporation system.
Data-Driven Detection of Needle Buckling Events in Robotic Needle Steering
Authors: Narayan Meenakshi , Choti Michael A. , Fey Ann Majewicz
Published: March 2018

In robotic needle steering, flexible asymmetric-tip needles can steer around obstacles to reach targets deep within tissue. Due to tissue inhomogeneity and needle flexibility, needle buckling can occur, preventing accurate placement. This paper focuses on detecting needle buckling using axial force and needle-tip position readings from sensors. Our algorithm uses errors between the force readings and a predictive force model generated from those readings to track rapid changes in the measured forces. Using this prediction error and needle-tip position, the algorithm detects unexpected force increase, strict needle buckling, and buckling with sliding events at the needle-tip. The metrics for the detections are derived using a standard three-sigma rule and a sigmoid function to ensure generalizability of this method to a variety of tissue types. Our algorithm was tested using insertions into a gelatin tissue with an embedded rectangular obstacle designed to elicit buckling events. Needle buckling was detected at a maximum of 2[Formula: see text]mm after collision with the obstacle. Our algorithm was tested for robustness with insertions in an ex vivo tissue under different boundary conditions. Our algorithm was also able to detect buckling events 1–2[Formula: see text]s sooner than human detection times, showing significance for future autonomous control.
Petrography, mineralogy and geochemistry of jadeite-rich artefacts from the Playa Grande excavation site, northern Hispaniola: evaluation of local provenance from the Río San Juan Complex
Authors: Schertl Hans-Peter , Maresch Walter V. , Knippenberg Sebastiaan , Hertwig Andreas , López Belando Adolfo , Rodríguez Ramos Reniel , Speich Laura , Hofman Corinne L.
Published: March 2018

Many archaeological sites with jadeitite artefacts are known in the Caribbean region, but defining the source of the raw material is a major problem because of great mineralogical heterogeneity both in potential sources and in artefacts. The archaeological settlement site of Playa Grande on the northern coast of the Dominican Republic is particularly significant because it yielded evidence of on-site axe manufacture, and lies only 20–30 km NE of a recently discovered potential source area of serpentinite mélanges in the nearby Río San Juan Complex (RSJC). A suite of nine artefacts was chosen from a collection of over 100 excavated woodworking tools rich in jadeite, as well as two blueschist artefacts. Permission to perform destructive analysis allowed data on petrography, mineral chemistry and bulk-rock chemistry to be obtained. Seven of the nine artefacts are jadeitite
sensu stricto
(>90 vol% jadeite), which are identical to material known from the RSJC. Two artefacts are jadeite–lawsonite rocks. These and the two blueschists show only minor differences from corresponding rocks of the RSJC source. With this direct linking of source and site material, it is now possible to better define source discriminators for the Caribbean and to assess sampling bias.
Design and Simulation of a Solar Chimney PV/T Power Plant in Northwest China
Authors: Liu Qingjun , Cao Fei , Liu Yanhua , Zhu Tianyu , Liu Deyou
Published: March 2018

A solar chimney PV/T power plant (SCPVTPP) is proposed. Mathematical models are established for the PV/T solar collector, the chimney, and the power conversion unit, respectively. Performances of the designed SCPVTPP are then simulated. The SCPVTPPs with different PV module areas are finally discussed. It is found that the PV cells hold the highest temperature in the solar collector. Temperature rise of the PV module has significant influences to its power generation. Without cooling, the PV power capacity has an average decrease of 28.71%. The contradictory influences of temperature rise and airflow cooling lead to an 11.81% decrease of the average power capacity. By adding the power generated by PVT, the total PV-related power contribution increases by 4.72%. With the increase of the solar collector ratio, the temperature rise and the wind velocity both first decrease then increase, the SCPP power productivity decreases linearly, and the PV power productivity increases linearly, whereas the PVT power productivity first increases linearly then increases superlinearly. There is a reversed solar collector ratio, exceeding which the PV generates most power. In this study, solar thermal power takes the major role when the solar PV area ratio is smaller than 0.055.
Towards Optimal Platform-Based Robot Design for Ankle Rehabilitation: The State of the Art and Future Prospects
Authors: Miao Qing , Zhang Mingming , Wang Congzhe , Li Hongsheng
Published: March 2018

This review aims to compare existing robot-assisted ankle rehabilitation techniques in terms of robot design. Included studies mainly consist of selected papers in two published reviews involving a variety of robot-assisted ankle rehabilitation techniques. A free search was also made in Google Scholar and Scopus by using keywords “ankle∗,” and “robot∗,” and (“rehabilitat∗” or “treat∗”). The search is limited to English-language articles published between January 1980 and September 2016. Results show that existing robot-assisted ankle rehabilitation techniques can be classified into wearable exoskeleton and platform-based devices. Platform-based devices are mostly developed for the treatment of a variety of ankle musculoskeletal and neurological injuries, while wearable ones focus more on ankle-related gait training. In terms of robot design, comparative analysis indicates that an ideal ankle rehabilitation robot should have aligned rotation center as the ankle joint, appropriate workspace, and actuation torque, no matter how many degrees of freedom (DOFs) it has. Single-DOF ankle robots are mostly developed for specific applications, while multi-DOF devices are more suitable for comprehensive ankle rehabilitation exercises. Other factors including posture adjustability and sensing functions should also be considered to promote related clinical applications. An ankle rehabilitation robot with reconfigurability to maximize its functions will be a new research point towards optimal design, especially on parallel mechanisms.
Surface Morphology Study of Chemical Vapor Transport of ZnO Crystals
Authors: Fan Long , Li Jia , Yan Dawei , Peng Liping , Jiang Tao , Wang Xueming , Wu Weidong
Published: March 2018

A chemical vapor transport (CVT) method was implemented to grow bulk ZnO crystals. X-ray diffraction (XRD), field emission scanning electron microscopy (SEM), and optical microscope (OM) studies were carried out to characterize the surface properties of the grown crystal. The XRD result indicated the exposed solid-vapor interface of the as-grown crystal was composed of (0001) and {101-1} faces. Using SEM and OM, we observed small hexagonal pyramids and microstructures formed of crosslines on the as-grown crystal and found hexagonal thermal etching pits on the surfaces of seed crystals. The formation, evolution, and distribution mechanisms of the microstructures were investigated.
Study on Pulse Characteristic of Produced Crude Composition in CO2 Flooding Pilot Test
Authors: Diwu Pengxiang , Liu Tongjing , You Zhenjiang , Hou Ganggang , Qiao Runwei , Zhao Lekun
Published: March 2018

It has been observed in many laboratory tests that the carbon number of the maximum concentration components (CNMCC) of produced oil varies monotonically with CO2 injection volume at the core scale. However, in CO2 flooding pilot test at the field scale, we find that the CNMCC is usually nonmonotonic function of CO2 injection volume, which is called “pulse characteristic” of CNMCC. To investigate the mechanism of this phenomenon, we analyze the physical process of CO2 flooding in heterogeneous reservoir and explain the reason of the pulse characteristic of CNMCC. Moreover, two 3D reservoir models with 35 nonaqueous components are proposed for numerical simulation to validate the conjecture. The simulation results show that pulse characteristic of CNMCC only occurs in the heterogeneous model, confirming that the pulse characteristic results from the channeling path between wells, which yields nonmonotonic variation of oil-CO2 mixing degree. Based on it, a new method can be developed to identify and quantify the reservoir heterogeneity.
Development of a New Robotic Ankle Rehabilitation Platform for Hemiplegic Patients after Stroke
Authors: Liu Quanquan , Wang Chunbao , Long Jian Jun , Sun Tongyang , Duan Lihong , Zhang Xin , Zhang Bo , Shen Yajing , Shang Wanfeng , Lin Zhuohua , Wang Yulong , Xia Jinfeng , Wei Jianjun , Li Weiguang , Wu Zhengzhi
Published: March 2018

A large amount of hemiplegic survivors are suffering from motor impairment. Ankle rehabilitation exercises act an important role in recovering patients’ walking ability after stroke. Currently, patients mainly perform ankle exercise to reobtain range of motion (ROM) and strength of the ankle joint under a therapist’s assistance by manual operation. However, therapists suffer from high work intensity, and most of the existed rehabilitation devices focus on ankle functional training and ignore the importance of neurological rehabilitation in the early hemiplegic stage. In this paper, a new robotic ankle rehabilitation platform (RARP) is proposed to assist patients in executing ankle exercise. The robotic platform consists of two three-DOF symmetric layer-stacking mechanisms, which can execute ankle internal/external rotation, dorsiflexion/plantarflexion, and inversion/eversion exercise while the rotation center of the distal zone of the robotic platform always coincides with patients’ ankle pivot center. Three exercise modes including constant-speed exercise, constant torque-impedance exercise, and awareness exercise are developed to execute ankle training corresponding to different rehabilitation stages. Experiments corresponding to these three ankle exercise modes are performed, the result demonstrated that the RARP is capable of executing ankle rehabilitation, and the novel awareness exercise mode motivates patients to proactively participate in ankle training.
QRS Detection Based on Improved Adaptive Threshold
Authors: Lu Xuanyu , Pan Maolin , Yu Yang
Published: March 2018

Cardiovascular disease is the first cause of death around the world. In accomplishing quick and accurate diagnosis, automatic electrocardiogram (ECG) analysis algorithm plays an important role, whose first step is QRS detection. The threshold algorithm of QRS complex detection is known for its high-speed computation and minimized memory storage. In this mobile era, threshold algorithm can be easily transported into portable, wearable, and wireless ECG systems. However, the detection rate of the threshold algorithm still calls for improvement. An improved adaptive threshold algorithm for QRS detection is reported in this paper. The main steps of this algorithm are preprocessing, peak finding, and adaptive threshold QRS detecting. The detection rate is 99.41%, the sensitivity (Se) is 99.72%, and the specificity (Sp) is 99.69% on the MIT-BIH Arrhythmia database. A comparison is also made with two other algorithms, to prove our superiority. The suspicious abnormal area is shown at the end of the algorithm and RR-Lorenz plot drawn for doctors and cardiologists to use as aid for diagnosis.
Nonsmall Cell Lung Carcinoma with Giant Cell Features Expressing Programmed Death-Ligand 1: A Report of a Patient Successfully Treated with Pembrolizumab
Authors: Nakayama Shingo , Sasaki Mamoru , Morinaga Shojiroh , Minematsu Naoto
Published: March 2018

Giant cell carcinoma, a rare variant of nonsmall cell lung carcinoma (NSCLC), is characterized by aggressive progression and poor response to conventional chemotherapy. This report is the first to describe a patient with NSCLC and giant cell features who was successfully treated with pembrolizumab, an antibody targeting programmed death-1 (PD-1). A 69-year-old woman was diagnosed with NSCLC with multiple brain metastases. Histological evaluation of lung biopsy specimens revealed proliferation of pleomorphic giant tumor cells with poor cohesiveness, findings consistent with giant cell carcinoma. Immunostaining showed that a high proportion of the tumor cells were positive for expression of programmed death-ligand 1 (PD-L1). The patient received stereotactic radiotherapy for the brain metastases, followed by administration of pembrolizumab. Treatment with pembrolizumab resulted in the rapid regression of the primary lung nodule, with the progression-free period maintained for at least four treatment cycles. Immunotherapy targeting PD-1/PD-L1 may be an option for patients with PD-L1-positive NSCLC with giant cell features.
Once-Weekly Hypofractionated Radiotherapy for Breast Cancer in Elderly Patients: Efficacy and Tolerance in 486 Patients
Authors: Sanz Javier , Zhao Min , Rodríguez Nuria , Granado Raquel , Foro Palmira , Reig Ana , Membrive Ismael , Algara Manuel
Published: March 2018

Purpose. Radiation therapy is a key treatment of breast cancer. Elderly patients with associated diseases that modify their performance status do not tolerate long periods of daily irradiation. The objective of this study is to analyze the results of weekly hypofractionated treatment in these patients. Material and Methods. Between 1992 and 2016, we included 486 elderly patients presenting concomitant pathology or sociofamilial problems in which it was not feasible to propose conventional treatment. They were treated with conservative surgery or mastectomy and then adjuvant hypofractionated irradiation, administering 5 Gy or 6.25 Gy in 6 fractions, once a week (total dose 30–37.5 Gy) over 6 weeks. Results. Breast cancer overall survival according to the Kaplan-Meier method at 5 years was 74.2%±2.3%; breast cancer disease-free survival was 90%±1.6%; local relapse-free survival was 96.5%±1% showing that patients die more from other causes and not from their neoplasia. Acute dermatitis was mild (75.6% of the patients grades I–III) and 30.6% had moderate chronic fibrosis. Conclusions. The once-weekly hypofractionated radiotherapy is a feasible and convenient option for elderly patients with breast cancer. It is a safe treatment modality with similar survival and local control results compared to standard fractionation, while the side effects are acceptable.
The Role of Regulatory T Cell in Nontypeable Haemophilus influenzae-Induced Acute Exacerbation of Chronic Obstructive Pulmonary Disease
Authors: Guan Xuewa , Lu Yanjiao , Wang Guoqiang , Gibson Peter , Chen Fang , Fang Keyong , Wang Ziyan , Pang Zhiqiang , Guo Yingqiao , Lu Junying , Yuan Yuze , Ran Nan , Wang Fang
Published: March 2018

Chronic obstructive pulmonary disease (COPD) is associated with irreversible persistent airflow limitation and enhanced inflammation. The episodes of acute exacerbation (AECOPD) largely depend on the colonized pathogens such as nontypeable Haemophilus influenzae (NTHi), one of the most commonly isolated bacteria. Regulatory T cells (Tregs) are critical in controlling inflammatory immune responses and maintaining tolerance; however, their role in AECOPD is poorly understood. In this study, we hypothesized a regulatory role of Tregs, as NTHi participated in the progress of COPD. Immunological pathogenesis was investigated in a murine COPD model induced by cigarette smoke (CS). NTHi was administrated through intratracheal instillation for an acute exacerbation. Weight loss and lung function decline were observed in smoke-exposed mice. Mice in experimental groups exhibited serious inflammatory responses via histological and cytokine assessment. Expression levels of Tregs and Th17 cells with specific cytokines TGF-β1 and IL-17 were detected to assess the balance of pro-/anti-inflammatory influence partially. Our findings suggested an anti-inflammatory activity of Tregs in CS-induced model. But this activity was suppressed after NTHi administration. Collectively, these data suggested that NTHi might play a necessary role in downregulating Foxp3 to impair the function of Tregs, helping development into AECOPD.
Biodegradable Magnesium Alloys Developed as Bone Repair Materials: A Review
Authors: Liu Chen , Ren Zheng , Xu Yongdong , Pang Song , Zhao Xinbing , Zhao Ying
Published: March 2018

Bone repair materials are rapidly becoming a hot topic in the field of biomedical materials due to being an important means of repairing human bony deficiencies and replacing hard tissue. Magnesium (Mg) alloys are potentially biocompatible, osteoconductive, and biodegradable metallic materials that can be used in bone repair due to their in situ degradation in the body, mechanical properties similar to those of bones, and ability to positively stimulate the formation of new bones. However, rapid degradation of these materials in physiological environments may lead to gas cavities, hemolysis, and osteolysis and thus, hinder their clinical orthopedic applications. This paper reviews recent work on the use of Mg alloy implants in bone repair. Research to date on alloy design, surface modification, and biological performance of Mg alloys is comprehensively summarized. Future challenges for and developments in biomedical Mg alloys for use in bone repair are also discussed.
Effect of the Reduction Temperature of PdAg Nanoparticles during the Polyol Process in the Ethanol Electrooxidation Reaction
Authors: Carrera-Cerritos R. , Salazar-Hernandez C. , Galindo-Esquivel I. R. , Fuentes-Ramirez R.
Published: March 2018

This work reports the effect of reduction temperature during the synthesis of PdAg catalysts through the polyol process and their evaluation in the ethanol electrooxidation reaction (EOR). The characterization was performed using Transmission Electron Microscopy (TEM) and X-Ray Diffraction (XRD). The electrochemical evaluation for the ethanol electrooxidation reaction was implemented in alkaline medium using chronoamperometry (CA) and cyclic voltammetry (CV). An important effect of the reduction temperature on electroactivity and catalytic stability was observed: both the maximum current density and the catalytic stability were higher in the catalyst synthesized at the highest temperature (135°C). This performance was associated with the extent of the interaction between Pd and Ag which was measured in terms of the structural expansion of Pd.
Tratamiento del asma en fase estable
Authors: Moreno Bolton Rodrigo
Published: March 2018

Sin resumen
Casos radiológicos
Authors: Garcia Bruce Cristian , Traipe Castro Elfrides , Huete Lira Isidro
Published: March 2018

Sin resumen
Crónica
Authors: Marinovic Chaparro Ivan
Published: March 2018

Sin resumen
Control continuo de calidad y costo efectividad de problemas médicos comunes
Authors: Gazitua H. Ricardo
Published: March 2018

Sin resumen
Contribución de lo genético: Relación entre el antígeno de la histocompatibilidad HLA-B27 y las espondiloartropatías
Authors: Jacobelli Gabrielli Sergio
Published: March 2018

Sin resumen
Diagnóstico de la obesidad y sus métodos de evaluación
Authors: Moreno Gonzalez Manuel I.
Published: March 2018

Sin resumen
Consecuencias patológicas de la obesidad: hipertensión arterial, diabetes mellitus y dislipidemia
Authors: Maiz Gurruchaga Alberto
Published: March 2018

Sin resumen
Actividad física y obesidad
Authors: Valdes Corbalan Raúl
Published: March 2018

Sin resumen
Contribuciones de la biopsia pleural al estudio de las enfermedades de la pleura
Authors: González Bombardiere Sergio
Published: March 2018

Sin resumen
Rol de la tomografía computada helicoidal en el diagnóstico de la embolia pulmonar
Authors: Cruz Olivos Francisco , Varela Ubilla Cristian
Published: March 2018

Sin resumen
Folate Receptor Alpha Peptide Vaccine Generates Immunity in Breast and Ovarian Cancer Patients
Authors: Kalli Kimberly R. , Block Matthew S. , Kasi Pashtoon M. , Erskine Courtney L. , Hobday Timothy J. , Dietz Allan , Padley Douglas , Gustafson Michael P. , Shreeder Barath , Puglisi-Knutson Danell , Visscher Dan W. , Mangskau Toni K. , Wilson Glynn , Knutson Keith L.
Published: March 2018

Purpose: Folate receptor alpha (FR) is overexpressed in several cancers. Endogenous immunity to the FR has been demonstrated in patients and suggests the feasibility of targeting FR with vaccine or other immune therapies. CD4 helper T cells are central to the development of coordinated immunity, and prior work shows their importance in protecting against relapse. Our previous identification of degenerate HLA-class II epitopes from human FR led to the development of a broad coverage epitope pool potentially useful in augmenting antigen-specific immune responses in most patients.

Patients and Methods: We conducted a phase I clinical trial testing safety and immunogenicity of this vaccine, enrolling patients with ovarian cancer or breast cancer who completed conventional treatment and who showed no evidence of disease. Patients were initially treated with low-dose cyclophosphamide and then vaccinated 6 times, monthly. Immunity and safety were examined during the vaccine period and up to 1 year later.

Results: Vaccination was well tolerated in all patients. Vaccine elicited or augmented immunity in more than 90% of patients examined. Unlike recall immunity to tetanus toxoid (TT), FR T-cell responses developed slowly over the course of vaccination with a median time to maximal immunity in 5 months. Despite slow development of immunity, responsiveness appeared to persist for at least 12 months.

Conclusions: The results demonstrate that it is safe to augment immunity to the FR tumor antigen, and the developed vaccine is testable for therapeutic activity in most patients whose tumors express FR, regardless of HLA genotype. Clin Cancer Res; 24(13); 3014–25. ©2018 AACR.
TFAP2E Methylation and Expression Status Does Not Predict Response to 5-FU-based Chemotherapy in Colorectal Cancer
Authors: Murcia Oscar , Jover Rodrigo , Egoavil Cecilia , Perez-Carbonell Lucia , Juárez Miriam , Hernández-Illán Eva , Rojas Estefania , Alenda Cristina , Balaguer Francesc , Andreu Montserrat , Llor Xavier , Castells Antoni , Boland C. Richard , Goel Ajay
Published: March 2018

Purpose: A recent study reported that 5-fluorouracil (5-FU)-based chemotherapy is less effective in treating patients with advanced colorectal cancer demonstrating hypermethylation of the TFAP2E gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts.

Experimental Design: Two cohorts of 783 patients with colorectal cancer: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of TFAP2E methylation and expression as a predictor of response of colorectal cancer patients to 5-FU–based chemotherapy. DNA methylation status of the TFAP2E gene in patients with colorectal cancer was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed.

Results: Correlation between TFAP2E methylation status and IHC staining was performed in 607 colorectal cancer samples. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by TFAP2E hypermethylation in stage IV patients [HR, 1.21; 95% confidence interval (CI), 0.79–1.87; log-rank P = 0.6]. In stage II–III cases, disease-free survival was not influenced by TFAP2E hypermethylation status in 5-FU–treated (HR, 0.91; 95% CI, 0.52–1.59; log-rank P = 0.9) as well as in nontreated patients (HR, 0.88; 95% CI, 0.5–1.54; log-rank P = 0.7).

Conclusions: TFAP2E hypermethylation does not correlate with loss of its protein expression. Our large, systematic, and comprehensive study indicates that TFAP2E methylation and expression may not play a major role in predicting response to 5-FU–based chemotherapy in patients with colorectal cancer. Clin Cancer Res; 24(12); 2820–7. ©2018 AACR.
ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment
Authors: Patel Hetal , Periyasamy Manikandan , Sava Georgina P. , Bondke Alexander , Slafer Brian W. , Kroll Sebastian H. B. , Barbazanges Marion , Starkey Richard , Ottaviani Silvia , Harrod Alison , Aboagye Eric O. , Buluwela Laki , Fuchter Matthew J. , Barrett Anthony G. M. , Coombes R. Charles , Ali Simak
Published: March 2018

Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including estrogen receptor (ER)-α. Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40 nmol/L; IC50 values for CDK1, CDK2, CDK5, and CDK9 were 45-, 15-, 230-, and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI50 values ranging between 0.2 and 0.3 μmol/L. In xenografts of both breast and colorectal cancers, the drug has substantial antitumor effects. In addition, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia and small-cell lung cancer. Mol Cancer Ther; 17(6); 1156–66. ©2018 AACR.
Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein
Authors: Oberst Michael D. , Augé Catherine , Morris Chad , Kentner Stacy , Mulgrew Kathy , McGlinchey Kelly , Hair James , Hanabuchi Shino , Du Qun , Damschroder Melissa , Feng Hui , Eck Steven , Buss Nicholas , de Haan Lolke , Pierce Andrew J. , Park Haesun , Sylwester Andrew , Axthelm Michael K. , Picker Louis , Morris Nicholas P. , Weinberg Andrew , Hammond Scott A.
Published: March 2018

Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies. Mol Cancer Ther; 17(5); 1024–38. ©2018 AACR.
PI3K Positively Regulates YAP and TAZ in Mammary Tumorigenesis Through Multiple Signaling Pathways
Authors: Zhao Yulei , Montminy Tess , Azad Taha , Lightbody Elizabeth , Hao Yawei , SenGupta Sandip , Asselin Eric , Nicol Christopher , Yang Xiaolong
Published: March 2018

Breast cancer is a leading cause of death in women worldwide. Active mutations of PI3K catalytic subunit PIK3CA (e.g., H1047R) and amplification of its homolog PIK3CB are observed in a large number of breast cancers. In recent years, aberrant activation of Transcriptional coactivator with PDZ binding motif (TAZ) and its paralog Yes-associated protein (YAP) have also been found to be important for breast cancer development and progression. However, whether PI3K interacts with YAP/TAZ during mammary tumorigenesis is unknown. Through a systematic gain-of-function screen for kinases involved in mammary tumorigenesis, we identified PIK3CB as a transformation-inducing kinase in breast cells. We further determined that PIK3CB positively regulates YAP and TAZ to promote transformation and inhibit mammary cell death in vitro. PIK3CB coexpression with TAZ, rather than PIK3CB or TAZ alone, in human MCF10A nontumorigenic mammary cells is sufficient for tumor formation in mice in vivo. Interestingly, we also determined that PIK3CA-H1047R enhances YAP and TAZ activity in mammary tumorigenesis in vitro. Mechanistically, the regulation of YAP/TAZ by both PIK3CA and PIK3CB occurs through multiple signaling pathways including LATS-dependent and LATS-independent pathways. Therefore, in this study, we determine that PI3K and YAP/TAZ interact to promote breast cancer cell transformation.

Implications: This study provides the first evidence that the Hippo pathway effectors TAZ and YAP are critical mediators of PI3K-induced mammary tumorigenesis and synergistically function together with PI3K in transformation of mammary cells. These findings may provide a novel rationale for targeting YAP/TAZ alone or in combination with PI3K inhibitors for breast cancer therapy in the future. Mol Cancer Res; 16(6); 1046–58. ©2018 AACR.
Tissue-Specific Immunoregulation: A Call for Better Understanding of the “Immunostat” in the Context of Cancer
Authors: Pao William , Ooi Chia-Huey , Birzele Fabian , Ruefli-Brasse Astrid , Cannarile Michael A. , Reis Bernhard , Scharf Sebastian H. , Schubert David A. , Hatje Klas , Pelletier Nadege , Spleiss Olivia , Reed John C.
Published: March 2018

Checkpoint inhibitor therapy has been a breakthrough in cancer research, but only some patients with cancer derive substantial benefit. Although mechanisms underlying sensitivity and resistance to checkpoint inhibitors are being elucidated, the importance of organ-specific regulation of immunity is currently underappreciated. Here, we call for a greater understanding of tissue-specific immunoregulation, namely, “tissue-specific immunostats,” to make advances in treatments for cancer. A better understanding of how individual organs at baseline regulate the immune system could enable an improved precision medicine approach to cancer immunotherapy. Cancer Discov; 8(4); 395–402. ©2018 AACR.
Characteristics of Extracellular Vesicles in Red Blood Concentrates Change with Storage Time and Blood Manufacturing Method
Authors: Almizraq Ruqayyah J. , Holovati Jelena L. , Acker Jason P.
Published: March 2018

Background: Extracellular vesicles (EVs) in blood products are potential effectors of inflammation and coagulation after transfusion. The aim of this study was to assess the impact of different blood manufacturing methods and duration of hypothermic storage on the EV subpopulations in relation to other in vitro quality parameters of red blood cell concentrate (RCC) products. Methods: RCCs were produced using whole blood filtration (WBF) or red cell filtration (RCF) (n = 12/method), refrigerated for 43 days, and evaluated for EV size profile and concentration, red cell deformability, ATP and 2,3-DPG, hemolysis, and hematological indices. Results: The total number of EVs increased significantly with storage in both methods, and WBF-RCCs contained the higher numbers of EVs compared to RCF-RCCs. The concentration of small EVs was greater in WBF-RCCs versus RCF-RCCs, with difference between the two methods observed on day 43 of storage (p = 0.001). Throughout storage, significant decreases were identified in ATP, 2,3-DPG, and EImax, while an increase in hemolysis was observed in both RCC products. Conclusion: The dynamic shift in the size and concentration of the EV subpopulations is dependent on the blood manufacturing method and length of storage. Better understanding of the potential clinical implications of these heterogeneous populations of EVs are needed.
Humanized Exposures of a β-Lactam-β-Lactamase Inhibitor, Tazobactam, versus Non-β-Lactam-β-Lactamase Inhibitor, Avibactam, with or without Colistin, against Acinetobacter baumannii in Murine Thigh and Lung Infection Models
Authors: Monogue Marguerite L. , Sakoulas George , Nizet Victor , Nicolau David P.
Published: March 2018

β-lactam-β-lactamase inhibitors (BLIs) have previously demonstrated antimicrobial activity against Acinetobacter baumannii (AB). Colistin retains the highest susceptibility rate against A. baumannii, and has demonstrated synergy with other antimicrobials, including β-lactam-BLIs. Therefore, we assessed the potential individual activity and synergistic combinations in vivo against carbapenem-susceptible (CS) and multidrug-resistant (MDR) A. baumannii isolates in neutropenic thigh and lung infection models. In vitro, colistin and tazobactam MICs were 1 and 16 µg/mL against AB 25–49 (CS) and 1 and 128 µg/mL against AB 5075 (MDR) respectively. In the lung model, tazobactam alone and in combination with colistin achieved a 1-log reduction in CFU, while colistin alone was not active against AB 25–49. No activity was observed against AB 5075. In the thigh model, tazobactam with and without colistin was bacteriostatic against AB 25–49 but did not demonstrate any activity against AB 5075. Avibactam and colistin alone and in combination were not active against either isolate. No synergy was observed; however, we found tazobactam activity against A. baumannii. This activity was not observed for the non-β-lactam-BLI, avibactam. This suggests that binding to penicillin-binding proteins of the β-lactam molecule is required for tazobactam activity against A. baumannii. These data point to an added role of β-lactam-BLIs beyond their primary purpose of β-lactamase inhibition in the treatment of MDR A. baumannii infections by enhancing the activity of peptide antibiotics, a property that is not shared by the novel non-β-lactam-BLIs. Future studies are needed to define tazobactam and colistin activity in an A. baumannii infection model.
A Phase I/Randomized Phase II Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Nintedanib versus Sorafenib in Asian Patients with Advanced Hepatocellular Carcinoma
Authors: Yen Chia-Jui , Kim Tae-You , Feng Yin-Hsun , Chao Yee , Lin Deng-Yn , Ryoo Baek-Yeol , Huang Dennis Chin-Lun , Schnell David , Hocke Julia , Loembé Arsène-Bienvenu , Cheng Ann-Lii
Published: March 2018

Background: Nintedanib is an oral, triple angiokinase inhibitor of vascular endothelial growth factor/platelet-derived growth factor/fibroblast growth factor receptors. This randomized, multicenter, open-label, phase I/II study evaluated the safety, pharmacokinetics, maximum tolerated dose (MTD) in terms of dose-limiting toxicities (DLTs), and efficacy of nintedanib versus sorafenib in Asian patients with unresectable advanced hepatocellular carcinoma (HCC). Patients and Methods: For the phase I portion, patients were stratified into two groups according to their alanine aminotransferase/aspartate aminotransferase (ALT/AST) and Child-Pugh score at baseline. For phase I, the primary endpoint was determination of the MTD in terms of DLTs. For phase II, patients with a Child-Pugh score of 5–6, an Eastern Cooperative Oncology Group performance score ≤2, and an ALT/AST ≤2× the upper limit of normal were enrolled and randomized 2: 1 to nintedanib 200 mg twice daily (b.i.d.) (the MTD determined in phase I) or sorafenib 400 mg b.i.d. continuously in 28-day cycles until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. The primary endpoint for phase II was time to progression (TTP) by central independent review (CIR; by Response Evaluation Criteria in Solid Tumors v1.0); the secondary endpoints included overall survival (OS). All analyses were exploratory. Results: The MTD was 200 mg in both groups. For phase II, 95 patients were randomized to nintedanib (n = 63) or sorafenib (n = 32). For nintedanib and sorafenib, respectively, the median CIR TTP was 2.8 vs. 3.7 months (hazard ratio [HR] = 1.21, 95% confidence interval [CI] 0.73–2.01) and the median OS 10.2 vs. 10.7 months (HR = 0.94, 95% CI 0.59–1.49). Nintedanib-treated patients had fewer grade 3 or higher AEs (56 vs. 84%), serious AEs (46 vs. 56%), and AEs leading to dose reduction (19 vs. 59%) and drug discontinuation (24 vs. 34%). AEs associated more frequently with nintedanib were vomiting and nausea, whereas those associated more frequently with sorafenib were ALT/AST increases, diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome. Conclusions: Nintedanib showed numerically similar efficacy to sorafenib for CIR TTP and OS in Asian patients with advanced HCC and adequate liver function. AEs were generally manageable.
First-in-Class Combination Therapy of a Copper(II) Metallo-Phosphorus Dendrimer with Cytotoxic Agents
Authors: Mignani Serge , El Brahmi Nabil , Cresteil Thierry , Majoral Jean-Pierre
Published: March 2018

The metallo-phosphorus dendrimer 1G3-Cu (generation 3 dendrimer bearing 48 conjugated copper(II) on its surface) has antiproliferative activity related to its capacity to activate Bax translocation. In the present study, we evaluate the activity of an association of 1G3-Cu with 5 cytotoxic agents used in chemotherapy having different modes of action. Data show no additive effect with camptothecin and cisplatin, additivity with paclitaxel and MG132, and synergy with doxorubicin. Results suggest that the multivalent Cu-conjugated dendrimer 1G3-Cu (activator of Bax translocation) plays an important role in boosting the clinical impact of Bax accumulation stimulated by the proteasome inhibitor MG132, antimitotic taxanes, and the topo II inhibitor doxorubicin.
Prelimbic Cortex Deep Brain Stimulation Reduces Binge Size in a Chronic Binge Eating Rat Model
Authors: Sarica Can , Ozkan Mazhar , Hacioglu Bay Husniye , Sehirli Umit , Onat Filiz , Ziyal M. Ibrahim
Published: March 2018

Background: Binge eating (BE) involves the consumption of a large amount of food in a short period of time and a loss of control during the binge episode. It is a key feature of the major subtypes of eating disorders like bulimia nervosa, BE disorder, anorexia nervosa binge/purge type. Alterations in the mesocorticolimbic pathway play a crucial role in its pathophysiology. Objectives: We hypothesized that BE rats receiving deep brain stimulation (DBS) in the prelimbic cortex, a functional analog of the dorsolateral prefrontal cortex in humans, would have a reduced binge size compared with those receiving sham stimulation. Methods: Eight male Sprague-Dawley rats were implanted with a DBS electrode in the left prelimbic cortex. A protocol which included limited access to a “sweet-fat” diet was used to achieve a chronic BE state in the rats. After reaching a stable binge size, each rat had undergone sham, low-frequency stimulation (60 Hz), and high-frequency (130 Hz) stimulation for 3 sessions each, and 2 consecutive treatments were separated by at least 2 empty sessions to allow a washout of the effects. A one-way ANOVA was used for the data analysis. Results: Low-frequency (60 Hz) stimulation of the prelimbic cortex significantly reduced the binge size compared to the sham stimulation (p < 0.0001). High-frequency DBS (130 Hz) had no significant influence on this behavior when compared to sham stimulation (p = 0.9). Conclusions: This study suggests that low-frequency prelimbic cortex stimulation in BE would be useful for correcting prefrontal hypofunction which is strongly associated with BE and addiction pathogenesis.
Rivastigmine Improves Appetite by Increasing the Plasma Acyl/Des-Acyl Ghrelin Ratio and Cortisol in Alzheimer Disease
Authors: Furiya Yoshiko , Tomiyama Takami , Izumi Tesseki , Ohba Naoki , Ueno Satoshi
Published: March 2018

Background: Weight loss accelerates cognitive decline and increases mortality in patients with dementia. While acetylcholinesterase (AChE) inhibitors are known to cause appetite loss, we sometimes encounter patients in whom switching from donepezil (AChE inhibitor) to rivastigmine (AChE and butyrylcholinesterase [BuChE] inhibitor) improves appetite. Since BuChE inactivates ghrelin, a potent orexigenic hormone, we speculated that rivastigmine improves appetite by inhibiting BuChE-mediated ghrelin inactivation. Methods: The subjects were patients with mild to moderate Alzheimer disease treated with either rivastigmine patch (n = 11) or donepezil (n = 11) for 6 months. Before and after treatment, we evaluated appetite (0, decreased; 1, slightly decreased; 2, normal; 3, slightly increased; 4, increased), cognitive function, and blood biochemical variables, including various hormones. Results: Rivastigmine treatment significantly improved appetite (from 1.6 ± 0.5 to 2.6 ± 0.7), whereas donepezil treatment did not (from 2.0 ± 0.0 to 1.8 ± 0.4). Simultaneously, rivastigmine, but not donepezil, significantly decreased the serum cholinesterase activity (from 304.3 ± 60.5 to 246.8 ± 78.5 IU/L) and increased the cortisol level (from 11.86 ± 3.12 to 14.61 ± 3.29 μg/dL) and the acyl/des-acyl ghrelin ratio (from 4.03 ± 2.96 to 5.28 ± 2.72). The levels of leptin, insulin, total ghrel­in, and cognitive function were not significantly affected by either treatment. Conclusions: Our results suggest that compared with donepezil, rivastigmine has the advantage of improving appetite by increasing the acyl/des-acyl ghrelin ratio and cortisol level, thereby preventing weight loss.
The Effect of Improved Dysphagia Care on Outcome in Patients with Acute Stroke: Trends from 8-Year Data of a Large Stroke Register
Authors: Suntrup-Krueger Sonja , Minnerup Jens , Muhle Paul , Claus Inga , Schröder Jens Burchard , Marian Thomas , Warnecke Tobias , Kalic Marianne , Berger Klaus , Dziewas Rainer
Published: March 2018

Background: Early dysphagia screening and appropriate management are recommended by current guidelines to reduce complications and case fatality in acute stroke. However, data on the potential benefit of changes in dysphagia care on patient outcome are limited. Our objective was to assess the degree of implementation of dysphagia guidelines and determine the impact of modifications in dysphagia screening and treatment practices on disease complications and outcome in stroke patients over time. Methods: In this prospective register-based study (“Stroke Register of Northwestern Germany”), all adult stroke patients admitted to 157 participating hospitals between January, 2008 and December, 2015 were included (n = 674,423). Dysphagia incidence upon admission, the proportion of patients receiving a standardized swallowing screening, and the percentage of dysphagic patients being referred to a speech language therapist (SLT) for treatment were obtained per year. Pneumonia rate, modified Rankin Scale (mRS) at discharge, and in-hospital mortality were compared between groups of dysphagic vs. non-dysphagic patients over time. Results: Screening proportions continuously increased from 47.2% in 2008 to 86.6% in 2015. But the proportion diagnosed with dysphagia remained stable with about 19%. The number of dysphagic patients receiving SLT treatment grew from 81.6 up to 87.0%. Pneumonia incidence was higher in dysphagic stroke cases (adjusted OR 5.4 [5.2–5.5], p < 0.001), accompanied by a worse mRS at discharge (adjusted OR for mRS ≥3: 3.1 [3.0–3.1], p < 0.001) and higher mortality (adjusted OR 3.1 [3.0–3.2], p < 0.001). The order of magnitude of these end points did not change over time. Conclusion: Although advances have been made in dysphagia care, prevalent screening and treatment practices remain insufficient to reduce pneumonia rate, improve functional outcome, and decrease case fatality in dysphagic stroke patients. More research is urgently needed to develop more effective swallowing therapies.
ОСОБЛИВОСТІ ПОЄДНАНОГО ПЕРЕБІГУ ХРОНІЧНОГО ОБСТРУКТИВНОГО ЗАХВОРЮВАННЯ ЛЕГЕНЬ ТА ГІПЕРТОНІЧНОЇ ХВОРОБИ
Authors: Maksiv K. Ya. , Pirus I. V. , Osinchuk R. R. , Habor H. H. , Krynytska I. Ya. , Marushchak M. I.
Published: March 2018

Мета: проаналізувано особливості поєднаного перебігу хронічного обструктивного захворювання легень (ГХ) ІІ стадії та гіпертонічної хвороби ІІ стадії в гендерному аспекті.Матеріали і методи. Ретроспективно проаналізовано 420 історій хвороб пацієнтів, які перебували на стаціонарному лікуванні у  пульмонологічному відділенні Тернопільської університетської лікарні з діагнозом «хронічне обструктивне захворювання легень» (ХОЗЛ) протягом 2014 і 2016 рр.Результати. Серед пацієнтів з ХОЗЛ переважали особи чоловічої статі (65,95 %). Розподіл за статтю пацієнтів з ХОЗЛ II стадії виглядає наступним чином: чоловіки – 59,86 %, жінки – 40,14 %.Висновки. Серед пацієнтів з ХОЗЛ II стадії 28, 67 % хворих не мали супутньої патології, 27,27 % - перебіг основного захворювання поєднувався з гіпертонічною хворобою II стадії, 43,36 % - ХОЗЛ поєднувався з іншими захворюваннями. Аналіз отриманих даних за гендерною ознакою вказує на переважання у пацієнтів чоловічої статі коморбідності ХОЗЛ з іншими патологіями, причому найчастіше (у 33 % хворих) з гіпертонічною хворобою. В осіб жіночої статі, хворих на ХОЗЛ, окрім гіпертонічної хвороби, з високою частотою зустрічалась ішемічна хвороба серця й захворювання ендокринної системи.
СТАН НОРМАТИВНО-ПРАВОВОГО РЕГУЛЮВАННЯ УПРАВЛІННЯ ПРОФІЛАКТИКОЮ НЕІНФЕКЦІЙНИХ ЗАХВОРЮВАНЬ
Authors: Gandziuk V. A.
Published: March 2018

Мета: визначити напрямки удосконалення нормативно-правового забезпечення заходів профілактики неінфекційних захворювань у дорослого населення в умовах багатопрофільного закладу охорони здоров’я на основі узагальнення та аналізу діючих в системі охорони здоров’я України правових актів.Матеріали і методи. Розглянуто офіційні нормативні документи щодо управління профілактикою неінфекційних захворювань. При проведенні їх аналізу використано контент-аналіз, системний підхід і аналіз, бібліографічний та історичний методи.Результати. Покращення профілактичних заходів серед населення, виходячи із загальної дефініції «диспансеризація», передбачає розробку та впровадження періодичних профілактичних оглядів серед дорослого населення за принципом їх проведення у цільових групах, методологічним базисом для яких мають стати скринінгові програми з раннього виявлення найпоширеніших неінфекційних захворювань.Висновки. При проведенні контент-аналізу нормативно-правової бази щодо управління профілактикою в Україні, встановлено, що серед чинних наказів МОЗ України відсутні чіткі критерії, що відображають ступінь дотримання організаційних принципів надання профілактичної допомоги, як наслідок цього оцінка якості профілактичної допомоги та її ефективності не проводиться, а сучасні управлінські технології не використовуються.